The strict human pathogen Neisseria gonorrhoeae has caused gonorrhea for thousands of years, and currently gonorrhea is the second most prevalent bacterial sexually transmitted infection worldwide. Given the ancient nature of N. gonorrhoeae and its unique obligate relationship with humankind over the millennia, its remarkable ability to adapt to the host immune system and cause repeated infections, and its propensity to develop resistance to all clinically useful antibiotics, the gonococcus is an ideal pathogen on which to study the evolution of bacterial pathogenesis, including antimicrobial resistance, over the long term and within the host during infection. Recently, the first gonococcus displaying high-level resistance to ceftriaxone, identified in Japan, was characterized in detail. Ceftriaxone is the last remaining option for empirical first-line treatment, and N. gonorrhoeae now seems to be evolving into a true “superbug.” In the near future, gonorrhea may become untreatable in certain circumstances. Herein, the history of antibiotics used for treatment of gonorrhea, the evolution of resistance emergence in N. gonorrhoeae, the linkage between resistance and biological fitness of N. gonorrhoeae, lessons learned, and future perspectives are reviewed and discussed.
Neisseria gonorrhoeae; gonorrhea; antimicrobial resistance; genetics; evolution
The receptor for advanced glycation endproducts (RAGE) was first described as a signal transduction receptor for advanced glycation endproducts (AGEs), the products of nonenzymatic glycation and oxidation of proteins and lipids that accumulate in diabetes and in inflammatory foci. The discovery that RAGE was a receptor for inflammatory S100/calgranulins and high mobility group box 1 (HMGB1) set the stage for linking RAGE to both the consequences and causes of types 1 and 2 diabetes. Recent discoveries regarding the structure of RAGE as well as novel intracellular binding partner interactions advance our understanding of the mechanisms by which RAGE evokes pathological consequences and underscore strategies by which antagonism of RAGE in the clinic may be realized. Finally, recent data tracking RAGE in the clinic suggest that levels of soluble RAGEs and polymorphisms in the gene encoding RAGE may hold promise for the identification of patients who are vulnerable to the complications of diabetes and/or are receptive to therapeutic interventions designed to prevent and reverse the damage inflicted by chronic hyperglycemia, irrespective of its etiology.
diabetes; complications; RAGE; inflammation; signal transduction
Bisphosphonates are used in the treatment of hypercalcemia of malignancy, skeletal complications associated with metastastic bone disease, Paget’s disease, and osteoporosis. Osteonecrosis of the jaw (ONJ) is a recently described clinical condition that has been associated with the use of nitrogen-containing bisphosphonates. Reports describing this entity first appeared in the literature in 2003. While there have been significant numbers of case reports and a limited number of retrospective and prospective studies examining risk factors associated with ONJ, the pathophysiology of this condition remains elusive. In this review, we explore proposed mechanisms underlying ONJ development and identify potential areas for future investigation.
bisphosphonates; pathophysiology; osteonecrosis; ONJ
Early detection of primary immunodeficiency is recognized as important for avoiding infectious complications that compromise outcomes. In particular, severe combined immunodeficiency (SCID) is fatal in infancy unless affected infants can be diagnosed before the onset of devastating infections and provided with an immune system through allogenic hematopoietic cell transplantation, enzyme replacement, or gene therapy. A biomarker of normal T cell development, T cell receptor excision circles (TRECs), can be measured in DNA isolated from the dried blood spots routinely obtained for newborn screening; infants identified as lacking TRECs can thus receive confirmatory testing and prompt intervention. Early results of TREC testing of newborns in five states indicate that this addition to the newborn screening panel can be successfully integrated into state public health programs. A variety of cases with typical SCID genotypes and other T lymphocytopenic conditions have been detected in a timely manner and referred for appropriate early treatment.
primary immunodeficiency; T cell receptor excision circle (TREC); severe combined immunodeficiency (SCID); lymphocytopenia; dried blood spot; newborn screening
The noninvasive quantification of peripheral compartment-specific bone microarchitecture is feasible with high-resolution peripheral quantitative computed tomography (HR-pQCT) and high-resolution magnetic resonance imaging (HR-MRI). In addition to classic morphometric indices, both techniques provide a suitable basis for virtual biomechanical testing using finite element (FE) analyses. Methodical limitations, morphometric parameter definition, and motion artifacts have to be considered to achieve optimal data interpretation from imaging studies. With increasing availability of in vivo high-resolution bone imaging techniques, special emphasis should be put on quality control including multicenter, cross-site validations. Importantly, conclusions from interventional studies investigating the effects of antiosteoporotic drugs on bone microarchitecture should be drawn with care, ideally involving imaging scientists, translational researchers, and clinicians.
