Effects of different training models and subsequent exercise cessation on adipose tissue and associated variables.

BACKGROUND: The General Adaptation Syndrome and the supercompensation Model are concepts widely applied in exercise science. Considering that fat is essential for tissue and the main energy source during continuous moderate-intensity exercise (MICE), the hypothesis arises that this type of effort may pay off after a detraining period. OBJECTIVE: This study aimed to investigate how different exercise models, followed by a period of detraining, affected adipose tissue cellularity in adult rats. Two specific models were examined: moderate-intensity continuous exercise (MICE) and high-intensity intermittent exercise (HIIT). MATERIALS AND METHODS: This is an experimental study in which rats were allocated into three groups: i) Continuous moderate-intensity exercise (MICE); ii) High-intensity intermittent exercise (HIIT); and iii) Control group (GC). Data were collected in three moments, namely: baseline values (T1), after which the animals exercised on a treadmill for eight weeks (T2) and then were followed up for four weeks after interruption of physical exercise (T3). For statistical analysis, a two-way analysis of variance (ANOVA) was performed, with Tukey's post-hoc for the group (GC, MICE, or HIIT) and Bonferroni's for the moment (T1, T2 and T3). RESULTS: Regarding the periepididymal mass, GC showed an increase of 45% in T3 compared to T2. The HIIT and MICE groups had lower T3 values when compared to the CG. Comparing groups relative to the delta variation between T2 and T3 showed a difference in periepididymal mass (p = 0.012), with HIIT showing lower values than CG (p = 0.009). Analysis of the number of periepididymal adipocytes showed that HIIT (p < 0.001) and GC (p = 0.003) captured smaller numbers of cells than MICE. CONCLUSION: In conclusion, our findings demonstrated positive effects of both interventions (HIIT and MICE) in the control of periepididymal adipose tissue mass of adult rats after 4 weeks of exercise interruption, with less mass gain in HIIT. More adipocytes were observed in MICE compared to HIIT and GC. These results suggest that both exercise models helped control fat accumulation, even after detraining.

Microgravity studies of solidification patterns in model transparent alloys onboard the International Space Station.

We review recent in situ solidification experiments using nonfaceted model transparent alloys in science-in-microgravity facilities onboard the International Space Station (ISS), namely the Transparent Alloys (TA) apparatus and the Directional Solidification Insert of the DEvice for the study of Critical Liquids and Crystallization (DECLIC-DSI). These directional-solidification devices use innovative optical videomicroscopy imaging techniques to observe the spatiotemporal dynamics of solidification patterns in real time in large samples. In contrast to laboratory conditions on ground, microgravity guarantees the absence or a reduction of convective motion in the liquid, thus ensuring a purely diffusion-controlled growth of the crystalline solid(s). This makes it possible to perform a direct theoretical analysis of the formation process of solidification microstructures with comparisons to quantitative numerical simulations. Important questions that concern multiphase growth patterns in eutectic and peritectic alloys on the one hand and single-phased, cellular and dendritic structures on the other hand have been addressed, and unprecedented results have been obtained. Complex self-organizing phenomena during steady-state and transient coupled growth in eutectics and peritectics, interfacial-anisotropy effects in cellular arrays, and promising insights into the columnar-to-equiaxed transition are highlighted.

Patient navigation for colorectal cancer screening in deprived areas: the COLONAV cluster randomized controlled trial.

BACKGROUND: The objective of this study was to assess the effectiveness of a Patient Navigation Intervention targeting deprived patients for Colo-Rectal Cancer (CRC) screening participation. METHODS: A cluster randomized controlled trial was conducted in 5 districts. Peer Lay Patient Navigators were recruited to operate in deprived areas. Eligible participants had to be between 50 and 74 years old, live in these deprived areas and receive an invitation to the nationally organized Colo-Rectal Cancer (CRC) screening during the study period. The theory-driven navigation intervention was deployed for 18 months. A population Health Intervention Research assessment method was used to assess effectiveness and context interaction. The primary criterion was screening participation at 12 months. RESULTS: Twenty-four thousand two hundred eighty-one individuals were included inside 40 clusters. The increase in participation in the intervention group was estimated at 23%, (ORa = 1.23, CI95% [1.07-1.41], p = 0.003). For the subgroup of individuals who participated, the time delay to participating was reduced by 26% (ORa = 0.74, CI95% [0.57-0.96], p = 0.021). Main factors modulating the effect of the intervention were: closeness of navigator profiles to the targeted population, navigators' abilities to adapt their modus operandi, and facilitating attachment structure. CONCLUSION: The ColoNav Intervention succeeded in demonstrating its effectiveness, for CRC screening. Patient Navigation should be disseminate with broader health promotion goals in order to achieve equity in health care. TRIAL REGISTRATION: clinicaltrials.gov NCT02369757 24/02/2015.

