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1.  Geographic Model and Biomarker-Derived Measures of Pesticide Exposure and Parkinson’s Disease 
For more than two decades, reports have suggested that pesticides and herbicides may be an etiologic factor in idiopathic Parkinson’s disease (PD). To date, no clear associations with any specific pesticide have been demonstrated from epidemiological studies perhaps, in part, because methods of reliably estimating exposures are lacking. We tested the validity of a Geographic Information Systems (GIS)-based exposure assessment model that estimates potential environmental exposures at residences from pesticide applications to agricultural crops based on California Pesticide Use Reports (PUR). Using lipid-adjusted dichlorodiphenyldichloroethylene (DDE) serum levels as the “gold standard” for pesticide exposure, we conducted a validation study in a sample taken from an ongoing, population-based case–control study of PD in Central California. Residential, occupational, and other risk factor data were collected for 22 cases and 24 controls from Kern county, California. Environmental GIS–PUR-based organochlorine (OC) estimates were derived for each subject and compared to lipid-adjusted DDE serum levels. Relying on a linear regression model, we predicted log-transformed lipid-adjusted DDE serum levels. GIS–PUR-derived OC measure, body mass index, age, gender, mixing and loading pesticides by hand, and using pesticides in the home, together explained 47% of the DDE serum level variance (adjusted r2 = 0.47). The specificity of using our environmental GIS–PUR-derived OC measures to identify those with high-serum DDE levels was reasonably good (87%). Our environmental GIS–PUR-based approach appears to provide a valid model for assessing residential exposures to agricultural pesticides.
doi:10.1196/annals.1371.074
PMCID: PMC3656600  PMID: 17119217
pesticides; Geographic Information Systems (GIS); validation; exposure assessment; biomarker
2.  Posttraumatic Stress Disorder and Other Psychological Sequelae Among World Trade Center Clean Up and Recovery Workers 
We assessed the health of workers exposed to the World Trade Center (WTC) site and of a comparison group of unexposed workers, by means of a mail survey. Exposed workers reported higher frequency of symptoms consistent with posttraumatic stress disorder (PTSD), depression, anxiety, and other psychological problems, approximately 20 months after the disaster. PTSD was positively associated with traumatic on-site experiences and with respiratory problems. These findings may have important clinical and public health implications.
doi:10.1196/annals.1364.051
PMCID: PMC3622541  PMID: 16891606
September 11; World Trade Center; clean up and recovery; disaster workers; posttraumatic stress disorder; depression; respiratory problems; cough
3.  Conceptual Issues in Studies of Resilience 
We begin this article by considering the following critical conceptual issues in research on resilience: (1) distinctions between protective, promotive, and vulnerability factors; (2) the need to unpack underlying processes; (3) the benefits of within-group experimental designs; and (4) the advantages and potential pitfalls of an overwhelming scientific focus on biological and genetic factors (to the relative exclusion of familial and contextual ones). The next section of the article is focused on guidelines for the selection of vulnerability and protective processes in future research. From a basic science standpoint, it is useful and appropriate to investigate all types of processes that might significantly affect adjustment among at-risk individuals. If the research is fundamentally applied in nature, however, it would be most expedient to focus on risk modifiers that have high potential to alter individuals’ overall life circumstances. The final section of this article considers conceptual differences between contemporary resilience research on children versus adults. Issues include differences in the types and breadth of outcomes (e.g., the tendencies to focus on others’ ratings of competence among children and on self-reports of well-being among adults respectively).
doi:10.1196/annals.1376.009
PMCID: PMC3480733  PMID: 17347344
resilience; protective processes; risk modifiers; interventions
4.  Modeling Cardiac Ischemia 
Myocardial ischemia is one of the main causes of sudden cardiac death, with 80% of victims suffering from coronary heart disease. In acute myocardial ischemia, the obstruction of coronary flow leads to the interruption of oxygen flow, glucose, and washout in the affected tissue. Cellular metabolism is impaired and severe electrophysiological changes in ionic currents and concentrations ensue, which favor the development of lethal cardiac arrhythmias such as ventricular fibrillation. Due to the burden imposed by ischemia in our societies, a large body of research has attempted to unravel the mechanisms of initiation, sustenance, and termination of cardiac arrhythmias in acute ischemia, but the rapidity and complexity of ischemia-induced changes as well as the limitations in current experimental techniques have hampered evaluation of ischemia-induced alterations in cardiac electrical activity and understanding of the underlying mechanisms. Over the last decade, computer simulations have demonstrated the ability to provide insight, with high spatiotemporal resolution, into ischemic abnormalities in cardiac electrophysiological behavior from the ionic channel to the whole organ. This article aims to review and summarize the results of these studies and to emphasize the role of computer simulations in improving the understanding of ischemia-related arrhythmias and how to efficiently terminate them.