high-resolution peripheral quantitative computed tomography (HR-pQCT); high-resolution magnetic resonance imaging (HR-MRI); bone microarchitecture; bone quality
The hypothalamus is one of the master regulators of various physiological processes, including energy balance and nutrient metabolism. These regulatory functions are mediated by discrete hypothalamic regions that integrate metabolic sensing with neuroendocrine and neural controls of systemic physiology. Neurons and non-neuronal cells in these hypothalamic regions act supportively to execute metabolic regulations. Under conditions of brain and hypothalamic inflammation, which may result from overnutrition-induced intracellular stresses or disease-associated systemic inflammatory factors, extracellular and intracellular environments of hypothalamic cells are disrupted, leading to central metabolic dysregulations and various diseases. Recent research has begun to elucidate the effects of hypothalamic inflammation in causing diverse components of metabolic syndrome leading to diabetes and cardiovascular disease. These new understandings have provocatively expanded previous knowledge on the cachectic roles of brain inflammatory response in diseases, such as infections and cancers. This review describes the molecular and cellular characteristics of hypothalamic inflammation in metabolic syndrome and related diseases as opposed to cachectic diseases, and also discusses concepts and potential applications of inhibiting central/hypothalamic inflammation to treat nutritional diseases.
Hypothalamus; brain; inflammation; energy balance; metabolism; disease
Inflammation is a part of the host defense system, which provides protection against invading pathogens. However, it has become increasingly clear that inflammation can be evoked by endogenous mediators through Toll-like receptors (TLRs) to enhance tumor progression and metastasis. Here, we discuss the roles of TLR-mediated inflammation in tumor progression and the mechanisms through which it accomplishes this pathogenic function.
Toll-like receptor; inflammation; TNF-α; tumor progression; metastasis
The monoaminergic neuron, in particular the dopaminergic neuron, is central to mediating the hedonic and addictive properties of drugs of abuse. The effects of amphetamine (AMPH) and cocaine (COC), for example, depend on the ability to increase dopamine in the synapse, by effects on either the plasma membrane transporter DAT or the vesicular transporter for monoamine storage, VMAT2. The potential role of DAT as a target for AMPH and COC has been reviewed extensively. Here, we present VMAT2 as a target that enables the rewarding and addictive actions of these drugs, based on imaging, neurochemical, biochemical, cell biological, genetic, and immunohistochemical evidence. The presence of VMAT2 in noradrenergic, serotoninergic, histaminergic, and potentially trace aminergic neurons invites consideration of a wider role for aminergic neurotransmission in AMPH and COC abuse and addiction.
VMAT2; amphetamine; cocaine; addiction; monoamines; vesicular transporter
Significant progress has been made in the last few decades using animal models to recreate the esophagitis–metaplasia–carcinoma sequence similar to that seen in human Barrett’s esophagus (BE) and EAC. More recent works focus on molecular pathways associated with intestinal metaplasia and carcinogenesis, as well as similarities between genetic mutations occurring in humans and animal models, mouse, rat, pig, rabbit, guinea pig, dog, cat, ferret, and possum.
Despite the lack of a perfect model, there is still significant potential in using these models to clarify the contribution of different types of reflux (gastric, biliary, and pancreatic) to esophageal adenocarcinoma and to determine how the different types of refluxate interact.
Refluxed duodenal contents cause gastric and esophageal carcinoma in rats without exposure to carcinogens, and several rat duodenal contents reflux models have been developed. BE in the animal models has well-developed goblet cells positive forMUC2, gastric pyloric-type mucins positive for MUC6, and sometimes intermingled with gastric foveolar-type mucins positive for MUC5AC.
A gut regenerative cell lineage, characterized by pyloric–foveolar metaplasia followed by the appearance of goblet cells, occurs in the regenerative process in response to chronic inflammation.
High animal-fat dietary intake causes severe obesity, resulting in the development of increased abdominal pressure and increased refluxate, particularly of the duodenal contents. The N-nitroso bile acid conjugates, which have mutagenecity, play an important role in Barrett’s carcinogenesis, and are stabilized by gastric acid.