[How do patients manage their urostomy in everyday life? A questionnaire survey]. / Comment les patients prennent-ils en charge leur urostomie au quotidien ? Enquête par questionnaires.

INTRODUCTION: The complications of stoma and peristomal are encountered by nearly 80% of patients within two years of surgery. The objective of this study was to evaluate the practical modalities of daily management of stoma and possible skin complications in a series of patients with non-continent urinary stoma. METHODS: Monocentric study by questionnaires including all patients with non-continent urinary stoma between 2007 and 2019 in a French university center. The STOMA-QOL and a self-report questionnaire with 15 specific questions were used. RESULTS: Among the 87 patients included in the analysis whose median age was 71 years, 57.5% used a 2-piece system, 69% used leg or thigh pockets, 74.7% were self-sufficient in emptying their stoma pockets. Autonomy on cutaneous support change was 38%. 62.1% of patients reported a peristomal skin event and 74.7% reported leaking stoma. In multivariate analysis, BMI>30, the presence of leaks and physical activity were significantly associated with the onset of peristomal skin events. CONCLUSION: This study sheds light on the practical modalities of management of urinary stoma and the occurrence of skin complications related to stoma in terms of frequency and predisposing factors. The results obtained are likely to guide practitioners in the information of future operations and in the management of complications of urinary stoma. LEVEL OF EVIDENCE: III.

Green Recovery Policies for the COVID-19 Crisis: Modelling the Impact on the Economy and Greenhouse Gas Emissions.

The COVID-19 pandemic induces the worst economic downturn since the Second World War, requiring governments to design large-scale recovery plans to overcome this crisis. This paper quantitatively assesses the potential of government investments in eco-friendly construction projects to boost the economy and simultaneously realise environmental gains through reduced energy consumption and related greenhouse gas emissions. The analysis uses a Computable General Equilibrium model that examines the macroeconomic impact of the COVID-19 crisis in a small open economy (Belgium). Subsequently, the impact of the proposed policy is assessed through comparative analysis for macroeconomic parameters as well as CO2 equivalent emissions for four scenarios. Our findings demonstrate that the COVID-19 pandemic damages economies considerably, however, the reduction in emissions is less than proportionate. Still, well-designed public policies can reverse this trend, achieving both economic growth and a disproportionally large decrease in emissions. Moreover, the positive effect of such a decoupling policy on GDP is even stronger during the pandemic than compared to the pre-COVID-19 period. This is the result of a targeted, investment-induced green transition towards low energy-intensive economic activities. Finally, this paper describes how the net effect on the government budget is positive through the indirect gains of the economic uptake.

QFib: Fast and Efficient Brain Tractogram Compression.

Diffusion MRI fiber tracking datasets can contain millions of 3D streamlines, and their representation can weight tens of gigabytes of memory. These sets of streamlines are called tractograms and are often used for clinical operations or research. Their size makes them difficult to store, visualize, process or exchange over the network. We propose a new compression algorithm well-suited for tractograms, by taking advantage of the way streamlines are obtained with usual tracking algorithms. Our approach is based on unit vector quantization methods combined with a spatial transformation which results in low compression and decompression times, as well as a high compression ratio. For instance, a 11.5GB tractogram can be compressed to a 1.02GB file and decompressed in 11.3 seconds. Moreover, our method allows for the compression and decompression of individual streamlines, reducing the need for a costly out-of-core algorithm with heavy datasets. Last, we open a way toward on-the-fly compression and decompression for handling larger datasets without needing a load of RAM (i.e. in-core handling), faster network exchanges and faster loading times for visualization or processing.

