Arc Oligomerization Is Regulated by CaMKII Phosphorylation of the GAG Domain: An Essential Mechanism for Plasticity and Memory Formation.

Arc is a synaptic protein essential for memory consolidation. Recent studies indicate that Arc originates in evolution from a Ty3-Gypsy retrotransposon GAG domain. The N-lobe of Arc GAG domain acquired a hydrophobic binding pocket in higher vertebrates that is essential for Arc's canonical function to weaken excitatory synapses. Here, we report that Arc GAG also acquired phosphorylation sites that can acutely regulate its synaptic function. CaMKII phosphorylates the N-lobe of the Arc GAG domain and disrupts an interaction surface essential for high-order oligomerization. In Purkinje neurons, CaMKII phosphorylation acutely reverses Arc's synaptic action. Mutant Arc that cannot be phosphorylated by CaMKII enhances metabotropic receptor-dependent depression in the hippocampus but does not alter baseline synaptic transmission or long-term potentiation. Behavioral studies indicate that hippocampus- and amygdala-dependent learning requires Arc GAG domain phosphorylation. These studies provide an atomic model for dynamic and local control of Arc function underlying synaptic plasticity and memory.

Multiple pathways linking early socioeconomic circumstances and depressive symptoms in late Middle age in the U.S.

Objectives: A growing number of life course studies are examining the influence of earlier life experiences on morbidity, disability, and mortality in mid-old age.Method: Drawing from the social pathway model, this study expands the life course literature by utilizing data collected over 35 years from the National Longitudinal Survey of Youth, 1979 Cohort, spanning four life course phases (childhood, young adulthood, middle adulthood, and late-middle adulthood). Through structural equation analyses with a phantom model, we estimated depressive symptoms in late middle age as a result of pathway effects starting with childhood socio-economic status (SES) which effect young adulthood and middle adulthood. The multi-pathway life course model includes three potential mediators of middle adulthood: health risk behaviors, social activity, and negative life events.Results: We found limited support for a direct effect of childhood SES disadvantage on depressive symptoms in middle age. Instead, much of the effects of childhood SES on later-year depressive symptoms appear to be mediated by SES in young adulthood. Further, the long-term pathway is mediated through the influence of health risk behaviors and negative life events in middle adulthood.Conclusion: Our findings do not propose this chain is permanent and irreversible; rather, this study highlights the possibility that interventions focused on promoting health behaviors and improving living conditions for people from socioeconomically disadvantaged backgrounds could help reduce the instance of depression in middle age and health outcomes along the life course could be improved.

Ecological contexts of youth antisocial behaviors: A longitudinal perspective.

The current study examined and compared the relative influence of ecological factors on youth antisocial behaviors (i.e., aggression and rule-breaking) using longitudinal data while assessing the moderating effect of youth attention-deficit/hyperactivity disorder (ADHD) diagnosis. The study used the fifth and sixth wave of data from the Fragile Families and Child Wellbeing Study (n = 2595; mean age = 9.26 at wave five) for the analysis. Multivariate models show that youth ADHD, physically and psychologically abusive parenting, peer victimization, and community cohesion were important predictors of youth antisocial behaviors. Furthermore, youth ADHD diagnosis moderated some associations between the ecological factors and antisocial behaviors, suggesting that youth with and without ADHD may respond to some ecological contexts differently regarding the concerning behaviors. The findings imply that interventions targeting youth antisocial behaviors should involve collaboration across systems and coordination across programs to tackle a multilayered ecological context, especially when youth with ADHD are involved.

Racial Disparities in School Lunch Program Participation and Cigarette Use: Evidence from Arizona Youth Survey Data.