Experiments have been made in a rodent duodeno-esophageal reflux model using thioproline or cyclooxygenase-2 inhibitor to prevent the inflammation–metaplasia– adenocarcinoma sequence. Thioproline is one of the nitrite scavengers, which reduce the production of carcinogenic nitroso-compounds. Celecoxib could postpone the sequence itself, whereas thioproline could only prevent the evolution of Barrett’s esophagus to cancer.
The Levrat’s surgical model of esophago-duodenal anatomosis in rats has been shown to induce gastroduodenojejunal reflux. This in vivo model reproduces the sequence of histologic and molecular events that lead to the development of BE and esophageal adenocarcinoma in humans and, as such, provides a realistic and translatable model for development of therapeutics for EAC.
A pilot study using proteomics to evaluate for differentially expressed markers in the progression from metaplasia to dysplasia and ultimately adenocarcinoma in human tissues has been conducted.
Differential expression of cytokeratin 20 in specimens from human patients and the Levrat’s model substantiated the hypothesis that the animal model is representative of human cancer and, hence, further supporting the basis for its utilization.
Furthermore, if this data is confirmed, the Levrat’s approach may serve as a model for preclinical drug development. Up to ten potential novel target regimens identified and selected through the proteomics screen will be tested in a multi-arm study in rats.
esophageal neoplasm; Barrett’s esophagus; duodenogastric reflux; bile reflux; carcinoma; histogenesis; gut regenerative cell lineage; pyloric–foveolar metaplasia; fat intake; DNA adducts; N-nitroso bile acids; chemoprevention; duodenoesophageal reflux; thioproline; cyclooxygenase-2 inhibitor
The Knockout Mouse Project (KOMP) Repository archives and distributes vectors, embryonic stem cell clones, frozen germplasm, and live mutant mice for 8,500 knockout genes. Here, we describe the creation and functions of the KOMP Repository.
genetically altered mice; knockouts; gene targeting; ES cells
Visual acuity and motion perception are degraded during head movements unless the eyes counter-rotate so as to stabilize the line of sight and the retinal image. The vestibulo-ocular reflex (VOR) is assumed to produce this ocular counter-rotation. Consistent with this assumption, oscillopsia is a common complaint of patients with bilateral vestibular weakness.
Shanidze et al. (2010b) described compensatory eye movements in normal guinea pigs that appear to anticipate self-generated head movements. These responses effectively stabilize gaze and occur independently of the vestibular system. These new findings suggest that the VOR stabilizes gaze during passive perturbations of the head in space, but anticipatory responses may supplement or even supplant the VOR during actively generated head movements. This report reviews these findings, potential neurophysiological mechanisms, and their potential application to human clinical treatment of patients with vestibular disease.
vestibulo-ocular reflex (VOR); efference copy; cervico-ocular reflex (COR); vestibular nuclei; oscillopsia; guinea pigs
Although drug craving has received considerable research attention over the past several decades, to date there has been no systematic review of the general clinical significance of craving. This paper presents an overview of measurement issues of particular relevance to a consideration of use of craving in clinical settings. The paper then considers the relevance of craving across a broad array of clinical domains, including diagnosis, prognostic utility, craving as an outcome measure, and the potential value of craving as a direct target of intervention. The paper is both descriptive and prescriptive, informed by the current state of the science on craving with recommendations for the definition of craving, assessment practices, future research, and clinical applications. We conclude that craving has considerable utility for diagnosis and as a clinical outcome, and that findings from future research will likely expand the clinical potential of the craving construct in the domains of prognosis and craving as a treatment target.
craving; clinical significance; diagnosis; prognosis; clinical outcomes
The primate orbitofrontal cortex (OFC) is often treated as a single entity, but architectonic and connectional neuroanatomy indicates that it has distinguishable parts. Nevertheless, few studies have attempted to dissociate the functions of its subregions. Here we review findings from recent neuropsychological and neurophysiological studies that do so. The lateral OFC seems to be important for learning, representing and updating specific object–reward associations. Medial OFC seems to be important for value comparisons and choosing among objects on that basis. Rather than viewing this dissociation of function in terms of learning versus choosing, however, we suggest that it reflects the distinction between contrasts and comparisons: differences versus similarities. Making use of high-dimensional representations that arise from the convergence of several sensory modalities, the lateral OFC encodes contrasts among outcomes. The medial MFC reduces these contrasting representations of value to a single dimension, a common currency, in order to compare alternative choices.