The validity of Keiser-M3 stationary bicycle with standard ergometer for physiological measurements associated with maximum effort

Abstract Aim: This study aims to investigate the concordance between two cycle ergometers for variables measured in the test of maximum incremental effort. Methods: This correlation study enrolled 15 inactive women (19,2 ± 4,0 years old). At random, the participants performed two maximal effort incremental tests (MEIT), using cycle ergometers (Keiser-M3 and Ergo-167) on different days with a minimum interval of 72 hours. The test had stages of two minutes, and two-step increments were carried out at the end of each stage. Lactate concentration ([LAC]), and rated perceived exertion (RPE) were collected, in addition to monitoring oxygen uptake (VO2) and heart rate (HR). The Paired t-test was carried out to compare physiologic variables, Lin's test was used for correlation, and Bland Altman was used to measuring concordances among variables. Results: The correlations between physiologic parameters were considered strong for HR on the anaerobic threshold (Keiser M3 = 146 ± 14 bpm; Ergo-167 = 149 ± 9 bpm; r = 0.762), greater blood lactate value (Keiser M3 = 9,97 ± 2,51 mmol/L; Ergo-167 = 9.71 ± 2.56 mmol/L; r = 0.820), VO2max (Keiser M3 = 38,37 ± 6,97 mL/kg/min; Ergo-167 = 36.06 ± 8.4 mL/kg/min; r = 0,806) and HRmax (Keiser M3 = 186 ± 53 bpm; Ergo-167 = 188 ± 11 bpm; r = 0.716). Conclusion: The results show the feasibility of using the cycle ergometer Keiser, model M3, to perform the maximal effort incremental test, whereas there was high concordance in the physiologic responses in both ergometers for inactive women.

Captive uterus syndrome: An unrecognized complication of cesarean sections?

Cesarean sections are a common surgical procedure at risk of complications including adhesions and chronic pelvic pain. This case series presents 10 cases of patients presenting with chronic pelvic pain following a cesarean section which were found upon surgical exploration to have developed adhesions between the abdominal wall and the uterus. When they first consulted, patients were evaluated clinically with a questionnaire and physical exam, and with ultrasonography to evaluate pelvic anatomy when necessary. The evaluation was completed with diagnostic laparoscopy which revealed atypical post-cesarean adhesions which were treated by adhesion lysis or hysterectomy. Surgical protocols of the cesarean sections were retrieved and analysed for potential adhesion risk factors. Patients presented with chronic pelvic pain that appeared in the early post-operative period. Physical exam revealed a subinvoluted uterus with a high fixed cervix. Ultrasound examination revealed clues of adhesions manifested by points of traction and an irregular uterine border. No other diagnosis such as endometriosis, pelvic inflammatory disease, ovarian or bowel anomalies were identified during surgery. After laparoscopic adhesion lysis or hysterectomy, all patients who were treated noted a complete resolution of the pain that lasted during a follow-up of at least 5 years. These findings suggest that adhesions that create traction and fix the uterus to the abdominal wall following caesarian section can be the cause of severe chronic pelvic pain. In the presence of such pain, clinicians should suspect the presence of adhesions and investigate and treat patients accordingly.

Newborn follow-up after discharge from the maternity unit: Compliance with national guidelines.

BACKGROUND: In the context of shorter hospital stays in maternity units, in 2014 the French health authorities issued guidelines for newborn follow-up after discharge from maternity units. A medical visit is recommended between the 6th and 10th day of life, as are home visits from midwives. This study was designed to evaluate compliance with these guidelines. METHODS: The study was observational, prospective, multicenter, and was conducted in March and April 2015 in three maternity units in northern France that participate in the Baby Friendly Hospital Initiative (BFHI). Follow-up practices (medical visit between the 6th and 10th day, home visits from a midwife) and demographic, social, and medical data were recorded during the stay in the maternity unit, and through a phone interview 1 month later, in singleton term-born infants. RESULTS: The study population included 108 mother-infant pairs. The recommended medical visit was effectively performed by a physician between the 6th and 10th day of life for 20 newborns (19%) (95% CI: [11; 26]). During the 1st month, at least one home visit from a midwife was recorded for 96 mother-infant pairs (89%). The only factor positively correlated with a medical visit between the 6th and 10th day was the mother's choice, made early during the hospital stay and independently of the real length of stay, for early discharge from the maternity unit. CONCLUSION: Compliance with national guidelines was poor for the recommended medical visit between the 6th and 10th day of life. Information needs to be improved.

Impact of structured programs on breastfeeding initiation rates in preterm neonates in a socioeconomically deprived area in France: A 10-year population-based study.

Structured programs have a positive impact on breastfeeding (BF) but have rarely been evaluated for preterm neonates, frequently combining prematurity and socioeconomic deprivation as risk factors of a low BF rate. We aimed to assess BF initiation rates in very preterm (<33 weeks' gestational age), moderately preterm (33-36 weeks), and term neonates from 2002 to 2011 in a French administrative district characterized by socioeconomic deprivation. Structured activities to promote and support BF have been implemented in this area since 2002; they all started in neonatal units. This retrospective population-based study analyzed 302,102 first health certificates. Overall, the BF initiation rate significantly increased, from 52.9% [95% CI: (52.3; 53.4)] in 2002 to 61.0% [95% CI: (60.4; 61.6)] in 2011. In 2002, BF initiation rates did not differ between groups, but in 2011, it was higher for very preterm than for term and moderately preterm neonates [74.7% (69.7; 79.6)] vs. 60.9% (60.3; 61.5) and 59.9% (57.6; 62.2), respectively, both P<0.001. In 2011, however, no difference was observed between moderately preterm children and term-born children (P=0.40). The 2.2% yearly increase observed in very preterm neonates significantly differed from the 0.9% yearly increase in the French general population (P<0.001). CONCLUSION: Structured BF programs initiated in neonatal care units may have a positive impact on BF initiation rates in very preterm neonates, but not in moderately preterm neonates, whose specific needs should be further evaluated.

Visual biofeedback using transperineal ultrasound in second stage of labor.

OBJECTIVE: To assess the obstetric and psychological effects of visual biofeedback by transperineal ultrasound (TPU) during the second stage of labor. METHODS: This was a prospective, single-center observational study of low-risk nulliparous women with epidural analgesia undergoing vaginal delivery. Visual biofeedback using TPU was provided to 26 women during the second stage of labor. Pushing efficacy was assessed by the change in the angle of progression (AoP) at rest and during pushing efforts, before and after biofeedback. Obstetric outcomes included incidence of perineal tearing, mode of delivery and length of second stage of labor. Psychological outcomes were assessed by self-reported measures obtained during the postnatal hospital stay and included measures of perceived control and maternal satisfaction with childbirth, as well as level of maternal feelings of connectedness with the newborn. Obstetric and psychological results were compared with those of a control group of 69 women who received standard obstetric coaching from midwives. RESULTS: Pushing efficacy increased significantly following visual biofeedback by TPU (P = 0.01), as indicated by a significantly lower delta AoP before (mean, 22.2° (95% CI, 13.9-31.7°)) compared with after (mean, 35.2° (95% CI, 25.9-45.3°)) biofeedback. A significant association was found between visual biofeedback and an intact perineum following delivery (P = 0.03). No significant differences were found between the two groups with regard to mode of delivery or length of the second stage. Feelings of maternal connectedness with the newborn were significantly stronger (P = 0.003) in women who received visual biofeedback than in those who did not. However, perceived control during childbirth and maternal satisfaction with childbirth did not differ significantly between the biofeedback and control groups. CONCLUSIONS: This pilot study suggests that biofeedback using TPU may serve as a complementary tool to coached maternal pushing during the second stage of labor, with obstetric as well as psychological benefits. Further studies are required to confirm our findings and define the optimal duration of the intervention. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

17q21.31 duplication causes prominent tau-related dementia with increased MAPT expression.

To assess the role of rare copy number variations in Alzheimer's disease (AD), we conducted a case-control study using whole-exome sequencing data from 522 early-onset cases and 584 controls. The most recurrent rearrangement was a 17q21.31 microduplication, overlapping the CRHR1, MAPT, STH and KANSL1 genes that was found in four cases, including one de novo rearrangement, and was absent in controls. The increased MAPT gene dosage led to a 1.6-1.9-fold expression of the MAPT messenger RNA. Clinical signs, neuroimaging and cerebrospinal fluid biomarker profiles were consistent with an AD diagnosis in MAPT duplication carriers. However, amyloid positon emission tomography (PET) imaging, performed in three patients, was negative. Analysis of an additional case with neuropathological examination confirmed that the MAPT duplication causes a complex tauopathy, including prominent neurofibrillary tangle pathology in the medial temporal lobe without amyloid-ß deposits. 17q21.31 duplication is the genetic basis of a novel entity marked by prominent tauopathy, leading to early-onset dementia with an AD clinical phenotype. This entity could account for a proportion of probable AD cases with negative amyloid PET imaging recently identified in large clinical series.