Background: Cigarette and other tobacco product use among youth has become a serious public health issue in the United States. Thus, it is important to understand the social and contextural factors of cigarette use, especially for the young population. This study explores the relationship between participation in the National School Lunch Program (NSLP) and youth cigarettes use. Further, this study examines how this relationship differs across racial/ethnic groups. Methods: The 2016 Arizona Youth Survey (n = 34,373) data and multivariate logistic regressions were used to examine the association between NSLP participation (free and reduced-cost) and youth cigarette use, both lifetime and past 30-day smoking behaviors. In addition, subgroup analyses were conducted to test the racial disparities in NSLP participation and cigarette use. Results: Results showed that free lunch participation was associated with significantly higher odds of youth cigarette use, both lifetime (OR = 1.25; p < .001) and in the past 30-days (OR = 1.14; p < .05). However, reduced-cost lunch participation was associated with significantly higher odds only for lifetime cigarette use (OR = 1.20; p < .01). Subgroup analyses revealed differences across the six racial/ethnic groups. White and Latinx youth showed a significant relationship between NSLP participation and lifetime cigarette smoking, whereas only Latinx youth showed a significant relationship between NSLP participation and past 30-day smoking. Implications: The findings suggest that intervention approaches to smoking cessation and prevention should be tailored to different racial/ethnic groups to account for their differences. Given the findings that youth (especially Latinxs) who participate in free and reduced-cost lunch programs are at a higher risk of using cigarettes than youth who do not, this study suggests that health intervention programs can enhance their reach and effectiveness by building partnerships with schools with sizable NSLP programs.

Effects of 4-Hydroxyphenyl 4-Isoprooxyphenylsulfone (BPSIP) Exposure on Reproduction and Endocrine System of Zebrafish.

The compound 4-hydroxyphenyl 4-isoprooxyphenylsulfone (BPSIP), a derivative of bisphenol S (BPS), has been detected in thermal paper and human urine samples; however, its potential effects on the endocrine system are largely unknown. The present study was conducted to determine the adverse effects of BPSIP on egg production, relative organ weights, plasma levels of sex hormones, and transcription of genes related to the hypothalamus-pituitary-gonad (HPG) axis in zebrafish (Danio rerio). In male fish, the gonadosomatic index was significantly decreased at concentrations of 5 and 50 µg/L BPSIP. The estrogenic (increase in the 17ß-estradiol/testosterone [E2/T] ratio) and antiandrogenic (decrease in T) effects were observed in fish exposed to BPSIP and males were more sensitive to the adverse effects than females. The changes in sex hormones were supported by the regulation of genes along the HPG axis, such as cyp19, 17ßhsd, and cyp17 transcripts. Although the effective concentration for endocrine disruption was greater than that of BPS, the actions of BPSIP on the steroidogenic pathway were similar to the effects of BPS exposure.

Elevated levels of short carbon-chain PFCAs in breast milk among Korean women: Current status and potential challenges.

Breast milks can be contaminated with perfluoroalkyl substances (PFASs). Exposure to PFASs during early stages of life may lead to adverse health effects among breastfed infants. To date, perfluorootanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) have been most frequently measured PFASs in breast milks worldwide. Information on shorter carbon-chain PFASs in breast milk is scarce. In this study, breast milks were sampled from 264 Korean lactating women, and measured for seventeen PFASs, including ten perfluoroalkyl carboxylates (PFCAs), four perfluoroalkyl sulfonates, and three perfluoroalkyl sulfonamides. PFOA and PFOS were detected in 98.5% of the breast milk samples, with median concentrations of 0.072 and 0.050ng/mL, respectively. Perfluoropentanoic acid (PFPeA), perfluorohexanoic acid (PFHxA), and perfluoroheptanoic acid (PFHpA) were detected in higher frequencies, ranging between 67.4% and 81.8%. The concentrations of short carbon-chain PFCAs in breast milk such as PFPeA and PFHxA were the highest ever reported to date, and were comparable to that of PFOS. Concentrations of shorter chain PFCA in breast milk tended to be higher among the women with longer lactation period, while those of PFOA showed the opposite trend, suggesting a possibility that breastfeeding might be an important route of excretion for PFOA among lactating women. Fish consumption and the use of consumer products, e.g., skin care products, cosmetics and non-stick coated cooking utensils, were identified as significant predictors of PFAS concentrations in breast milk. Health risks associated with PFOA and PFOS exposure through breastfeeding were estimated negligible, however, risks of the short carbon-chain PFCAs could not be assessed because of lack of relevant toxicological information. Further efforts for source identification and exposure management measures for shorter chain PFCAs are necessary.

