Zelluläre und molekulare Mechanismen der Entzündungsauflösung im postoperativen Ileus

Nach postoperativen Eingriffen kommt es regelhaft zu einer Darmmotilitätsstörung, dem sogenannte postoperativen Ileus (POI). Die Dauer und Intensität des POI werden von einer komplexen Entzündungsreaktion in der Muscularis externa (ME) bestimmt. Nach Aktivierung residenter Makrophagen kommt es zur Infiltration weiterer Leukozyten, die auch noch Tage nach funktioneller Normalisierung der postoperativen Darmmotilität in der ME zu finden sind. Dies lässt eine entscheidende Rolle dieser Zellen in der Entzündungsauflösung des POI. Im ersten Projekt wurden in einem standardisierten Mausmodell des POI die an der Auflösung beteiligten Leukozyten und deren regulatorische Funktion untersucht. Hierbei zeigte sich die Präsenz sogenannter anti-inflammatorischer M2 Makrophagen in der postoperativen ME. Die M2-Polarisierung erfolgte dabei in Abhängigkeit von Interleukin-10 (IL-10). Mit Hilfe eines Makrophagen/Monozyten-spezifischen IL-10 Knockoutmodells, konnten wir neben den residenten Gewebsmakrophagen in die ME infiltrierende Blutmonozyten als Hauptquelle für IL-10 identifizieren. Weitere Versuche zeigten, dass eine ubiquitäre sowie Monozyten/Makrophagen-spezifische IL-10- Defizienz mit einer überschießenden Immunantwort in der ME während der frühen postoperativen Phase einhergeht. In der klinisch relevanten Spätphase führte dies jedoch zu einer beschleunigten Auflösung des POI, welche durch eine Reduktion infiltrierter Neutrophiler Granulozyten begründet ist. Das zweite Projekt beschäftigte sich mit der Bedeutung entzündungsauflösender Lipidmediatoren im POI. Diese werden aus mehrfach ungesättigten Fettsäuren (PUFA) gebildet. Schlüsselenzyme in der Biosynthese dieser Mediatoren sind Lipoxygenasen (LOX), insbesondere die 12/15-LOX. Unsere Studien zeigen, dass es nach einer intestinalen Manipulation zu einer erhöhten Expression und Aktivität der 12/15-LOX innerhalb der ME kommt. Diese wird dabei primär von infiltrierten Monozyten/Makrophagen exprimiert. Massenspektrometrische Analysen der postoperativen ME zeigten hohe Konzentrationen der Endprodukte der 12/15-LOX- Metabolisierung aus der PUFA Docosahexanensäure (DHA). 12/15-LOX defiziente Mäusen (ALOX15) zeigten ein vermehrtes leukozytäres Infiltrat in der ME, was eine entzündungsauflösende Funktion der 12/15-LOX entstammenden Lipidmediatoren bestätigt. Die Supplementierung einer DHA-angereicherten Lipidemulsion führte zu einer Verbesserung der postoperativen Entzündung und des POI. Dieser Effekte wurde jedoch nicht unter 12/15-LOX Defizienz beobachtet. In weiteren Studien stellte sich Protektin DX als Schlüsselmediator in der 12/15-LOX vermittelten Immunmodulation heraus. So wirkte sich dessen perioperative Supplementierung protektiv auf den Entzündungsverlauf und den POI aus. Aus dieser Studie ergeben sich neue vielsprechende Ansätze zur Therapie des POI durch natürlich vorkommende hochpotente, immunmodulierende Lipidmediatoren

AIM2 inflammasome-derived IL-1 beta induces postoperative ileus in mice

Postoperative ileus (POI) is an intestinal dysmotility frequently occurring after abdominal surgery. An orchestrated neuroimmune response within the muscularis externa (ME) involves activation of resident macrophages, enteric glia and infiltration of blood-derived leukocytes. Interleukin-1 receptor type-I (IL1R1) signalling on enteric glia has been shown to be involved in POI development. Herein we investigated the distinct role of the IL1R1 ligands interleukin (IL)-1 alpha and IL-1 beta and focused on the mechanism of IL-1 beta production. IL-1 alpha and IL-1 beta deficient mice were protected from POI. Bone-marrow transplantation studies indicated that IL-1 alpha originated from radio-resistant cells while IL-1 beta was released from the radio-sensitive infiltrating leukocytes. Mouse strains deficient in inflammasome formation identified the absent in melanoma 2 (AIM2) inflammasome to be crucial for IL-1 beta production in POI. Mechanistically, antibiotic-treated mice revealed a prominent role of the microbiome in IL-1 beta production. Our study provides new insights into distinct roles of IL-1 alpha and IL-1 beta signalling during POI. While IL-1 alpha release is most likely an immediate passive response to the surgical trauma, IL-1 beta production depends on AIM2 inflammasome formation and the microbiome. Selective interaction in this pathway might be a promising target to prevent POI in surgical patients