doi:10.1196/annals.1380.029
PMCID: PMC3313589  PMID: 17132797
myocardial ischemia; computer simulations; cardiac arrhythmias; vulnerability to electric shocks
5.  Three-Dimensional Models of Individual Cardiac Histoanatomy: Tools and Challenges 
There is a need for, and utility in, the acquisition of data sets of cardiac histoanatomy, with the vision of reconstructing individual hearts on the basis of noninvasive imaging, such as MRI, enriched by reference to detailed atlases of serial histology obtained from representative samples. These data sets would be useful not only as a repository of knowledge regarding the specifics of cardiac histoanatomy, but could form the basis for generation of individualized high-resolution cardiac structure–function models. The current article presents a step in this general direction: it illustrates how whole-heart noninvasive imaging can be combined with whole-heart histology in an approach to achieve automated construction of histoanatomically detailed models of cardiac 3D structure and function at hitherto unprecedented resolution and accuracy (based on 26.4 × 26.4 × 24.4 μm MRI voxel size, and enriched by histological detail). It provides an overview of the tools used in this quest and outlines challenges posed by the approach in the light of applications that may benefit from the availability of such data and tools.
doi:10.1196/annals.1380.023
PMCID: PMC3313659  PMID: 17132791
noninvasive imaging; MRI; serial histology; three-dimensional histoanatomy; cardiac modeling; personalized medicine
6.  The Relationship Between Cognitive and Brain Changes in Posttraumatic Stress Disorder 
Preclinical studies show that stress is associated with changes in structure of the hippocampus, a brain area that plays a critical role in memory, inhibition of neurogenesis, and memory deficits. Studies in animals showed that both serotonin reuptake inhibitors (SSRIs) and the epilepsy medication phenytoin (dilantin) block the effects of stress on the hippocampus. Imaging studies in posttraumatic stress disorder (PTSD) have found smaller volume of the hippocampus as measured with magnetic resonance imaging (MRI) in patients with PTSD related to both combat and childhood abuse. These patients were also found to have deficits in memory on neuropsychological testing. Functional imaging studies using positron emission tomography (PET) found decreased hippocampal activation with memory tasks. In an initial study, we found that a year of treatment with paroxetine led to a 5% increase in hippocampal volume and a 35% increase in memory function. A second study showed that phenytoin was efficacious for symptoms of PTSD and led to a significant 6% increase in both right hippocampal and right whole brain volume, with no significant change in memory. These studies suggest that medications may counteract the effects of stress on the brain in patients with PTSD.
doi:10.1196/annals.1364.008
PMCID: PMC3233753  PMID: 16891564
PTSD; hippocampus; pharmacotherapy; stress; neurogenesis; paroxetine; depression
7.  Alterations in Stress Reactivity After Long-Term Treatment with Paroxetine in Women with Posttraumatic Stress Disorder 
Posttraumatic stress disorder (PTSD) is typically accompanied by both acute and chronic alterations in the stress response. These alterations have mostly been described in individuals under baseline conditions, but studies have also used a challenge model to assess the role of the hypothalamic-pituitary-adrenal (HPA) axis in the stress response. The purpose of this article was to assess the effect of long-term treatment with the selective reuptake inhibitor (SSRI), paroxetine, on stress reactivity in patients with PTSD. We assessed diurnal salivary cortisol and urinary cortisol as well as cortisol, heart rate, and behavioral responses to a standardized cognitive stress challenge, in 13 female patients with chronic PTSD before and after 12 months of paroxetine treatment. Treatment resulted in a significant decrease in PTSD symptoms. Twenty-four-hour urinary cortisol was lower compared to base line after successful treatment. Treatment resulted in a decrease of salivary cortisol levels on all time points on a diurnal curve. Despite similar stress perception, cortisol response to the cognitive stress challenge resulted in a 26.5% relative decrease in stress-induced salivary cortisol with treatment. These results suggest that successful treatment with SSRI in chronic PTSD is associated with a trend for a decrease in baseline diurnal cortisol and with reduced cortisol reactivity to stress.