Chaperone stress 70 protein (STCH) binds and regulates two acid/base transporters NBCe1-B and NHE1.

Regulation of intracellular pH is critical for the maintenance of cell homeostasis in response to stress. We used yeast two-hybrid screening to identify novel interacting partners of the pH-regulating transporter NBCe1-B. We identified Hsp70-like stress 70 protein chaperone (STCH) as interacting with NBCe1-B at the N-terminal (amino acids 96-440) region. Co-injection of STCH and NBCe1-B cRNA into Xenopus oocytes significantly increased surface expression of NBCe1-B and enhanced bicarbonate conductance compared with NBCe1-B cRNA alone. STCH siRNA decreased the rate of Na(+)-dependent pHi recovery from NH4(+) pulse-induced acidification in an HSG (human submandibular gland ductal) cell line. We observed that in addition to NBCe1-B, Na(+)/H(+) exchanger (NHE)-dependent pHi recovery was also impaired by STCH siRNA and further confirmed the interaction of STCH with NHE1 but not plasma membrane Ca(2+) ATPase. Both NBCe1-B and NHE1 interactions were dependent on a specific 45-amino acid region of STCH. In conclusion, we identify a novel role of STCH in the regulation of pHi through site-specific interactions with NBCe1-B and NHE1 and subsequent modulation of membrane transporter expression. We propose STCH may play a role in pHi regulation at times of cellular stress by enhancing the recovery from intracellular acidification.

Arc-dependent synapse-specific homeostatic plasticity.

Both theoretical and experimental research has indicated that the synaptic strength between neurons in a network needs to be properly fine-tuned and controlled by homeostatic mechanisms to ensure proper network function. One such mechanism that has been extensively characterized is synaptic homeostatic plasticity or global synaptic scaling. This mechanism refers to the bidirectional ability of all synapses impinging on a neuron to actively compensate for changes in the neuron's overall excitability. Here, using a combination of electrophysiological, two-photon glutamate uncaging and imaging methods, we show that mature individual synapses, independent of neighboring synapses, have the ability to autonomously sense their level of activity and actively compensate for it in a homeostatic-like fashion. This synapse-specific homeostatic plasticity, similar to global synaptic plasticity, requires the immediate early gene Arc. Together, our results document an extra level of regulation of synaptic function that bears important computational consequences on information storage in the brain.

A review of bullying prevention and intervention in South Korean schools: an application of the social-ecological framework.

School bullying is a serious social problem that results in potentially severe and long lasting consequences for youth, parents, teachers, and school officials. Commensurate with the serious nature and outcomes of bullying, there has been a number of bullying prevention and intervention programs and measures in schools. The current review provides a synthesis and evaluation of the existing research on bullying prevention and intervention strategies in South Korean schools, set within Bronfenbrenner's social-ecological contexts, including the micro- (i.e., family, peer, school), meso- (i.e., family-school), and macro- (i.e., religion, policies) systems. We also discuss the strengths and limitations of the research reviewed and provide directions for future research focusing on major empirical gaps in the literature on bullying prevention and intervention strategies in South Korea.

Intracellular acidification is associated with changes in free cytosolic calcium and inhibition of action potentials in rat trigeminal ganglion.

