Activated platelets promote increased monocyte expression of CXCR5 through prostaglandin E2-related mechanisms and enhance the anti-inflammatory effects of CXCL13

Background

We have previously shown that the homeostatic chemokine CXCL13 is up-regulated in monocytes in atherosclerosis, mediating anti-apoptotic and anti-inflammatory effects.

Objective

To investigate the regulation of CXCL13s receptor, CXCR5.

Methods/patients

In vitro studies in THP-1 and primary monocytes and studies of CXCR5 expression in thrombus material obtained at the site of plaque rupture during myocardial infarction (MI).

Results

Our major findings were: (i) toll-like receptor agonists and particularly β-adrenergic receptor activation and releasate from thrombin-activated platelets increased CXCR5 mRNA levels in monocytes. (ii) The platelet-mediated induction of CXCR5 involved prostaglandin E₂/cAMP/protein kinase A-dependent as well as RANTES-dependent pathways with NFκB activation as a potential common down-stream mediator. (iii) Releasate from thrombin-activated platelets augmented the anti-inflammatory effects of CXCL13 in monocytes at least partly by enhancing the effects of CXCL13 on CXCR5 expression. (iv) We found strong immunostaining of CXCR5 in thrombus material obtained at the site of plaque rupture in patients with ST elevation MI (STEMI) and in unstable carotid lesions, co-localized with platelets.

Conclusion

Our findings suggest that platelet-mediated signaling through CXCR5 may be active in vivo during plaque destabilization, potentially representing a counteracting mechanism to inflammation.     

Handheld ECG in analysis of arrhythmia and heart rate variability in children with Fontan circulation

Background

Our aim was to evaluate the intermittent use of a handheld ECG system for detecting silent arrhythmias and cardiac autonomic dysfunction in children with univentricular hearts.

Methods

Twenty-seven patients performed intermittent ECG recordings with handheld devices during a 14-day period. A manual arrhythmia analysis was performed. We analyzed heart rate variability (HRV) using scatter plots of all interbeat intervals (Poincaré plots) from the total observation period. Reference values of HRV indices were determined from Holter-ECGs in 41 healthy children.

Results

One asymptomatic patient had frequent ventricular extra systoles. Another patient had episodes with supraventricular tachycardia (with concomitant palpitations). Seven patients showed reduced HRV.

Conclusions

Asymptomatic arrhythmia was detected in one patient. The proposed method for pooling of intermittent recordings from handheld or similar devices may be used for detection of arrhythmias as well as for cardiac autonomic dysfunction.     

Engaging a state medical society in oral health: a community action report

Increasingly, the medical community is recognizing how oral health relates to overall health and engaging in oral health promotion. In 2012, the Massachusetts Medical Society set out to explore how to prioritize oral health as a part of its public health agenda. It began with an Oral Health Forum, which evolved into a Committee on Oral Health. This committee is the first of its kind in a state medical society and is comprised of a diverse group of medical and dental professionals. In this article, we review the process by which the committee was established, report on projects, and reflect on lessons learned.     

The PML domain of PML–RARα blocks senescence to promote leukemia

In most acute promyelocytic leukemia (APL) cases, translocons produce a promyelocytic leukemia protein–retinoic acid receptor α (PML–RARα) fusion gene. Although expression of the human PML fusion in mice promotes leukemia, its efficiency is rather low. Unexpectedly, we find that simply replacing the human PML fusion with its mouse counterpart results in a murine PML–RARα (mPR) hybrid protein that is transformed into a significantly more leukemogenic oncoprotein. Using this more potent isoform, we show that mPR promotes immortalization by preventing cellular senescence, impeding up-regulation of both the p21 and p19^ARF cell-cycle regulators. This induction coincides with a loss of the cancer-associated ATRX/Daxx–histone H3.3 predisposition complex and suggests inhibition of senescence as a targetable mechanism in APL therapy.Acute promyelocytic leukemia (APL) is characterized by chromosomal translocations involving retinoic acid receptor alpha (RARα) with a limited number of translocation partners. A common feature of APL-promoting fusion proteins is their ability to self-associate. Indeed, previous studies have shown that fusion of RARα with self-associating domains is sufficient to render RARα leukemogenic (1). In APL patients, the predominant leukemogenic protein found in 95–99% of cases is the result of the fusion of promyelocytic leukemia protein (PML) with RARα (human PML–RARα; hPR) (2, 3). RARα and PML are regulatory proteins implicated in multiple aspects of differentiation and development (4) and apoptosis and cellular senescence (5, 6), respectively. Despite speculation, the relevance of senescence in APL is not fully understood (7, 8).Current mouse models recapitulate many key features of the human disease, including a malignant promyelocytic phenotype and sensitivity to all-trans retinoic acid (ATRA), but suffer from incomplete penetrance and long latency until disease presentation (1, 9, 10). We reasoned that the relatively low leukemogenic activity of hPR in mice might be due to modest sequence identity between human and mouse PML (PML: 63% identity; RARα: 98% identity). Consistent with this notion, we have designed an “experimental oncoprotein” corresponding to the fusion of mouse PML with RARα (mPR), which produced myelocytic leukemia similar to hPR-induced murine APL (10) but with higher penetrance and shorter latency periods. Notably, expression of mPR disrupted PML nuclear bodies (PML-NBs), phenocopying hPR-induced APL (11, 12). We show here that senescence-related up-regulation of p21 and p19 is completely lost in primary murine bone marrow cells upon expression of mPR. Furthermore, we find that the assembly of the death domain associated protein (Daxx)–alpha thalassemia/mental retardation syndrome X-linked (ATRX) complex at PML-NBs is disrupted by mPR expression, implicating this PML–ATRX–Daxx (PAX) complex in cellular senescence and tumor suppressor activity for PML (13). This study provides experimental evidence for the relevance of PML-NB disruption in APL genesis.     

Textural features of hypoxia PET predict survival in head and neck cancer during chemoradiotherapy

European Journal of Nuclear Medicine and Molecular Imaging - The aim of this study was to investigate whether textural features of tumour hypoxia, assessed with serial [18F]fluoromisonidazole...     

Colorectal Cancer Screening Among American Indians in a Pacific Northwest Tribe: Cowlitz Tribal BRFSS Project, 2009–2010

Objectives

Colorectal cancer (CRC) screening is low among American Indians (AIs). We describe the demographics, health status, prevalence of modifiable CRC risk factors, and use of CRC screening modalities in a Pacific Northwest AI tribe.

Methods

We conducted a survey among Cowlitz tribal members using a Behavioral Risk Factor Surveillance System (BRFSS) questionnaire. We analyzed demographic, health status, behavioral risk factor, and CRC screening variables. Using the Washington State 2010 BRFSS, we compared tribal members with non-Hispanic white (NHW) people. We used logistic regression to examine factors associated with CRC screening for tribal members.

Results

A greater proportion of tribal members than NHW people reported living below the federal poverty level (12% vs. 7%, p=0.013). A greater proportion of tribal members than NHW people aged ≥50 years had poor self-reported health (27% vs. 16%, p=0.006) and were without health insurance (12% vs. 6%, p=0.004). A greater proportion of tribal members than NHW people had a fecal occult blood test within the past year (20% vs. 13%, p=0.006). Being 60–69 years of age (odds ratio [OR] = 2.6, 95% confidence interval [CI] 1.4, 4.9), ≥70 years of age (OR=2.2, 95% CI 1.1, 4.5), and having a personal health-care provider (OR=3.7, 95% CI 1.4, 9.6) were associated with increased screening adherence in tribal members.