doi:10.1196/annals.1364.014
PMCID: PMC3230329  PMID: 16891570
cortisol; PTSD; stress; paroxetine; SSRI; challenge; HPA axis
8.  Cardiac Defibrillation and the Role of Mechanoelectric Feedback in Postshock Arrhythmogenesis 
Ventricular dilatation increases the defibrillation threshold (DFT). In order to elucidate the mechanisms responsible for this increase, the present article investigates changes in the postshock behavior of the myocardium upon stretch. A two-dimensional electro-mechanical model of cardiac tissue incorporating heterogeneous fiber orientation was used to explore the effect of sustained stretch on postshock behavior via (a) recruitment of mechanosensitive channels (MSC) and (b) tissue deformation and concomitant changes in tissue conductivities. Recruitment of MSC had no influence on vulnerability to electric shocks as compared to control, but increased the complexity of postshock VF patterns. Stretch-induced deformation and changes in tissue conductivities resulted in a decrease in vulnerability to electric shocks.
doi:10.1196/annals.1380.024
PMCID: PMC2925201  PMID: 17132792
defibrillation; mechanoelectric feedback; reentry; myocardial stretch; bidomain model
9.  Distinct Mechanisms Mediating Methamphetamine-Induced Neuronal Apoptosis and Dopamine Terminal Damage Share the Neuropeptide Substance P in the Striatum of Mice 
Methamphetamine (METH) is an addictive psychostimulant that induces damage to the dopamine terminals and the apoptosis of some neurons of the striatum. Our laboratory demonstrated using either a single bolus dose (30 mg/kg) or a binge (10 mg/kg 4× at 2-h intervals) of METH that pharmacological blockade of the substance P receptor (neurokinin-1) attenuates METH-induced damage to both the presynaptic dopamine terminals and the apoptosis of some neurons of the striatum. To determine the phenotype of striatal neuron ablated by METH, we combined TUNEL (Terminal Deoxyncleotidyl Transferase-Mediated dUTP Nick End Labeling) with immunofluorescence for selective markers of projection and interneurons. METH induces the loss of approximately 20% of the projection neurons. The cholinergic and γ-aminobutyric acid (GABA)-parvalbumin interneurons sustain losses of 30% and 50%, respectively. The somatostatin/neuropeptide Y (NPY)/nitric oxide synthase (NOS) interneurons are not impacted by METH. To investigate the mechanism by which substance P mediates METH-induced damage in this part of the brain, we ablated the striatal interneurons that express the neurokinin-1 receptor (NK-1R) with the selective neurotoxin substance P-SAP. Ablation of the NK-1R-expressing interneurons prevented METH-induced apoptosis in the striatum but was without effect on depletion of dopamine terminal markers. We propose that substance P mediates the apoptosis of some striatal neurons via the intrastriatal activation of nitric oxide synthesis. In contrast, substance P may mediate damage of the dopamine terminals via an extrastriatal mechanism involving the substantia nigra and cortical glutamate release.
doi:10.1196/annals.1369.013
PMCID: PMC2892968  PMID: 17105911
striatum; methamphetamine; neurotoxicity; apoptosis; substance P; neurokinin-1 receptor
10.  Sex Steroids and Prostate Carcinogenesis Integrated, Multifactorial Working Hypothesis 
Androgens are thought to cause prostate cancer, but there is little epidemiological support for this notion. Animal studies, however, demonstrate that androgens are very strong tumor promotors for prostate carcinogenesis after tumor-initiating events. Even treatment with low doses of testosterone alone can induce prostate cancer in rodents. Because testosterone can be converted to estradiol-17β by the enzyme aromatase, expressed in human and rodent prostate, estrogen may be involved in prostate cancer induction by testosterone. When estradiol is added to testosterone treatment of rats, prostate cancer incidence is markedly increased and even a short course of estrogen treatment results in a high incidence of prostate cancer. The active testosterone metabolite 5α-dihydrotestosterone cannot be aromatized to estrogen and hardly induces prostate cancer, supporting a critical role of estrogen in prostate carcinogenesis. Estrogen receptors are expressed in the prostate and may mediate some or all of the effects of estrogen. However, there is also evidence that in the rodent and human prostate conversion occurs of estrogens to catecholestrogens. These can be converted to reactive intermediates that can adduct to DNA and cause generation of reactive oxygen species, and thus estradiol can be a weak DNA damaging (genotoxic) carcinogen. In the rat prostate DNA damage can result from estrogen treatment; this occurs prior to cancer development and at exactly the same location. Inflammation may be associated with prostate cancer risk, but no environmental carcinogenic risk factors have been definitively identified. We postulate that endogenous factors present in every man, sex steroids, are responsible for the high prevalence of prostate cancer in aging men, androgens acting as strong tumor promoters in the presence of a weak, but continuously present genotoxic carcinogen, estradiol-17β.