The effect of intracellular acidification and subsequent pH recovery in sensory neurons has not been well characterized. We have studied the mechanisms underlying Ca(2+)-induced acidification and subsequent recovery of intracellular pH (pH(i)) in rat trigeminal ganglion neurons and report their effects on neuronal excitability. Glutamate (500 µM) and capsaicin (1 µM) increased intracellular Ca(2+) concentration ([Ca(2+)](i)) with a following decrease in pH(i). The recovery of [Ca(2+)](i) to the prestimulus level was inhibited by LaCl(3) (1 mM) and o-vanadate (10 mM), a plasma membrane Ca(2+)/ATPase (PMCA) inhibitor. Removal of extracellular Ca(2+) also completely inhibited the acidification induced by capsaicin. TRPV1 was expressed only in small and medium sized trigeminal ganglion neurons. mRNAs for Na(+)/H(+) exchanger type 1 (NHE1), pancreatic Na(+)-HCO(3)(-) cotransporter type 1 (pNBC1), NBC3, NBC4, and PMCA types 1-3 were detected by RT-PCR. pH(i) recovery was significantly inhibited by pretreatment with NHE1 or pNBC1 siRNA. We found that the frequency of action potentials (APs) was dependent on pH(i). Application of the NHE1 inhibitor 5'-(N-ethyl-N-isopropyl) amiloride (5 µM) or the pNBC1 inhibitor 4',4'-di-isothiocyanostilbene-2',2'-sulfonic acid (500 µM) delayed pH(i) recovery and decreased AP frequency. Simultaneous application of 5'-(N-ethyl-N-isopropyl) amiloride and 4',4'-di-isothiocyanostilbene-2',2'-sulfonic acid almost completely inhibited APs. In summary, our results demonstrate that the rise in [Ca(2+)](i) in sensory neurons by glutamate and capsaicin causes intracellular acidification by activation of PMCA type 3, that the pH(i) recovery from acidification is mediated by membrane transporters NHE1 and pNBC1 specifically, and that the activity of these transporters has direct consequences for neuronal excitability.

Primary gastrointestinal follicular lymphoma: single-center 12-year experiences.

BACKGROUND/AIMS: Primary gastrointestinal follicular lymphoma (GI-FL) is very rare and its natural course is barley known. This study aimed to evaluate the clinical characteristics of primary gastrointestinal follicular lymphoma (GI-FL). METHODOLOGY: From May 1996 to October 2008, the records of five patients diagnosed with primary GI-FL were retrieved from pathological files and retrospectively analyzed in terms of characteristics of endoscopic and clinical findings. RESULTS: The five patients consisted of 3 males and 2 females with a median age of 52 years. Abdominal pain was the most common (n=4, 80%) symptom. The most frequent site was the terminal ileum in the small bowel (n=3, 60%). Endoscopic findings were 3 of mass forming type, 1 of irregular ulcer type and 1 of whitish granular type. Three cases (60%) had a component of diffuse large B cell lymphoma. All cases received chemotherapy. While complete remission occurred in every patient, relapse occurred in the two patients with a higher grade and more advanced stage than the other cases. At a median follow-up time of 37 months (range, 27-58 months; mean, 38.8 months), four patients (80%) were disease free and one patient had died of cardiovascular disease. CONCLUSIONS: In South Korea, primary gastrointestinal follicular lymphoma is very rare and symptomatic. Endoscopic findings were variable from early whitish granular lesions to advanced mass forming lesions.

COVID-19 Pandemic Impacts on Children with Developmental Disabilities: Service Disruption, Transition to Telehealth, and Child Wellbeing.

The COVID-19 pandemic has resulted in substantial service disruption and transition from in-person services to telehealth for children with developmental disabilities. However, there is limited knowledge about the specific dimensions and consequences of the disruption and transition. This study aims to examine the extent of service disruption and transition, the experiences of client children and their caregivers with telehealth vis-à-vis in-person services, and the impacts of the disruption and transition on child wellbeing. The cross-sectional study collected data from parents of children with developmental disabilities using an online survey. McNemar's tests were used to compare service changes before and after the pandemic outbreak, and multivariate analyses were used to examine how service changes were associated with child wellbeing. Results show that more than two-thirds of the children experienced reduction in service amount, and one-third lost services for more than two months in about five months into the pandemic. While telehealth had comparable features relative to in-person services, it had lower ratings with respect to diagnostic accuracy, treatment effectiveness, and rapport building. Service disruption/transition and social isolation were associated with behavioral and emotional deterioration in children. However, child and family stress may have confounded these adverse effects. We concluded that the magnitude of service disruption and transition was large in the first half year after the pandemic outbreak, and the amount and duration of service loss varied substantially across clients. Diagnostic accuracy, treatment efficacy, and rapport building were areas in which parents had major concerns toward telehealth relative to in-person services. However, such drawbacks may partially be due to the limited logistics in telehealth implementation during the pandemic. Service disruption and transition seemed to contribute to family stress, which played a direct role in eroding child wellbeing. Implications of these findings for future research and practices are discussed.

A Latent Transition Analysis of Youth Bullying Victimization Patterns over Time and Their Relations to Delinquency.