Readiness to Change as a Mediator of the Effect of a Brief Motivational Intervention on Posttreatment Alcohol-Related Consequences of Injured Emergency Department Hazardous Drinkers

Evaluated impact of motivational enhancement (ME) of substance abuse treatment compared to relaxation training (RT) on sex without condoms (overall and involving substance use) 3 months following release among incarcerated adolescents. This randomized clinical trial involved 114 incarcerated adolescents from the Northeast. Regression analyses determined if treatment condition, baseline levels of depressive symptoms, and their interaction predicted condom non-use 3 months post-release, controlling for baseline condom non-use. Among those who reported fewer baseline depressive symptoms, those in ME condition reported significantly less condom non-use, in general and involving marijuana use compared with those in RT condition. Periods of incarceration represent opportunities to help juvenile detainees reduce behaviors that impact their health and the health of those with whom they interact in the community

Participation in the Georgia Food for Health program and cardiovascular disease risk factors: A longitudinal observational study

Abstract Objective To assess the relationship between program attendance in a produce prescription program and changes in cardiovascular risk factors. Design The Georgia Food for Health (GF4H) program provided 6 monthly nutrition education sessions, 6 weekly cooking classes, and weekly produce vouchers. Participants became program graduates attending at least 4 of the 6 of both the weekly cooking classes and monthly education sessions. We used a longitudinal, single-arm approach to estimate the association between the number of monthly program visits attended and changes in health indicators. Setting GF4H was implemented in partnership with a large safety-net health system in Atlanta, GA. Participants 331 participants living with or at-risk of chronic disease and food insecurity were recruited from primary care clinics. Over three years, 282 participants graduated from the program. Results After adjusting for program site, year, participant sex, age, race & ethnicity, SNAP participation, and household size, we estimated that each additional program visit attended beyond 4 visits was associated with a 0.06 kg/m2 reduction in BMI (95% CI: -0.12, -0.01; p=0.02), a 0.37 inch reduction in waist circumference (95% CI: -0.48, -0.27; p<0.001), a 1.01 mmHg reduction in systolic blood pressure (95% CI: -1.45, -0.57; p<0.001), and a 0.43 mmHg reduction in diastolic blood pressure (95% CI: -0.69, -0.17; p=0.001). Conclusions Each additional cooking and nutrition education visit attended beyond the graduation threshold was associated with modest but significant improvements in cardiovascular disease risk factors, suggesting that increased engagement in educational components of a produce prescription program improves health outcomes

The quality of different types of child care at 10 and 18 months. A comparison between types and factors related to quality.

The quality of care offered in four different types of non-parental child care to 307 infants at 10 months old and 331 infants at 18 months old was compared and factors associated with higher quality were identified. Observed quality was lowest in nurseries at each age point, except that at 18 months they offered more learning activities. There were few differences in the observed quality of care by child-minders, grandparents and nannies, although grandparents had somewhat lower safety and health scores and offered children fewer activities. Cost was largely unrelated to quality of care except in child-minding, where higher cost was associated with higher quality. Observed ratios of children to adults had a significant impact on quality of nursery care; the more infants or toddlers each adult had to care for, the lower the quality of the care she gave them. Mothers' overall satisfaction with their child's care was positively associated with its quality for home-based care but not for nursery settings

Myogenic progenitors contribute to open but not closed fracture repair

<p>Abstract</p> <p>Background</p> <p>Bone repair is dependent on the presence of osteocompetent progenitors that are able to differentiate and generate new bone. Muscle is found in close association with orthopaedic injury, however its capacity to make a cellular contribution to bone repair remains ambiguous. We hypothesized that myogenic cells of the MyoD-lineage are able to contribute to bone repair.</p> <p>Methods</p> <p>We employed a <it>MyoD</it>-Cre⁺:Z/AP⁺conditional reporter mouse in which all cells of the MyoD-lineage are permanently labeled with a <it>human alkaline phosphatase (hAP) </it>reporter. We tracked the contribution of MyoD-lineage cells in mouse models of tibial bone healing.</p> <p>Results</p> <p>In the absence of musculoskeletal trauma, MyoD-expressing cells are limited to skeletal muscle and the presence of reporter-positive cells in non-muscle tissues is negligible. In a closed tibial fracture model, there was no significant contribution of hAP⁺cells to the healing callus. In contrast, open tibial fractures featuring periosteal stripping and muscle fenestration had up to 50% of hAP⁺cells detected in the open fracture callus. At early stages of repair, many hAP⁺cells exhibited a chondrocyte morphology, with lesser numbers of osteoblast-like hAP⁺cells present at the later stages. Serial sections stained for hAP and type II and type I collagen showed that MyoD-lineage cells were surrounded by cartilaginous or bony matrix, suggestive of a functional role in the repair process. To exclude the prospect that osteoprogenitors spontaneously express MyoD during bone repair, we created a metaphyseal drill hole defect in the tibia. No hAP⁺staining was observed in this model suggesting that the expression of MyoD is not a normal event for endogenous osteoprogenitors.</p> <p>Conclusions</p> <p>These data document for the first time that muscle cells can play a significant secondary role in bone repair and this knowledge may lead to important translational applications in orthopaedic surgery.</p> <p>Please see related article: <url>http://www.biomedcentral.com/1741-7015/9/136</url></p