doi:10.1196/annals.1386.040
PMCID: PMC2821822  PMID: 17261765
prostate; prostate cancer; estrogen, androgen; carcinogenesis; hormonal carcinogenesis
11.  Who Wins in the Status Games? Violence, Sexual Violence, and an Emerging Single Standard among Adolescent Women 
Throughout U.S. history, women have changed their sexual behaviors in response to, or as actors affecting, economic, political, and legal imperatives; to preserve health; to promote new relationship, identity or career paths; to assert a set of values; as a result of new reproductive technologies; or to gain status. In adjusting to pressures or goals, women have not always acted, or been able to act, in the interests of their own health, identity, or status. As this article will demonstrate, women, in the short or long run, may attempt to preserve status at the cost of other values such as health. This may occur through conscious and critical choice or through less conscious processes in reaction to relatively larger forces whose impact has not been critically analyzed. With the awareness in the 1980s in the United States of an emergent and incurable sexually transmissible infection, HIV, it would have been anticipated that a new sexual caution may have appeared. Yet, across several research projects in the late 1990s and into the 21st century, as our research team interviewed youth in a high HIV seroprevalence neighborhood in New York City about HIV prevention, we began to hear that a substantial minority of young women and men were participating in social settings for sexual behavior that (1) put youth at risk for HIV; (2) appeared to be motivated by acquisition of status (“props,” “points”); and (3) offered few ways for women to win in these status games. We estimate from one random dwelling unit sample that about one in eight youth have been present in these settings and half of them have participated in risky sexual behavior in such settings. The settings are often characterized by men’s publicly offhand attitudes toward sexual encounters, are organized around men’s status maintenance, and evidence peer pressures that are poorly understood by both young men and women participants. To regain status, some women participants have adopted attitudes more characteristic of men.
doi:10.1196/annals.1385.001
PMCID: PMC2814298  PMID: 17189498
adolescents; women; sexual risk; status; HIV; violence
12.  Clarifying the Origin of Biological Abnormalities in PTSD Through the Study of Identical Twins Discordant for Combat Exposure 
A biological abnormality found to be associated with post-traumatic stress disorder (PTSD) may be, among other things, a pre-trauma vulnerability factor, that is, it may have been present prior to the event’s occurrence and increased the individual’s likelihood of developing PTSD upon traumatic exposure. Alternately, it may be an acquired PTSD sign, that is, it may have developed after the traumatic exposure, along with the PTSD. We have studied pairs of Vietnam combat veterans and their noncombat-exposed, identical twins in an effort to resolve these competing origins. Combat veterans were diagnosed as current PTSD or non-PTSD (i.e., never had). Average heart rate responses (HRRs) to a series of sudden, loud-tone presentations were larger in Vietnam combat veteran twins with PTSD, but these larger responses were not shared by their noncombat-exposed cotwins, whose responses were similar to those of the non-PTSD combat veterans and their noncombat-exposed cotwins. These results suggest that larger HRRs to sudden, loud tones represent an acquired sign of PTSD. In contrast, increased neurological soft signs (NSSs), diminished hippocampal volume, and presence of abnormal cavum septum pellucidum (CSP) were found in Vietnam combat veteran twins with PTSD and their “high-risk,” unexposed cotwins compared to Vietnam combat veteran twins without PTSD and their “low-risk,” unexposed cotwins. These results support the conclusion that the latter abnormalities represent antecedent, familial vulnerability factors for developing chronic PTSD upon exposure to a traumatic event.
doi:10.1196/annals.1364.019
PMCID: PMC2770249  PMID: 16891575
stress disorders; posttraumatic; twins; monozygotic; startle response; neurological examination; magnetic resonance imaging; hippocampus; septum pellucidum
13.  Cellular and Molecular Mechanisms of Synovial Joint and Articular Cartilage Formation 
Synovial joints and articular cartilage play crucial roles in skeletal function, but relatively little is actually known about their embryonic development. Here we first focused on the interzone, a thin mesenchymal cell layer forming at future joint sites that is widely thought to be critical for joint and articular cartilage development. To determine interzone cell origin and fate, we microinjected the vital fluorescent dye DiI at several peri-joint sites in chick limbs and monitored behavior and fate of labeled cells over time. Peri-joint mesenchymal cells located immediately adjacent to incipient joints migrated, became part of the interzone, and were eventually found in epiphyseal articular layer and joint capsule. Interzone cells isolated and reared in vitro expressed typical phenotypic markers, including GDF-5, Wnt-14 and CD-44, and differentiated into chondrocytes over time. To determine the molecular mechanisms of articular chondrocyte formation, we carried out additional studies on the ets transcription factor family member ERG and its alternatively-spliced variant C-1-1 that we previously found to be expressed in developing avian articular chondrocytes. We cloned the human counterpart of avian C-1-1 (ERGp55Δ81) and conditionally expressed it in transgenic mice under cartilage-specific Col2 gene promoter-enhancer control. The entire transgenic mouse limb chondrocyte population exhibited an immature articular-like phenotype and a virtual lack of growth plate formation and chondrocyte maturation compared to wild type littermate. Together, our studies reveal that peri-joint mesenchymal cells take part in interzone and articular layer formation, interzone cells can differentiate into chondrocytes, and acquisition of a permanent articular chondrocyte phenotype is aided and perhaps dictated by ets transcription factor ERG.
doi:10.1196/annals.1346.010
PMCID: PMC2697570  PMID: 16831907
Synovial joint formation; articular cartilage; progenitor stem cells; transcription factor ERG
14.  Cell-based Approaches for Cardiac Repair 
Many forms of cardiovascular disease are associated with cardiomyocyte loss via necrosis and/or apoptosis. The cumulative loss of contractile cells ultimately results in diminished cardiac function. Numerous approaches have been employed to reduce the rate of cardiomyocyte loss, or alternatively, to repopulate the heart with new cardiomyocytes. Strategies aimed at repopulating the heart include cardiomyocyte cell therapy, myogenic stem cell therapy, and cell cycle activation therapy. All three approaches are based on the assumption that the de novo cardiomyocytes will participate in a functional syncytium with the surviving myocardium. This review will discuss the current status of interventions aimed at repopulating the heart with functional cardiomyocytes.
doi:10.1196/annals.1380.004
PMCID: PMC2600713  PMID: 17132773
Myocardial Regeneration; Stem Cells; Cardiomyocyte Proliferation; Apoptosis
15.  Effects of AT1 Receptor-Mediated Endocytosis of Extracellular Ang II on Activation of Nuclear Factor-κB in Proximal Tubule Cells 
Angiotensin II (Ang II) exerts powerful proinflammatory and growth effects on the development of Ang II-induced hypertensive glomerulosclerosis and tubulo-interstitial fibrosis. The proinflammatory and growth actions of Ang II are primarily mediated by activation of cell surface type 1 receptors (AT1) and the transcription factor nuclear factor-κB (NF-κB). However, binding of cell surface receptors by extra-cellular Ang II also induces receptor-mediated endocytosis of the agonist-receptor complex in renal cells. The purpose of the present study was to determine whether AT1 receptor-mediated endocytosis of extracellular Ang II is required for Ang II-induced NF-κB activation and subsequent proliferation of rabbit renal proximal tubule cells. Expression of AT1 (primarily AT1a or human AT1) receptors in these cells was confirmed by Western blot, showing that transfection of a human AT1 receptor-specific 20–25 nucleotide siRNA knocked down more than 70% of AT1 receptor protein (P < 0.01). Stimulation of proximal tubule cells by Ang II (1 nM) induced fourfold increases in NF-κB activity (P < 0.01). The Ang II-increased NF-κB activity was significantly attenuated by coadministration of losartan (10 μM), an AT1 receptor-selective blocker, or colchicine (1 μM), a selective cytoskeleton microtubule inhibitor known to block receptor-mediated endocytosis (P < 0.01). Furthermore, Ang II significantly increased 3H-thymidine incorporation (>55%, P < 0.01), an index of cell proliferation and DNA synthesis, and the effect was also attenuated by coadministration of losartan and colchicine (P < 0.01). Our results therefore suggest that AT1 receptor-mediated endocytosis of extracellular Ang II may be required for Ang II-induced NF-κB activation and subsequent cell proliferation in renal proximal tubule cells.