Orbitofrontal cortex; macaque; reward; reversal learning
Patients with primary immunodeficiency (PID) provide rare opportunities to study the impact of specific gene mutations on the regulation of human B cell tolerance. Alterations in B cell receptor and Toll-like receptor signaling pathways result in a defective central checkpoint and a failure to counterselect developing autoreactive B cells in the bone marrow. In contrast, CD40L- and MHC class II–deficient patients only displayed peripheral B cell tolerance defects, suggesting that decreased numbers of regulatory T cells and increased concentration of B cell activating factor (BAFF) may interfere with the peripheral removal of autoreactive B cells. The pathways regulating B cell tolerance identified in PID patients are likely to be affected in patients with rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes who display defective central and peripheral B cell tolerance checkpoints. Indeed, risk alleles encoding variants altering BCR signaling, such as PTPN22 alleles associated with the development of these diseases, interfere with the removal of developing autoreactive B cells. Hence, insights into B cell selection from PID patients are highly relevant to the understanding of the etiology of autoimmune conditions.
B cell tolerance; B cell receptor; Toll-like receptors; receptor editing
Neocortex is an important part of the mammalian brain that is quite different from its homologue of the dorsal cortex in the reptilian brain. Whereas dorsal cortex is small, thin, and composed of a single layer of neurons, neocortex is thick and has six layers, while being variable across species in size, number of functional areas, and architectonic differentiation. Early mammals had little neocortex, with perhaps 20 areas of poor structural differentiation. Many extant mammals continue to have small brains with little neocortex, but they often have sensory specializations reflected in the organization of sensory areas in neocortex. In primates, neocortex is variously enlarged and characterized by structural and other specializations, including those of cortical networks devoted to vision and visuomotor processing.In humans, neocortex occupies 80% of the volume of the brain, where as many as 200 areas may exist.
primates; reptiles; dorsal cortex; visual cortex; marsupials; monotremes
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
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
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
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
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
Time and time perceptions are integral to decision making because any meaningful choice is embedded in a temporal context and requires the evaluation of future preferences and outcomes. The present review examines the influence of chronological age on time perceptions and horizons and discusses implications for decision making across the life span. Time influences and interacts with decision making in multiple ways. Specifically, this review examines the following topic areas: (1) processing speed and decision time, (2) internal clocks and time estimation, (3) mental representations of future time and intertemporal choice, and (4) global time horizons. For each aspect, patterns of age differences and implications for decision strategies and quality are discussed. The conclusion proposes frameworks to integrate different lines of research and identifies promising avenues for future inquiry.
We outline a contextual and motivational model of judgment and decision-making (JDM) biases across the life span. Our model focuses on abilities and skills that correspond to deliberative, experiential, and affective decision-making processes. We review research that addresses links between JDM biases and these processes as represented by individual differences in specific abilities and skills (e.g., fluid and crystallized intelligence, executive functioning, emotion regulation, personality traits). We focus on two JDM biases—the sunk-cost fallacy (SCF) and the framing effect. We trace the developmental trajectory of each bias from preschool through middle childhood, adolescence, early adulthood, and later adulthood. We conclude that life-span developmental trajectories differ depending on the bias investigated. Existing research suggests relative stability in the framing effect across the life span and decreases in the SCF with age, including in later life. We highlight directions for future research on JDM biases across the life span, emphasizing the need for process-oriented research and research that increases our understanding of JDM biases in people’s everyday lives.
sunk costs; framing effect; dual processes; heuristics; biases
Everyday problem solving involves examining the solutions that individuals generate when faced with problems that take place in their everyday experiences. Problems can range from medication adherence and meal preparation to disagreeing with a physician over a recommended medical procedure or compromising with extended family members over where to host Thanksgiving dinner. Across the life span, research has demonstrated divergent patterns of change in performance based on the type of everyday problems used as well as based on the way that problem-solving efficacy is operationally defined. Advancing age is associated with worsening performance when tasks involve single-solution or fluency-based definitions of effectiveness. However, when efficacy is defined in terms of the diversity of strategies used, as well as by the social and emotional impact of solution choice on the individual, performance is remarkably stable and sometimes even improves in the latter half of life. This article discusses how both of these approaches to everyday problem solving inform research on the influence that aging has on everyday functioning.
everyday problem solving; aging; coping; practical intelligence; decision making