Conclusion

Data from the Cowlitz Tribal BRFSS demonstrate that members are receiving CRC screening in the same proportions as NHW people despite lower sociodemographic and health status indicators among members. Unique characteristics of the tribe likely contribute to this finding.Cancer is the second leading cause of death among American Indian/Alaska Native (AI/AN) people; cardiovascular disease is the leading cause of death.¹ Overall, colorectal cancer (CRC) is the third most common cancer among AI/ANs behind prostate and lung cancer for men and breast and lung cancer for women.^2,3 In the most recent “Annual Report to the Nation on the Status of Cancer,” the incidence of CRC decreased among men and women in all racial/ethnic groups except AI/ANs.⁴Based on the Surveillance, Epidemiology, and End Results (SEER) program, the incidence of CRC is lower for AI/AN people than for those in other racial/ethnic groups.⁵ However, regional diversity in CRC incidence and racial misclassification can bias these nationwide estimates.^3,6,7 One strategy to overcome these biases is to link Indian Health Service (IHS) records with state cancer registries. Using the linkage strategy, researchers in the Pacific Northwest have found that the incidence of CRC is greater, and “one- and five-year CRC-related survival is lower among Pacific Northwest AI/ANs than among non-Hispanic white (NHW) people”⁷ (Unpublished thesis. Peterson PS. Colorectal cancer survival among American Indian and Alaska Native people in the Pacific Northwest. Oregon Health and Science University, 2011). Thus, investigations are needed to understand CRC screening patterns in this region, as well as barriers to screening that are unique to these tribal communities.Self-reported history of CRC screening is lower among AI/ANs than among NHW people.⁸ IHS Government Performance and Results Act (GPRA) data indicate improvement in CRC screening adherence among AI/ANs nationwide; however, these numbers are significantly lower than the Healthy People 2020 target of 70.5%.^9,10 According to GPRA 2010 data, the percentage of CRC screening adherence among IHS tribal users in the Pacific Northwest aged ≥50 years was 38%.¹⁰CRC screening behaviors vary regionally and are influenced by a complex set of sociodemographic, health-care-access, and cultural factors.^11–13 Among Northern Plain and Southwest AIs, Perdue et al. found an inverse association between cultural identity measures and screening by endoscopy or colonoscopy, but no trend with fecal occult blood tests (FOBTs).¹¹ In a study conducted in Alaska and the Southwest, researchers demonstrated that age >60 years, state of residence, urban residence, higher education, family history of CRC, former smoking, multiple medical conditions, English language spoken at home, and higher income were factors associated with an increase in age-appropriate CRC screening.¹² In another study conducted among AIs in North Carolina, self-rated health status, nonsmoking, and physical activity were associated with CRC screening.¹³While progress has been made, disparities persist in CRC screening, incidence of CRC cases, and CRC-related mortality in AI/ANs nationwide, including in the Pacific Northwest.^2–10 To date, no published research has addressed factors associated with CRC screening in Pacific Northwest tribes. The Cowlitz Tribal Behavioral Risk Factor Surveillance System (BRFSS) Project 2009–2010 provided a unique opportunity to investigate the health information of a tribe that has not been previously studied and to gain a better understanding of factors associated with cancer screening behaviors in this at-risk population.     

Screening for autism spectrum disorders: state of the art in Europe

A large number of studies have reported on the validity of autism spectrum disorder (ASD) screening procedures. An overall understanding of these studies’ findings cannot be based solely on the level of internal validity of each, since screening instruments might perform differently according to certain factors in different settings. Europe has led the field with the development of the first screening tool and first prospective screening study of autism. This paper seeks to provide an overview of ASD screening studies and ongoing programmes across Europe, and identify variables that have influenced the outcomes of such studies. Results show that, to date, over 70,000 children have been screened in Europe using 18 different screening procedures. Differences among findings across studies have enabled us to identify ten factors that may influence screening results. Although it is impossible to draw firm conclusions as to which screening procedure is most effective, this analysis might facilitate the choice of a screening method that best fits a specific scenario, and this, in turn, may eventually improve early ASD detection procedures.     

Human and monkey infant attention to dynamic social and nonsocial stimuli

The present study explored behavioral norms for infant social attention in typically developing human and nonhuman primate infants. We examined the normative development of attention to dynamic social and nonsocial stimuli longitudinally in macaques (Macaca mulatta) at 1, 3, and 5 months of age (N = 75) and humans at 2, 4, 6, 8, and 13 months of age (N = 69) using eye tracking. All infants viewed concurrently played silent videos—one social video and one nonsocial video. Both macaque and human infants were faster to look to the social than the nonsocial stimulus, and both species grew faster to orient to the social stimulus with age. Further, macaque infants’ social attention increased linearly from 1 to 5 months. In contrast, human infants displayed a nonlinear pattern of social interest, with initially greater attention to the social stimulus, followed by a period of greater interest in the nonsocial stimulus, and then a rise in social interest from 6 to 13 months. Overall, human infants looked longer than macaque infants, suggesting humans have more sustained attention in the first year of life. These findings highlight potential species similarities and differences, and reflect a first step in establishing baseline patterns of early social attention development.