doi:10.1196/annals.1378.078
PMCID: PMC2276840  PMID: 17341626
angiotensin II; cell proliferation; chemokine; cytokines; kidney
16.  The Role of Estrogens in Normal and Abnormal Development of the Prostate Gland 
Estrogens play a physiologic role during prostate development with regard to programming stromal cells and directing early morphogenic events. However, if estrogenic exposures are abnormally high during the critical developmental period, permanent alterations in prostate branching morphogenesis and cellular differentiation will result, a process referred to as neonatal imprinting or developmental estrogenization. These perturbations are associated with an increased incidence of prostatic lesions with aging, which include hyperplasia, inflammation, and dysplasia. To understand how early estrogenic exposures can permanently alter the prostate and predispose it to neoplasia, we examined the effects of estrogens on prostatic steroid receptors and key developmental genes. Transient and permanent alterations in prostatic AR, ERα, ERβ, and RARs are observed. We propose that estrogen-induced alterations in these critical transcription factors play a fundamental role in initiating prostatic growth and differentiation defects by shifting the prostate from an androgen-dominated gland to one whose development is regulated by estrogens and retinoids. This in turn leads to specific disruptions in the expression patterns of key prostatic developmental genes that normally dictate morphogenesis and differentiation. Specifically, we find transient reductions in Nkx3.1 and permanent reductions in Hoxb-13, which lead to differentiation defects particularly within the ventral lobe. Prolonged developmental expression of Bmp-4 contributes to hypomorphic growth throughout the prostatic complex. Reduced expression of Fgf 10 and Shh and their cognate receptors in the dorsolateral lobes leads to branching defects in those specific regions in response to neonatal estrogens. We hypothesize that these molecular changes initiated early in life predispose the prostate to the neoplastic state upon aging.
doi:10.1196/annals.1386.009
PMCID: PMC2276871  PMID: 17261752
prostate; estradiol; estrogen; steroid receptors; Hoxb-13; Nkx3.1; sonic hedgehog; fibroblast growth factor-10
17.  Pathogenesis of Osteopenia/Osteoporosis Induced by Highly Active Anti-Retroviral Therapy for AIDS 
The advent of highly active anti-retroviral therapy (HAART) has dramatically decreased the rate of AIDS-related mortality and significantly extended the life span of patients with AIDS. A variety of metabolic side effects are associated with these therapies, one of which is metabolic bone disease. A higher prevalence of osteopenia and osteoporosis in HIV-infected patients receiving anti-retroviral therapy than in patients not on therapy has now been reported in several studies. Several factors have been demonstrated to influence HIV-associated decreases in bone mineral density (BMD), including administration of nucleoside reverse transcriptase inhibitors (NRTIs). In this article, discussion will focus on the molecular pathogenesis and treatment of HAART-associated osteopenia and osteoporosis.
doi:10.1196/annals.1346.057
PMCID: PMC1634831  PMID: 16831930
HIV; osteopenia/osteoporosis; HAART; NRTI; osteoclastogenesis; T cell cytokines; mitochondrial toxicity; RANK/RANKL/OPG
18.  Functional Splice Variants of the Type II G Protein–Coupled Receptor (VPAC2) for Vasoactive Intestinal Peptide in Mouse and Human Lymphocytes 
A PCR-based search for splice variants of the VPAC2 G protein–coupled receptor for vasoactive intestinal peptide (VIP) revealed: (a) a short-deletion variant in mouse lymphocytes termed VPAC2de367–380, that lacks 14 amino acids in the seventh transmembrane domain, and (b) a long-deletion variant in human lymphocytes termed VPAC2de325–438(i325–334), that lacks 114 amino acids beginning with the carboxyl-terminal end of the third cytoplasmic loop and has 10 new carboxy-terminal amino acids. VPAC2de367–380 binds VIP normally, but shows reduced VIP-evoked signaling and effects on immune functions, whereas VPAC2de325–438(i325–334) shows reduced binding affinity for VIP and a complex pattern of functional differences. These splice variants may modify the immunoregulatory contributions of the VIP–VPAC2 axis.