ColoNav: patient navigation for colorectal cancer screening in deprived areas - Study protocol.

BACKGROUND: The mass colorectal cancer screening program was implemented in 2008 in France, targeting 16 million French people aged between 50 and 74. The current adhesion is insufficient and the participation rate is even lower among the underserved population, increasing health inequalities within our health care system. Patient Navigation programs have proved their efficiency to promote the access to cancer screening and diagnosis. METHODS/DESIGN: The purpose of the study is to assess the implementation of a patient navigation intervention that has been described in another cultural environment and another health care system. The main objective of the program is to increase the colorectal cancer screening participation rate among the deprived population through the intervention of a navigator to promote the Fecal Occult Blood Test (FOBT) and complementary exams. We performed a multisite cluster randomized controlled trial, with three groups (one experimental group and two control groups) for 18 months. DISCUSSION: The study attempts to give a better understanding of the adhesion barriers to colorectal cancer screening among underserved populations. If this project is cost-effective, it could create a dynamic based on peer approaches that could be developed for other cancer screening programs and other chronic diseases. TRIAL REGISTRATION: NCT02369757.

Olfactory stem cells reveal MOCOS as a new player in autism spectrum disorders.

With an onset under the age of 3 years, autism spectrum disorders (ASDs) are now understood as diseases arising from pre- and/or early postnatal brain developmental anomalies and/or early brain insults. To unveil the molecular mechanisms taking place during the misshaping of the developing brain, we chose to study cells that are representative of the very early stages of ontogenesis, namely stem cells. Here we report on MOlybdenum COfactor Sulfurase (MOCOS), an enzyme involved in purine metabolism, as a newly identified player in ASD. We found in adult nasal olfactory stem cells of 11 adults with ASD that MOCOS is downregulated in most of them when compared with 11 age- and gender-matched control adults without any neuropsychiatric disorders. Genetic approaches using in vivo and in vitro engineered models converge to indicate that altered expression of MOCOS results in neurotransmission and synaptic defects. Furthermore, we found that MOCOS misexpression induces increased oxidative-stress sensitivity. Our results demonstrate that altered MOCOS expression is likely to have an impact on neurodevelopment and neurotransmission, and may explain comorbid conditions, including gastrointestinal disorders. We anticipate our discovery to be a fresh starting point for the study on the roles of MOCOS in brain development and its functional implications in ASD clinical symptoms. Moreover, our study suggests the possible development of new diagnostic tests based on MOCOS expression, and paves the way for drug screening targeting MOCOS and/or the purine metabolism to ultimately develop novel treatments in ASD.

SORL1 rare variants: a major risk factor for familial early-onset Alzheimer's disease.

The SORL1 protein plays a protective role against the secretion of the amyloid ß peptide, a key event in the pathogeny of Alzheimer's disease. We assessed the impact of SORL1 rare variants in early-onset Alzheimer's disease (EOAD) in a case-control setting. We conducted a whole exome analysis among 484 French EOAD patients and 498 ethnically matched controls. After collapsing rare variants (minor allele frequency ≤1%), we detected an enrichment of disruptive and predicted damaging missense SORL1 variants in cases (odds radio (OR)=5.03, 95% confidence interval (CI)=(2.02-14.99), P=7.49.10(-5)). This enrichment was even stronger when restricting the analysis to the 205 cases with a positive family history (OR=8.86, 95% CI=(3.35-27.31), P=3.82.10(-7)). We conclude that predicted damaging rare SORL1 variants are a strong risk factor for EOAD and that the association signal is mainly driven by cases with positive family history.

Pre-employment examination for low back risk in workers exposed to manual handling of loads: French guidelines.