Peer victimization patterns from elementary school transitioning into late middle school have not been assessed in detail. Even less work has considered how these patterns differ across family context and then are linked to delinquency in adolescence. This study used longitudinal data (n = 2,892) from the Fragile Families and Child Wellbeing Study to examine peer victimization classification and change over six years while distinguishing across sex and family contexts. Latent transition analysis (LTA) shows that youth can be classified into minor victimization, mainly verbal victimization, and all-type victimization subgroups over time with some sex differences, regardless of whether they were in two-parent families. The majority of the youth were in either the mainly verbal victimization (53% for boys; 42% for girls) or all-type victimization (12% for boys; 21% for girls) statuses when they were about 9 years old, but substantial transition positioned most boys (84%) and girls (82%) in the minor victimization status instead when they were about 15 years old. Youth who were Hispanic, in two-parent families, and more open to parents had a reduced risk of peer victimization, but youth who were in a poor family had an increased risk of peer victimization. Peer victimization statuses were significantly associated with youth delinquency, and there were sex and time differences in the association. In year 9, 45% to 94% of boys and 24% to 75% of girls were involved in delinquency based on their victimization statuses, but the difference was 48% to 67% for boys and 39% to 59% for girls in year 15. The findings suggest developing and implementing peer victimization prevention starting from early elementary school, concurrently addressing peer victimization and delinquency, and paying close attention to sex and family context differences.

Longitudinal behavioral changes and factors related to reinforced risk aversion behavior among patients with chronic kidney disease during the COVID-19 pandemic.

In patients with chronic kidney disease (CKD), coronavirus disease 2019 (COVID-19) has a higher mortality rate than the general population; therefore, prevention is vital. To prevent COVID-19 infection, it is important to study individuals' risk aversion behavior. The objective of this study was to understand how the behavioral characteristics of physical distancing, hygiene practice, and exercise changed in patients with CKD during the COVID-19 pandemic and to identify the characteristics of patients who showed weakened or strengthened behavioral changes. We analyzed data from the Study on Kidney Disease and Environmental Chemicals (Clinical Trial No. NCT04679168), that examined a prospective cohort of patients with CKD. This cohort included patients with CKD who visited the participating hospitals for the first time between June and October 2020 and the second time between October 2020 and January 2021. Data on demographics, socio-economic details, and behavioral characteristics were collected through a questionnaire survey. Using a multivariable logistic regression model, we identified whether COVID-19 infection risk perception and previous strong behavioral changes affected behavioral changes during the first and second visits. A total of 277 patients (33.2% females) were included in the analysis. Nine out of 12 behaviors were reinforced at the first visit, and five out of nine reinforced behaviors were weakened at the second visit. A high-risk perception of COVID-19 infection was not associated with the tendency of overall behavioral reinforcement or maintaining behaviors in an enhanced state at the second visit. Strong behavioral changes at the patients' first visit to the hospital were associated with a tendency to strengthen or maintain reinforced behaviors at the second visit (adjusted odds ratio 1.99, 95% confidence interval 1.19-3.34; P = 0.009). Even if the initial COVID-19 risk perception is high, behavioral changes worsen over time. Individuals who showed more active behavioral changes at the beginning of the COVID-19 pandemic tended to maintain reinforced behavior over time. Continuous education and monitoring are needed to maintain changed behaviors, especially in patients with a high initial COVID-19 risk perception.

Bullying Reporting Concerns as a Mediator Between School Climate and Bullying Victimization/Aggression.

This study aimed to examine whether bullying reporting concerns mediate the relationship between school climate and student bullying victimization as well as aggressive behavior. Data were from a sample of 301 students in Grades 6 to 8 in two minority-predominant schools in a large U.S. metropolitan area. Findings from bootstrapped structural equation modeling (SEM) analyses indicated that for male students, a higher level of perceived anti-bullying school climate was negatively associated with bullying reporting concerns, while the reporting concerns subsequently were positively associated with bullying victimization and aggressive behavior. For female students, perceived school climate was not associated with bullying reporting concerns, but the latter were also positively associated with bullying victimization and aggressive behavior. Therefore, bullying reporting concerns mediated the association between perceived school climate and bullying victimization as well as aggressive behavior for male but not female students. The findings suggest the importance of strengthening anti-bullying school climate to help students overcome bullying reporting concerns to achieve effective outcomes. The gender difference of associations between school climate and bullying reporting concerns may reflect the variation of bullying types experienced by male and female students, which calls for attention to the development of anti-bullying strategies that take into account gender differences and address various types of bullying.

The Evolution of Telepractice Use during the COVID-19 Pandemic: Perspectives of Pediatric Speech-Language Pathologists.

The study investigated how pediatric speech-language pathologists (SLPs) applied telepractice to compensate for the loss of in-person services and the dynamics of telepractice use during the COVID-19 pandemic in a rural state. We conducted interviews with 10 SLPs and then a statewide survey in which 51 SLPs participated. The qualitative interviews revealed themes including changes in service environment due to the pandemic (e.g., transition to telepractice, losing clients), challenges in the transition to telepractice (e.g., limited training, difficulty engaging clients), worsening wellbeing of clinicians and clients, and SLPs' perspectives and suggestions towards telepractice in the future. Survey results showed service disruptions and transition dynamics during the pandemic. SLPs' weekly caseloads reduced from an average of 42.3 clients prior to the pandemic to 25.9 and 23.4 from March to May and from June to September 2020, respectively, and then recovered to 37.2 clients from October to December 2020. In contrast, the number of telepractice caseloads sharply increased from 0.2 clients per week prior to the pandemic to 14.8 from March to May 2020. The weekly telepractice caseloads then declined to 5.5 clients from June to September and 7.9 clients from October to December 2020. In the months right after the pandemic outbreak (i.e., March to May), client children struggled with treatment gains and behavioral wellbeing. However, their outcomes gradually improved by October to December and approached pre-pandemic levels. About one-third of the SLPs reported that they would be more likely or much more likely to use telepractice in the future regardless of the pandemic. However, only about a quarter perceived telepractice as comparable to in-person services. We concluded that the transition from in-person services to telepractice substantially mitigated service disruptions right after the pandemic outbreak and that telepractice's substitute role evolved over time.

Fbxo45 Binds SPRY Motifs in the Extracellular Domain of N-Cadherin and Regulates Neuron Migration during Brain Development.

Several events during the normal development of the mammalian neocortex depend on N-cadherin, including the radial migration of immature projection neurons into the cortical plate. Remarkably, radial migration requires the N-cadherin extracellular domain but not N-cadherin-dependent homophilic cell-cell adhesion, suggesting that other N-cadherin-binding proteins may be involved. We used proximity ligation and affinity purification proteomics to identify N-cadherin-binding proteins. Both screens detected MycBP2 and SPRY domain protein Fbxo45, two components of an intracellular E3 ubiquitin ligase. Fbxo45 appears to be secreted by a nonclassical mechanism, not involving a signal peptide and not requiring transport from the endoplasmic reticulum to the Golgi apparatus. Fbxo45 binding requires N-cadherin SPRY motifs that are not involved in cell-cell adhesion. SPRY mutant N-cadherin does not support radial migration in vivo Radial migration was similarly inhibited when Fbxo45 expression was suppressed. The results suggest that projection neuron migration requires both Fbxo45 and the binding of Fbxo45 or another protein to SPRY motifs in the extracellular domain of N-cadherin.

ß-Carotene exerts anti-colon cancer effects by regulating M2 macrophages and activated fibroblasts.