doi:10.1196/annals.1317.055
PMCID: PMC1557659  PMID: 16888203
neuropeptide; immunity; T cell; cytokine
19.  Cellular Basis for the Repolarization Waves of the ECG 
One hundred years after Willem Einthoven first recorded the electrocardiogram (ECG), physicians and scientists are still debating the cellular basis for the various waves of the ECG. In this review, our focus is on the cellular basis for the J, T, and U waves of the ECG. The J wave and T wave are thought to arise as a consequence of voltage gradients that develop as a result of the electrical heterogeneities that exist within the ventricular myocardium. The presence of a prominent action potential notch in epicardium but not endocardium gives rise to a voltage gradient during ventricular activation that inscribes the J wave. Transmural and apico-basal voltage gradients developing as a result of difference in the time course of repolarization of the epicardial, M, and endocardial cell action potentials, and the more positive plateau potential of the M cell contribute to inscription of the T wave. Amplification of these heterogeneities results in abnormalities of the J wave and T wave, leading to the development of the Brugada, long QT, and short QT syndromes. The basis for the U wave has long been a matter of debate. One theory attributes the U wave to mechanoelectrical feedback. A second theory ascribes it to voltage gradients within ventricular myocardium and a third to voltage gradients between the ventricular myocardium and the His–Purkinje system. Although direct evidence in support of any of these three hypotheses is lacking, recent studies involving the short QT syndrome have generated renewed interest in the mechanoelectrical hypothesis.
doi:10.1196/annals.1380.021
PMCID: PMC1952680  PMID: 17132789
heterogeneity; arrhythmias; electrophysiology; long QT; short QT; Brugada syndrome
20.  The Role of Verbal Competence and Multiple Risk on the Internalizing Behavior Problems of Costa Rican Youth 
This longitudinal study examined internalizing behavior problems (anxiety/depression) in early adolescence in relation to adversity in early childhood and child verbal competence. We hypothesized that verbal competence would act as a protective factor in the face of early adversity, that is, high verbal IQ would predict relatively lower internalizing problems in early adolescence primarily for those children who experienced the greatest adversity. The sample was based on 191 Costa Rican children and their mothers, who were recruited in infancy from an urban community and assessed again at 5 and 11–14 years. Families were generally lower-middle to working class. A total of 165 children (94 boys) participated in the early adolescent follow-up (mean age = 12.3 years). Internalizing problems were based on maternal report (Spanish Child Behavior Checklist). Our cumulative risk index (CRI) of adversity in early childhood consisted of home environment quality (HOME score), socioeconomic status, maternal depressed mood (CESD), and maternal IQ. Controlling for the effects of age, gender, internalizing problems at 5 years, and verbal IQ at 5 years, there was a significant interaction between early adversity and verbal IQ at age 11–14 years in predicting internalizing problems in early adolescence. Youth with high verbal IQ had comparable levels of internalizing problems regardless of high or low adversity in early childhood. In contrast, youth with low verbal IQ received higher internalizing problem ratings if they experienced high adversity early in life. The results raise the possibility that interventions to improve verbal competence might help lower the risk of internalizing problems in the face of early adversity.
doi:10.1196/annals.1376.034
PMCID: PMC1906701  PMID: 17347361
internalizing behavior problems; multiple risk; verbal competence; protective factor; vulnerability; longitudinal design
21.  Annexin 1, Glucocorticoids, and the Neuroendocrine–Immune Interface 
Annexin 1 (ANXA1) was originally identified as a mediator of the anti-inflammatory actions of glucocorticoids (GCs) in the host defense system. Subsequent work confirmed and extended these findings and also showed that the protein fulfills a wider brief and serves as a signaling intermediate in a number of systems. ANXA1 thus contributes to the regulation of processes as diverse as cell migration, cell growth and differentiation, apoptosis, vesicle fusion, lipid metabolism, and cytokine expression. Here we consider the role of ANXA1 in the neuroendocrine system, particularly the hypothalamo-pituitary-adrenocortical (HPA) axis. Evidence is presented that ANXA1 plays a critical role in effecting the negative feedback effects of GCs on the release of corticotrophin (ACTH) and its hypothalamic-releasing hormones and that it is particularly pertinent to the early-onset actions of the steroids that are mediated via a nongenomic mechanism. The paracrine/juxtacrine mode of ANXA1 action is discussed in detail, with particular reference to the significance of the secondary processing of ANXA1, the processes that control the intracellular and transmembrane trafficking of the protein of the molecule and the mechanism of ANXA1 action on its target cells. In addition, the role of ANXA1 in the perinatal programming of the HPA axis is discussed.
doi:10.1196/annals.1366.002
PMCID: PMC1855441  PMID: 17192583
annexin 1; HPA axis; glucocorticoids; cytokines

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