BACKGROUND: Low back pain (LBP) is a major cause of sickness absence and disability in the working population, and the pre-employment examination should insure that worker's state of health is compatible with the requirements of proposed job. This paper summarizes the main recommendations of the good practice guidelines of the French Society of Occupational Medicine for pre-employment examination in workers exposed to manual handling of loads apart from pre-employment test. METHODS: The recommendations were developed according to the Clinical Practice Guidelines proposed by the French National Health Authority and based on a systematic search of the literature 1990-2012 in several databases. The guidelines were written and reviewed by two multidisciplinary committees. On the basis of the level of evidence in the literature, the proposed guidelines are classified as grade A, B, C or expert consensus. RESULTS: The main recommendations of these guidelines are as follows: (1) medical contraindications alone should not exclude employment in a job associated with a low back risk on the basis of a history of "simple" nonspecific LBP; (2) the relevance of examining a previous history of LBP, which is the best predictor of future LBP due to the recurrent nature of LBP. CONCLUSIONS: These guidelines correspond to a constant concern with prevention of occupational risk. Primarily intended for occupational physicians, they are also intended for general practitioners who carry out pre-employment examinations in many countries and are likely to be increasingly faced with this type of situation because of the combination of increasing work constraints with ageing of the workforce.

Pre-return-to-work medical consultation for low back pain workers. Good practice recommendations based on systematic review and expert consensus.

OBJECTIVES: The pre-return-to-work medical consultation during sick leave for low back pain (LBP) aims at assessing the worker's ability to resume working without risk for his/her health, and anticipating any difficulties inherent to returning to work and job retention. This article summarizes the good practices guidelines proposed by the French Society of Occupational Medicine (SFMT) and the French National Health Authority (HAS), and published in October 2013. METHODS: Good practices guidelines developed by a multidisciplinary and independent task force (24 experts) and peer review committee (50 experts) based on a literature review from 1990 to 2012, according to the HAS methodology. RESULTS: According to the labour regulations, workers can request a medical consultation with their occupational physician at any time. The pre-return-to-work consultation precedes the effective return-to-work and can be requested by the employee regardless of their sick leave duration. It must be scheduled early enough to: (i) deliver reassuring information regarding risks to the lower back and managing LBP; (ii) evaluate prognostic factors of chronicity and prolonged disability in relations to LBP and its physical, social and occupational consequences in order to implement the necessary conditions for returning to work; (iii) support and promote staying at work by taking into account all medical, social and occupational aspects of the situation and ensure proper coordination between the different actors. CONCLUSION: A better understanding of the pre-return-to-work consultation would improve collaboration and coordination of actions to facilitate resuming work and job retention for patients with LBP.

De novo deleterious genetic variations target a biological network centered on Aß peptide in early-onset Alzheimer disease.

We hypothesized that de novo variants (DNV) might participate in the genetic determinism of sporadic early-onset Alzheimer disease (EOAD, onset before 65 years). We investigated 14 sporadic EOAD trios first by array-comparative genomic hybridization. Two patients carried a de novo copy number variation (CNV). We then performed whole-exome sequencing in the 12 remaining trios and identified 12 non-synonymous DNVs in six patients. The two de novo CNVs (an amyloid precursor protein (APP) duplication and a BACE2 intronic deletion) and 3/12 non-synonymous DNVs (in PSEN1, VPS35 and MARK4) targeted genes from a biological network centered on the Amyloid beta (Aß) peptide. We showed that this a priori-defined genetic network was significantly enriched in amino acid-altering DNV, compared with the rest of the exome. The causality of the APP de novo duplication (which is the first reported one) was obvious. In addition, we provided evidence of the functional impact of the following three non-synonymous DNVs targeting this network: the novel PSEN1 variant resulted in exon 9 skipping in patient's RNA, leading to a pathogenic missense at exons 8-10 junction; the VPS35 missense variant led to partial loss of retromer function, which may impact neuronal APP trafficking and Aß secretion; and the MARK4 multiple nucleotide variant resulted into increased Tau phosphorylation, which may trigger enhanced Aß-induced toxicity. Despite the difficulty to recruit Alzheimer disease (AD) trios owing to age structures of the pedigrees and the genetic heterogeneity of the disease, this strategy allowed us to highlight the role of de novo pathogenic events, the putative involvement of new genes in AD genetics and the key role of Aß network alteration in AD.

Down-regulation of IL-8 by high-dose vitamin D is specific to hyperinflammatory macrophages and involves mechanisms beyond up-regulation of DUSP1.

BACKGROUND AND PURPOSE: There is current interest in vitamin D as a potential anti-inflammatory treatment for chronic inflammatory lung disease, including cystic fibrosis (CF). Vitamin D transcriptionally up-regulates the anti-inflammatory gene DUSP1, which partly controls production of the inflammatory chemokine IL-8. IL-8 is overabundant in CF airways, potentially due to hyperinflammatory responses of CF macrophages. We tested the ability of vitamin D metabolites to down-regulate IL-8 production in CF macrophages. EXPERIMENTAL APPROACH: CF and healthy monocyte-derived macrophages (MDM) were treated with two vitamin D metabolites, 25-hydroxyvitamin D3 (25OHD3 ) and 1,25-dihydroxyvitamin D3 (1,25(OH)2 D3 ), or paricalcitol, synthetic analogue of 1,25(OH)2 D3 . 25OHD3 was tested at doses of 25-150 nM, whereas 1,25(OH)2 D3 and paricalcitol at doses of up to 100 nM. IL-8 was stimulated by bacterial virulence factors. As potential anti-inflammatory mechanism of vitamin D metabolites, we assessed up-regulation of DUSP1. KEY RESULTS: MDM from patients with CF and some healthy donors showed excessive production of stimulated IL-8, highlighting their hyperinflammatory phenotype. Vitamin D metabolites down-regulated stimulated IL-8 only in those hyperinflammatory MDM, and only when used at high doses (>100 nM for 25OHD3 , or >1 nM for 1,25(OH)2 D3 and paricalcitol). The magnitude of IL-8 down-regulation by vitamin D metabolites or paricalcitol was moderate (∼30% vs. >70% by low-dose dexamethasone). Transcriptional up-regulation of DUSP1 by vitamin D metabolites was seen in all tested MDM, regardless of IL-8 down-regulation. CONCLUSIONS AND IMPLICATIONS: Vitamin D metabolites and their analogues moderately down-regulate IL-8 in hyperinflammatory macrophages, including those from CF. This down-regulation appears to go through DUSP1-independent mechanisms.

Association study of molecular polymorphisms in candidate genes related to stress responses with production and meat quality traits in pigs.

The hypothalamic-pituitary-adrenal (HPA) axis exerts a large range of effects on metabolism, the immune system, inflammatory processes, and brain functions. Together with the sympathetic nervous system, it is also the most important stress-responsive neuroendocrine system. Both systems influence production traits, carcass composition, and meat quality. The HPA axis may be a critical target for genetic selection of more robust animals. Indeed, numerous studies in various species have demonstrated the importance of genetic factors in shaping the individual HPA axis phenotype, and genetic polymorphism can be found at each level of the axis, including hormone production by the adrenal cortices under stimulation by adrenocorticotropic hormone (ACTH), hormone bioavailability, or receptor and postreceptor mechanisms. The aim of the present experiment was to extend these findings to the brain neurochemical systems involved in stress responses. To this end, a number of candidate genes were sequenced for molecular polymorphisms and their association was studied with stress neuroendocrine and production traits in a genetically diverse population consisting of 100 female pigs from an advanced intercross (F10-F12) between 2 highly divergent breeds, Large White (LW) and Meishan (MS). The LW breed has a high production potential for lean meat and a low HPA axis activity, and the MS breed has low growth rate, fat carcasses-but large litters of highly viable piglets-and a high HPA axis activity. Candidate genes were chosen in the catecholaminergic and serotonergic pathways, in the pituitary control of cortisol production, among genes previously demonstrated to be differentially expressed in ACTH-stimulated adrenal glands from LW and MS pigs, and in cortisol receptors. Sixty new polymorphisms were found. The association study with carcass and meat quality traits and with endocrine traits showed a number of significant results, such as monoamine oxidase (MAOA) polymorphisms with growth rate (P = 0.01); lean content and intramuscular fat (P < 0.01), which are the most important traits for carcass value; dopamine receptor D3 (DRD3) with carcass composition (P < 0.05); and vasopressin receptor 1B (AVPR1B) with meat quality traits (P ≤ 0.05). The effect of these polymorphisms on neuroendocrine parameters (eg DRD3 and HPA axis or AVPR1B and catecholamines) indicates information regarding their biological mechanism of action.