The tumor microenvironment (TME), consisting of stromal fibroblasts, immune cells, cancer cells and other cell types, plays a crucial role in cancer progression and metastasis. M2 macrophages and activated fibroblasts (AFs) modulate behavior of cancer cells in the TME. Since nutritional effects on cancer progression, including colorectal cancer (CRC), may be mediated by alterations in the TME, we determined the ability of ß-carotene (BC) to mediate anti-cancer effects through regulation of macrophage polarization and fibroblast activation in CRC. The M2 macrophage phenotype was induced by treating U937 cells with phorbol-12-myristate-13-acetate and interleukin (IL)-4. Treatment of these M2 macrophages with BC led to suppression of M2-type macrophage-associated markers and of the IL-6/STAT3 signaling pathway. In separate experiments, AFs were induced by treating CCD-18Co cells with transforming growth factor-ß1. BC treatment suppressed expression of fibroblast activation markers. In addition, conditioned media from BC-treated M2 macrophages and AF inhibited cancer stem cell markers, colon cancer cell invasiveness and migration, and the epithelial-mesenchymal transition (EMT). In vivo, BC supplementation inhibited tumor formation and the expression of M2 macrophage markers in an azoxymethane/dextran sodium sulfate-induced colitis-associated CRC mouse model. To our knowledge, the present findings provide the first evidence suggesting that the potential therapeutic effects of BC on CRC are mediated by the inhibition of M2 macrophage polarization and fibroblast activation.

Effects of aging and hypoxia-inducible factor-1 activity on angiogenic cell mobilization and recovery of perfusion after limb ischemia.

Ischemia is a stimulus for production of angiogenic cytokines that activate local vascular cells and mobilize angiogenic cells to the circulation. These responses are impaired in elderly patients with peripheral arterial disease. Hypoxia-inducible factor (HIF)-1 mediates adaptive responses to ischemia, including production of angiogenic cytokines. In this study, we demonstrate that aging and HIF-1 loss-of-function impair the expression of multiple angiogenic cytokines, mobilization of angiogenic cells, maintenance of tissue viability, and recovery of limb perfusion following femoral artery ligation. We show that HIF-1 directly activates transcription of the gene encoding stem cell factor and that mice lacking the cognate receptor C-KIT have impaired recovery from ischemia. Administration of AdCA5, an adenovirus encoding a constitutively active form of HIF-1alpha, improved the recovery of perfusion in older mice to levels similar to those in young mice. Injection of AdCA5 into nonischemic limb was sufficient to increase the number of circulating angiogenic cells. These results indicate that HIF-1 activity is necessary and sufficient for the mobilization of angiogenic cells and that HIF-1alpha gene therapy can counteract the pathological effects of aging in a mouse model of limb ischemia.

[Comparison of clinical characteristics and outcomes between geriatric and non-geriatric patients in peptic ulcer bleeding].

BACKGROUND/AIMS: In geriatric patients with peptic ulcer, the use of NSAID and prevalence of chronic illness have been increased, but the Helicobacter pylori (H. pylori) infected portion decreased. The aim of this study was to evaluate the clinical characteristics and outcomes of geriatric patients (aged 65 or older) with peptic ulcer bleeding and compare with non-geriatric patients (less than 65 years old). METHODS: We conducted a retrospective study of 88 patients with peptic ulcer bleeding treated with therapeutic endoscopy from January 2006 to December 2006. We compared the clinical characteristics and outcomes of geriatric patients (n=34, 38.6%) with those of non-geriatric patients (n=54, 61.4%). RESULTS: Hypertension (52.9% vs. 24.1%), cardiovascular disease (35.3% vs. 13.0%), and chronic obstructive pulmonary disease (20.6% vs. 3.7%) were more prevalent in the geriatric group, compared with the non-geriatric group (p<0.05). The geriatric group had taken more ulcerogenic drugs than the non-geriatric group (64.7% vs. 33.3%, p<0.05); aspirin plus clopidogrel (23.6% vs. 13.0%) and aspirin (20.6% vs. 11.0%). Sixteen (21.1%) of the 76 cases had H. pylori-negative ulcer. Between the two groups, there was no difference in the prevalence of H. pylori-negative ulcer (25.9% vs. 18.4%, p>0.05). The amount of transfusion length of ICU stay, rebleeding rate, operation rate and mortality were not different between the two groups. The length of hospital stay in the geriatric patients was significantly longer than the non-geriatric group (12.3+/-10.6 vs. 7.2+/-5.9 days, p<0.05). In multiple regression analysis, old age was a significant risk factor for longer hospital stay (p<0.05). CONCLUSIONS: The geriatric patients with bleeding peptic ulcer had longer hospital stay than the non-geriatric patients in our study. The important emerging etiologies such as ulcerogenic drug and associated chronic illness should be checked and treated in these patients.