A global collaboration to study intimate partner violence-related head trauma: The ENIGMA consortium IPV working group

Intimate partner violence includes psychological aggression, physical violence, sexual violence, and stalking from a current or former intimate partner. Past research suggests that exposure to intimate partner violence can impact cognitive and psychological functioning, as well as neurological outcomes. These seem to be compounded in those who suffer a brain injury as a result of trauma to the head, neck or body due to physical and/or sexual violence. However, our understanding of the neurobehavioral and neurobiological effects of head trauma in this population is limited due to factors including difficulty in accessing/recruiting participants, heterogeneity of samples, and premorbid and comorbid factors that impact outcomes. Thus, the goal of the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium Intimate Partner Violence Working Group is to develop a global collaboration that includes researchers, clinicians, and other key community stakeholders. Participation in the working group can include collecting harmonized data, providing data for meta- and mega-analysis across sites, or stakeholder insight on key clinical research questions, promoting safety, participant recruitment and referral to support services. Further, to facilitate the mega-analysis of data across sites within the working group, we provide suggestions for behavioral surveys, cognitive tests, neuroimaging parameters, and genetics that could be used by investigators in the early stages of study design. We anticipate that the harmonization of measures across sites within the working group prior to data collection could increase the statistical power in characterizing how intimate partner violence-related head trauma impacts long-term physical, cognitive, and psychological health

Distribution and seasonality of rhinovirus and other respiratory viruses in a cross-section of asthmatic children in Trinidad, West Indies

<p>Abstract</p> <p>Background</p> <p>Childhood asthma in the Caribbean is advancing in prevalence and morbidity. Though viral respiratory tract infections are reported triggers for exacerbations, information on these infections with asthma is sparse in Caribbean territories. We examined the distribution of respiratory viruses and their association with seasons in acute and stable asthmatic children in Trinidad.</p> <p>Methods</p> <p>In a cross-sectional study of 70 wheezing children attending the emergency department for nebulisation and 80 stable control subjects (2 to 16 yr of age) in the asthma clinic, nasal specimens were collected during the dry (<it>n </it>= 38, January to May) and rainy (<it>n </it>= 112, June to December) seasons. A multitarget, sensitive, specific high-throughput Respiratory MultiCode assay tested for respiratory-virus sequences for eight distinct groups: human rhinovirus, respiratory syncytial virus, parainfluenza virus, influenza virus, metapneumovirus, adenovirus, coronavirus, and enterovirus.</p> <p>Results</p> <p>Wheezing children had a higher [χ²= 5.561, <it>p </it>= 0.018] prevalence of respiratory viruses compared with stabilized asthmatics (34.3% (24) versus (vs.) 17.5% (14)). Acute asthmatics were thrice as likely to be infected with a respiratory virus (OR = 2.5, 95% CI = 1.2 – 5.3). The predominant pathogens detected in acute versus stable asthmatics were the rhinovirus (RV) (<it>n </it>= 18, 25.7% vs. <it>n </it>= 7, 8.8%; <it>p </it>= 0.005), respiratory syncytial virus B (RSV B) (<it>n </it>= 2, 2.9% vs. <it>n </it>= 4, 5.0%), and enterovirus (<it>n </it>= 1, 1.4% vs. <it>n </it>= 2, 2.5%). Strong odds for rhinoviral infection were observed among nebulised children compared with stable asthmatics (<it>p </it>= 0.005, OR = 3.6, 95% CI = 1.4 – 9.3,). RV was prevalent throughout the year (Dry, <it>n </it>= 6, 15.8%; Rainy, <it>n </it>= 19, 17.0%) and without seasonal association [χ²= 0.028, <it>p </it>= 0.867]. However it was the most frequently detected virus [Dry = 6/10, (60.0%); Rainy = 19/28, (67.9%)] in both seasons.</p> <p>Conclusion</p> <p>Emergent wheezing illnesses during childhood can be linked to infection with rhinovirus in Trinidad's tropical environment. Viral-induced exacerbations of asthma are independent of seasons in this tropical climate. Further clinical and virology investigations are recommended on the role of infections with the rhinovirus in Caribbean childhood wheeze.</p

Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value &lt; 1 × 10-5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p &lt; 1 × 10-5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10-10, odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis