Research on consumer decision making and aging is especially important for fostering a better understanding of ways to maintain consumer satisfaction and high decision quality across the life span. We provide a review of extant research on the effects of normal aging on cognition and decision processes and how these age-related processes are influenced by task environment, meaningfulness of the task, and consumer expertise. We consider how research centered on these topics generates insights about changes in consumption decisions that occur with aging and identify a number of gaps and directions for future research.
aging; decision making; consumers
Evidence has accumulated over the past several years demonstrating that lung injury following inhalation of irritants like ozone is due, not only to direct effects of the chemical, but also indirectly to the actions of inflammatory mediators released by infiltrating macrophages. Among the mediators involved in the cytotoxic process, reactive nitrogen species (RNS) are of particular interest because of their well-documented cytotoxic potential. Findings that macrophage suppression blocks RNS production and ozone-induced toxicity provide strong support for a role of these cells and inflammatory mediators in lung injury. Recent investigations have focused on understanding pathways by which macrophages become activated to release RNS. One protein that has attracted considerable attention is caveolin-1, a membrane scaffolding molecule that functions to negatively regulate cell signaling. The fact that expression of caveolin-1 is down-regulated in macrophages after ozone inhalation suggests a mechanism controlling the release of cytotoxic mediators by these inflammatory cells.
macrophages; ozone; nitric oxide; caveolin; TNFα
Spinal motoneurons (MNs) amplify synaptic inputs by producing strong dendritic persistent inward currents (PICs), which allow the MN to generate the firing rates and forces necessary for normal behaviors. However, PICs prolong MN depolarization after the initial excitation is removed, tend to “wind-up” with repeated activation and are regulated by a diffuse neuromodulatory system that affects all motor pools. We have shown that PICs are very sensitive to reciprocal inhibition from Ia afferents of antagonist muscles and as a result PIC amplification is related to limb configuration. Because reciprocal inhibition is tightly focused, shared only between strict anatomical antagonists, this system opposes the diffuse effects of the descending neuromodulation that facilitates PICs. Because inhibition appears necessary for PIC control, we hypothesize that Ia inhibition interacts with Ia excitation in a “push–pull” fashion, in which a baseline of simultaneous excitation and inhibition allows depolarization to occur via both excitation and disinhibition (and vice versa for hyperpolarization). Push–pull control appears to mitigate the undesirable affects associated with the PIC while still taking full advantage of PIC amplification.
PIC; neuromodulation; push–pull; motoneuron
The following on esophageal disease in pediatrics contains commentaries on acquisition of neuromuscular maturation; physiology of esophageal peristaltic and sphincteric reflexes; implications for clinical practice; and conditions that predispose to severe gastroesophageal reflux disease (GERD) in children with potential risk for esophageal cancer.
embryology; peristalsis; sphincteric reflexes; fetal swallowing; airway protection; Barrett's esophagus; GERD
In a medical sense biomodulation could be considered a biochemical or cellular response to a disease or therapeutic stimulus. In cancer pathophysiology, the initial oncogenic stimulus leads to cellular and biochemical changes that allow cells, tissue, and organism to accommodate and accept the oncogenic insult. In epithelial cell cancer development, the process of carcinogenesis is frequently characterized by sequential cellular and biochemical adaptations as cells transition through hyperplasia, dysplasia, atypical dysplasia, carcinoma in situ, and invasive cancer. In some cases, the adaptations may persist after the initial oncogenic stimulus is gone in a type of “hit-and-run” oncogenesis. These pathophysiological changes may interfere with cancer prevention therapies targeted solely to the initial oncogenic insult, perhaps contributing to resistance development. Characterization of these accommodating adaptations could provide insight for development of cancer preventive regimens that might more effectively biomodulate preneoplastic cells towards a more normal state.
cancer prevention; biomodulation; hit and run oncogenesis; viral oncogenesis; hormonal oncogenesis
Neurorestorative therapy targets multiple types of parenchymal cells in the intact tissue of the injured brain tissue to increase neurogenesis, angiogenesis, oligodendrogenesis, and axonal remodeling during recovery from neurological injury. In our laboratory, we tested thymosin β4 (Tβ4) as a neurorestorative agent to treat models of neurological injury. This review discusses our results demonstrating that Tβ4 improves neurological functional outcome in a rat model of embolic stroke, a mouse model of multiple sclerosis, and a rat model of traumatic brain injury. Tβ4 is a pleiotropic peptide exhibiting many actions in several different types of tissues. One mechanism associated with improvement of neurological improvement from Tβ4 treatment is oligodendrogenesis involving the differentiation of oligodendrocyte progenitor cells to mature myelin-secreting oligodendrocytes. Moreover, our preclinical data provide a basis for movement of Tβ4 into clinical trials for treatment of these devastating neurological diseases and injuries.
thymosin β4; stroke; multiple sclerosis; traumatic brain injury; rat
Obesity, a growing health problem worldwide, has been associated with the metabolic syndrome, diabetes, cardiovascular disease, hypertension, and other chronic diseases. Recently, the obesity–cancer link has received much attention. Epidemiological studies have shown that obesity is also associated with increased risk of several cancer types, including colon, breast, endometrium, liver, kidney, esophagus, gastric, pancreatic, gallbladder, and leukemia, and can also lead to poorer treatment and increased cancer-related mortality. Biological mechanisms underlying the relationship between obesity and cancer are not well understood. They include modulation of energy balance and calorie restriction, growth factors, multiple signaling pathways and inflammatory processes. Key among the signaling pathways linking obesity and cancer is the PI3K/Akt/mTOR cascade, which is a target of many of the obesity-associated factors and regulates cell proliferation and survival. Understanding the molecular and cellular mechanisms of the obesity–cancer connection is important in developing potential therapeutics. The link between obesity with cancer underscores the recommendation to maintain a healthy body weight throughout life as one of the most important ways to protect against cancer.
obesity; cancer; mechanisms; recommendations; prevention
Traumatic brain injury (TBI) remains a leading cause of mortality and morbidity worldwide. No effective pharmacological treatments are available for TBI because all Phase II/III TBI clinical trials have failed. This highlights a compelling need to develop effective treatments for TBI. Endogenous neurorestoration occurs in the brain after TBI, including angiogenesis, neurogenesis, synaptogenesis, oligodendrogenesis and axonal remodeling, which may be associated with spontaneous functional recovery after TBI. However, the endogenous neurorestoration following TBI is limited. Treatments amplifying these neurorestorative processes may promote functional recovery after TBI. Thymosin beta4 (Tβ4) is the major G-actin-sequestering molecule in eukaryotic cells. In addition, Tβ4 has other properties including anti-apoptosis and anti-inflammation, promotion of angiogenesis, wound healing, stem/progenitor cell differentiation, and cell migration and survival, which provide the scientific foundation for the corneal, dermal, and cardiac wound repair multicenter clinical trials. Here, we describe Tβ4 as a neuroprotective and neurorestorative candidate for treatment of TBI.
thymosin beta4; traumatic brain injury; rat; neuroprotection; neurorestoration
Sponsored by the New York Academy of Sciences and with support from the National Institute of Mental Health, the Life Technologies Foundation, and the Josiah Macy Jr. Foundation, “Advancing Drug Discovery for Schizophrenia” was held March 9–11 at the New York Academy of Sciences in New York City. The meeting, comprising individual talks and panel discussions, highlighted basic, clinical, and translational research approaches, all of which contribute to the overarching goal of enhancing the pharmaceutical armamentarium for treating schizophrenia. This report surveys work by the vanguard of schizophrenia research in such topics as genetic and epigenetic approaches; small molecule therapeutics; and the relationships between target genes, neuronal function, and symptoms of schizophrenia.
schizophrenia; genetics; GWAS; neuronal function; small molecules; therapeutics
Sponsored by the New York Academy of Sciences, the Warren Alpert Medical School of Brown University and the University of Massachusetts Boston, “Behavioral Epigenetics” was held on October 29–30, 2010 at the University of Massachusetts Boston Campus Center, Boston, Massachusetts. This meeting featured speakers and panel discussions exploring the emerging field of behavioral epigenetics, from basic biochemical and cellular mechanisms to the epigenetic modulation of normative development, developmental disorders, and psychopathology. This report provides an overview of the research presented by leading scientists and lively discussion about the future of investigation at the behavioral epigenetic level.
behavior; epigenetics; chromosome; gene regulation; transcription; methylation
In this paper, we review the current literature to highlight relations between age-associated declines in dopaminergic and serotonergic neuromodulation and adult age differences in adaptive goal-directed behavior. Specifically, we focus on evidence suggesting that deficits in neuromodulation contribute to older adults’ behavioral disadvantages in learning and decision making. These deficits are particularly pronounced when reward information is uncertain or the task context requires flexible adaptations to changing stimulus–reward contingencies. Moreover, emerging evidence points to age-related differences in the sensitivity to rewarding and aversive outcomes during learning and decision making if the acquisition of behavior critically depends on outcome processing. These age-related asymmetries in outcome valuation may be explained by age differences in the interplay of dopaminergic and serotonergic neuromodulation. This hypothesis is based on recent neurocomputational and psychopharmacological approaches, which suggest that dopamine and serotonin serve opponent roles in regulating the balance between approach behavior and inhibitory control. Studying adaptive regulation of behavior across the adult life span may shed new light on how the aging brain changes functionally in response to its diminishing resources.
aging; neuromodulation; motivation; cognitive control
Social neuroscience offers a window onto the mental origins of empathy. People must appreciate another mind, in order to empathize. People first categorize the other as human, assuming a mind, and then differentiate among social categories according to universal dimensions of perceived traits: warmth and competence. The least warm and competent groups (poor people, homeless, drug addicts) may even be denied humanity and a meaningful mind, according to both neural and behavioral responses to allegedly disgusting outcasts. Other groups may be instead envied and viewed as tools or automatons, that is, objectified. The patterns can reverse when perceivers must consider the other’s preferences, that is, appreciate the other’s mind.
social cognition; social neuroscience; empathy; dehumanization; objectification; mPFC; amygdala; prejudice; mind
Mammalian reproduction requires that nursing mothers transfer large amounts of calcium to their offspring through milk. As a result, lactation is associated with dramatic alterations in bone and mineral metabolism, including reversible bone loss. One theme that has emerged from recent studies examining these adaptations is that the lactating breast actively participates in regulating bone and mineral metabolism. This review will detail our current knowledge of interactions between the breast, skeleton and hypothalamus during lactation and will consider implications that this reproductive physiology has for the pathophysiology of osteoporosis and breast cancer.
Osteoporosis; Bone Metastases; Lactation; Estrogen Deficiency; Calcium-Sensing Receptor; Parathyroid Hormone-Related Protein
Heart failure (HF) is a major cause of mortality and morbidity, representing a leading cause of death and hospitalization among U.S. Medicare beneficiaries. Advances in science have generated effective interventions to reduce adverse outcomes in HF, particularly in patients with reduced left ventricular ejection fraction. Unfortunately, effective therapies for heart failure are often not utilized in an effective, safe, timely, equitable, patient-centered, and efficient manner. Further, the risk of adverse outcomes for HF remains high. The last decades have witnessed the growth of efforts to measure and improve the care and outcomes of patients with HF. This paper will review the evolution of quality measurement for HF, including a brief history of quality measurement in medicine; the measures that have been employed to characterize quality in heart failure; how the measures are obtained; how measures are employed; and present and future challenges surrounding quality measurement in heart failure.
quality measurement; heart failure; outcomes
Epilepsy, bipolar disorder, and migraines are common disorders that are often associated with disturbances in menstrual function in adolescent girls. Women with untreated epilepsy are more likely to have irregular menstrual cycles than are nonepileptic controls, indicating that the disease itself plays a role in the etiology of these reproductive abnormalities. In addition, many girls with these disorders require chronic maintenance treatment with agents that may perturb the hypothalamic-pituitary-ovarian axis. Valproate is a highly effective antiepileptic drug used widely to treat epilepsy, bipolar disorder, and migraines. Valproate induces features of the polycystic ovary syndrome (PCOS) in approximately 7% of women. Girls with epilepsy, and possibly bipolar disorder, appear particularly susceptible to developing PCOS features on valproate, perhaps on account of the relative immaturity of their hypothalamic-pituitary-ovarian axes. Antipsychotics are highly effective drugs used widely to treat adolescents with bipolar disorder, psychotic disorders, and behavioral disturbances. Some, but not all of the antipsychotic, induce hyperprolactinemia, which may result in oligo- or amenorrhea. Prolonged amenorrhea in association with hyperprolactinemia incurs significant risks for bone health in adolescent girls. Because of the potential reproductive health risks associated with use of specific antiepileptic drugs and selective antipsychotics, these agents are vital treatments for adolescents with severe illnesses. Use of these agents should be considered and weighed against the risk of using alternative agents, which have their own side effects, or not treating these serious neurologic and psychiatric disorders.
bipolar disorder; epilepsy; hypothalamic-pituitary-gonadal (HPG) axis; menstrual cycle dysfunction; migraines; polycystic ovarian syndrome (PCOS); valproate
Mutations in genes encoding the Calcium-Release Activated Calcium (CRAC)
channel abolish calcium influx in cells of the immune system and cause severe
congenital immunodeficiency. Patients with autosomal recessive mutations in the
CRAC channel gene ORAI1, its activator Stromal
Interaction Molecule 1 (STIM1) and mice with
targeted deletion of Orai1, Stim1 and Stim2
genes reveal important roles for CRAC channels in adaptive and innate immune
responses to infection and in autoimmunity. Since CRAC channels have important
functions outside the immune system, ORAI1 and STIM1 deficiency are associated
with a unique clinical phenotype. This review will give an overview of CRAC
channel function in the immune system, examine the consequences of CRAC channel
deficiency for immunity in human patients and mice and discuss genetic defects
in immunoreceptor-associated signaling molecules that compromise calcium influx
and cause immunodeficiency.
Immunodeficiency; T cells; CRAC channels; ORAI1; STIM1
Addiction to opiates and illicit use of psychostimulants is a chronic, relapsing brain disease that, if left untreated, can cause major medical, social and economic problems. This article reviews recent progress in studies of association of gene variants with vulnerability to develop opiate and cocaine addictions, focusing primarily on genes of the opioid and monoaminergic systems. In addition, we provide the first evidence of a cis-acting polymorphism and a functional haplotype in the PDYN gene, of significantly higher DNA methylation rate of the OPRM1 gene in the lymphocytes of heroin addicts, and significant differences in genotype frequencies of three single nucleotide polymorphisms of the P-glycoprotein gene (ABCB1) between “higher” and “lower” methadone doses in methadone-maintained patients. In genome-wide and multi-gene association studies, we have found association of a number of new genes and new variants of known genes with heroin addiction. Finally, we have described the development and application of a novel technique: molecular haplotyping for studies in genetics of drug addiction.
opiate and cocaine addiction; genetics of drug addiction; epigenetics; pharmacogenetics; allele-specific gene expression; molecular haplotyping
Climate change is expected to lead to latitudinal and altitudinal temperature increases. High elevation regions such as the highlands of Africa, and those that have temperate climate are most likely to be affected. The highlands of Africa generally exhibit low ambient temperatures. This restricts the distribution of Anopheles mosquitoes, the vectors of malaria, filariasis and O’nyong’nyong fever. The development and survival of larval and adult mosquitoes are temperature dependent, as are mosquito biting frequency and pathogen development rate. Given that various Anopheles species are adapted to different climatic conditions, changes in the climate could lead to changes in species composition in an area which may change the dynamics of mosquito-borne disease transmission. It is important to consider the effect of climate change on rainfall which is critical to the formation and persistence of mosquito breeding sites. In addition, environmental changes such as deforestation could increase local temperatures in the highlands; this could enhance the vectorial capacity of the Anopheles. This experimental data will be invaluable in facilitating the understanding of the impact of climate change on Anopheles.
The critical epidemiological data for estimating the prevalence of chemosensory disorders in the US are lacking. Several reasons for this will be discussed, including the time-consuming nature of many existing tests, stimulus delivery in a large-scale study, and the rationale for inclusion in a large-scale epidemiological study. The opportunity to include measures of chemosensory function in ongoing population-based studies has greatly facilitated the collection of recent data that establishes the high prevalence of olfactory impairment in older adults in the US population and the inability of self-report measures to capture this impairment. Epidemiological studies of the complete range of the population that involve chemosensory testing pose considerable challenges, but are critical to establishing prevalence rates. These studies have the potential to suggest prevention or intervention strategies for chemosensory impairment. Key issues, including cross-cultural issues in stimulus design, testing of special populations, cohort effects and optimal analyses of population-based chemosensory data, are considered.
olfaction; olfactory impairment; smell; odor; prevalence; epidemiology; population studies
With life expectancy dramatically increasing throughout much of the world, people have to make choices with a longer future in mind than they ever had to before. Yet, many indicators suggest that undersaving for the long term often occurs: in America, for instance, many individuals will not be able to maintain their preretirement standard of living in retirement. Previous research has tried to understand problems with intertemporal choice by focusing on the ways in which people treat present and future rewards. In this paper, the author reviews a burgeoning body of theoretical and empirical work that takes a different viewpoint, one that focuses on how perceptions of the self over time can dramatically affect decision making. Specifically, when the future self shares similarities with the present self, when it is viewed in vivid and realistic terms, and when it is seen in a positive light, people are more willing to make choices today that may benefit them at some point in the years to come.
future self-continuity; behavioral economics; intertemporal choice; temporal discounting; retirement saving
The integrity of the tight junction barrier in epithelial and endothelial cells is critical to human health, but we still lack a detailed mechanistic knowledge of how the barrier is formed during development or responds to pathological and pharmacological insults. This limits our understanding of barrier dysfunction in disease and slows the development of therapeutic strategies. Recent studies confirm the long-maintained but previously unsupported view that the zonula occludens (ZO) proteins ZO-1 and ZO-2 are critical determinants of barrier formation. However, ZO proteins can also be components of adherens junctions, and recent studies suggest that ZO proteins may also promote the assembly and function of these junctions during epithelial morphogenesis. We review these studies and outline several recent observations that suggest that one role of ZO proteins is to regulate cytoskeletal dynamics at cell junctions. Finally, we propose a model by which the functional activities of ZO proteins in the adherens junction and tight junction are differentiated by a novel regulatory motif known as the U6 or acidic motif.
tight junction; adherens junction; zonula occludens; ZO-1; ZO-2; E-cadherin; cytoskeleton; MAGUK; PDZ; scaffold; permeability; epithelia; morphogenesis
Modern neurostimulation approaches in humans provide controlled inputs into the operations of cortical regions, with highly specific behavioural consequences. This enables causal structure-function inferences, and in combination with neuroimaging has provided novel insights into the basic mechanisms of action of neurostimulation on distributed networks. For example more recent work has established the capacity of transcranial magnetic stimulation (TMS) to probe causal interregional influences, and their interaction with cognitive state changes. Combinations of neurostimulation and neuroimaging now face the challenge of integrating the known physiological effects of neurostimulation with theoretical and biological models of cognition, for example, when theoretical stalemates between opposing cognitive theories need to be resolved. This will be driven by novel developments including biologically informed computational network analyses for predicting the impact of neurostimulation on brain networks, as well as novel neuroimaging and neurostimulation techniques. We anticipate that such future developments will offer an expanded set of tools with which to interrogate structure-function relationships, and to formulate and reconceptualise testable hypotheses about complex neural network interactions and their causal role for cognition.
state-dependence; effective connectivity; transcranial direct current stimulation; transcranial magnetic stimulation; causal inference; EEG; fMRI; MRS; computational neurostimulation
As the second synapse in the central gustatory pathway of the rodent, the parabrachial nucleus of the pons (PbN) receives information about taste stimuli directly from the nucleus of the solitary tract (NTS). Data show that NTS cells amplify taste responses before transmitting taste-related signals to the PbN. NTS cells of varied response profiles send converging input to PbN cells, though input from NTS cells with similar profiles is more effective at driving PbN responses. PbN cells follow NTS input for the first 3 s of taste stimulation for NaCl, HCl, and quinine, but are driven in cyclic bursts throughout the response interval for sucrose. Analyses of the temporal characteristics of NTS and PbN responses show that both structures use temporal coding with equal effectiveness to identify taste quality. Thus, the NTS input to the PbN is comprehensive, in that PbN cells receive NTS input that could support broad sensitivity, systematic, in that the time course of PbN firing patterns depend reliably on the tastant, and efficient, in that information from the NTS is preserved as it is communicated across structures. Comparisons of NTS and PbN taste responses in rats form the basis for our speculation that in primates, where the central gustatory pathway does not synapse in the PbN, the function of the PbN in taste processing may have been incorporated into that of the NTS.
taste; parabrachial pons; temporal coding
Hemorrhagic transformation (HT) associated with recombinant tissue plasminogen activator (rt-PA) complicates and limits its use in stroke. Here, we provide a focused review on the involvement of matrix metalloproteinase 9 (MMP-9) in rt-PA–associated HT in cerebral ischemia, and we review emerging evidence that the selective inhibitor of the sulfonylurea receptor 1 (Sur1), glibenclamide (U.S. adopted name, glyburide), may provide protection against rt-PA–associated HT in cerebral ischemia. Glyburide inhibits activation of MMP-9, ameliorates edema formation, swelling, and symptomatic hemorrhagic transformation, and improves preclinical outcomes in several clinically relevant models of stroke, both without and with rt-PA treatment. A retrospective clinical study comparing outcomes in diabetic patients with stroke treated with rt-PA showed that those who were previously on and were maintained on a sulfonylurea fared significantly better than those whose diabetes was managed without sulfonylureas. Inhibition of Sur1 with injectable glyburide holds promise for ameliorating rt-PA–associated HT in stroke.
rt-PA; Sur1; glyburide; MMP-9; cerebral ischemia; stroke
Certain chromosomal regions called common fragile sites are prone to difficulty during replication. Many tumors have been shown to contain alterations at fragile sites. Several models have been proposed to explain why these sites are unstable. Here we describe work to investigate models of fragile site instability using a yeast artificial chromosome carrying human DNA from a common fragile site region. In addition, we describe a yeast system to investigate whether repair of breaks at a naturally-occurring fragile site in yeast, FS2, involves mitotic recombination between homologous chromosomes, leading to loss of heterozygosity (LOH). Our initial evidence is that repair of yeast fragile site breaks does lead to LOH, suggesting that human fragile site breaks may similarly contribute to LOH in cancer. This work is focused on gaining understanding that may enable us to predict and prevent the situations and environments that promote genetic changes that contribute to tumor progression.
fragile site; FRA3B; flexibility peak; mitotic crossover; loss of heterozygosity; cancer