Effect of cholesterol re-supplementation and atorvastatin on plaque composition in the thoracic aorta of New Zealand white rabbits.

BACKGROUND: Effects of re-supplementation of a cholesterol-enriched diet (CEDrs) on size, cholesterol content and morphology of already existing plaques are not known to date. METHODS: A group of rabbits received standard chow (SC) for 6 weeks ("negative control"; for plasma lipid measurements only). Group I-IV received 2% CED (induction) for 6 weeks; thereafter, groups II-IV have been fed a SC (= cholesterol withdrawal) for 68 weeks. Afterwards, feeding of groups II-IV was continued as follows: Group II - 10 weeks SC, group III - 4 weeks 0.5% CED (~re-supplementation), afterwards 6 weeks SC (~withdrawal again); group IV - 4 weeks 0.5% CED (re-supplementation) + atorvastatin (2.5 mg/kg body weight/day), afterwards 6 weeks SC (~withdrawal again) + atorvastatin. Plasma lipids, but also plaque size, morphology and cholesterol contents of thoracic aortas were quantified. RESULTS: After CEDrs, plasma cholesterol levels were increased. However, after withdrawal of CEDrs, plasma cholesterol levels decreased, whereas the cholesterol content of the thoracic aorta was increased in comparison with the group without CEDrs. Plaque size remained unaffected. Atorvastatin application did not change plasma cholesterol level, cholesterol content of the thoracic aorta and plaque size in comparison with the group without drug treatment. However, atorvastatin treatment increased the density of macrophages (MΦ) compared with the group without treatment, with a significant correlation between densities of MΦ (Mac-1+) and apoptotic (TUNEL+; TP53+), antigen-presenting (HLA-DR+) or oxidatively stressed (SOD2+) cells. CONCLUSIONS: In rabbits with already existing plaques, CEDrs affects plaque morphology and cellular composition, but not plaque size. Despite missing effects on plasma cholesterol levels, cholesterol content of the thoracic aorta and size of already existing atherosclerotic plaques, atorvastatin treatment transforms the already existing lesions to a more active form, which may accelerate the remodelling to a more stable plaque.

Prednisolone induces osteoporosis-like phenotype in regenerating zebrafish scales.

UNLABELLED: We demonstrate that glucocorticoids induce an osteoporotic phenotype in regenerating scales of zebrafish. Exposure to prednisolone results in altered mineral content, enhanced matrix breakdown, and an osteoporotic gene-expression profile in osteoblasts and osteoclasts. This highlights that the zebrafish scale provides a powerful tool for preclinical osteoporosis research. INTRODUCTION: This study aims to evaluate whether glucocorticoid (prednisolone) treatment of zebrafish induces an osteoporotic phenotype in regenerating scales. Scales, a readily accessible dermal bone tissue, may provide a tool to study direct osteogenesis and its disturbance by glucocorticoids. METHODS: In adult zebrafish, treated with 25 µM prednisolone phosphate via the water, scales were removed and allowed to regenerate. During regeneration scale morphology and the molar calcium/phosphorus ratio in scales were assessed and osteoblast and osteoclast activities were monitored by time profiling of cell-specific genes; mineralization was visualized by Von Kossa staining, osteoclast activity by tartrate-resistant acid phosphatase histochemistry. RESULTS: Prednisolone (compared to controls) enhances osteoclast activity and matrix resorption and slows down the build up of the calcium/phosphorus molar ratio indicative of altered crystal maturation. Prednisolone treatment further impedes regeneration through a shift in the time profiles of osteoblast and osteoclast genes that commensurates with an osteoporosis-like imbalance in bone formation. CONCLUSIONS: A glucocorticoid-induced osteoporosis phenotype as seen in mammals was induced in regenerating scalar bone of zebrafish treated with prednisolone. An unsurpassed convenience and low cost then make the zebrafish scale a superior model for preclinical studies in osteoporosis research.

On the concept of individual in ecology and evolution.

Part of the art of theory building is to construct effective basic concepts, with a large reach and yet powerful as tools for getting at conclusions. The most basic concept of population biology is that of individual. An appropriately reengineered form of this concept has become the basis for the theories of structured populations and adaptive dynamics. By appropriately delimiting individuals, followed by defining their states as well as their environment, it become possible to construct the general population equations that were introduced and studied by Odo Diekmann and his collaborators. In this essay I argue for taking the properties that led to these successes as the defining characteristics of the concept of individual, delegating the properties classically invoked by philosophers to the secondary role of possible empirical indicators for the presence of those characteristics. The essay starts with putting in place as rule for effective concept engineering that one should go for relations that can be used as basis for deductive structure building rather than for perceived ontological essence. By analysing how we want to use it in the mathematical arguments I then build up a concept of individual, first for use in population dynamical considerations and then for use in evolutionary ones. These two concepts do not coincide, and neither do they on all occasions agree with common intuition-based usage.

Daphnias: from the individual based model to the large population equation.

The class of deterministic 'Daphnia' models treated by Diekmann et al. (J Math Biol 61:277-318, 2010) has a long history going back to Nisbet and Gurney (Theor Pop Biol 23:114-135, 1983) and Diekmann et al. (Nieuw Archief voor Wiskunde 4:82-109, 1984). In this note, we formulate the individual based models (IBM) supposedly underlying those deterministic models. The models treat the interaction between a general size-structured consumer population ('Daphnia') and an unstructured resource ('algae'). The discrete, size and age-structured Daphnia population changes through births and deaths of its individuals and through their aging and growth. The birth and death rates depend on the sizes of the individuals and on the concentration of the algae. The latter is supposed to be a continuous variable with a deterministic dynamics that depends on the Daphnia population. In this model setting we prove that when the Daphnia population is large, the stochastic differential equation describing the IBM can be approximated by the delay equation featured in (Diekmann et al., loc. cit.).

Dosimetric consequences of pancreatic tumor motion when predetermined treatment margins are employed during intensity-modulated radiation therapy.

PURPOSE: To quantify the dosimetric consequences of pancreatic tumor motion on the pancreatic intensity-modulated radiation therapy (IMRT) plans. METHODS: Dose map of IMRT plans for 5 patients with pancreatic cancer were measured using a 2D diode array placed on a computer-controlled platform to simulate 2D pancreatic tumor motion. Dosimetric analysis was then performed to obtain IMRT quality assurance (QA) passing rates. The convolution method, which used a motion kernel to simulate 2D pancreatic motion, was also applied to the treatment and phantom verification plans for a wide range of magnitudes of motion (0.8-2.0 cm). The resulting motion-convolved verification dose maps (VDMs) were compared with the dynamic measurements to evaluate IMRT QA passing rates as well as the dose-volume histogram, the V95% of the planning target volume (PTV) and V98% of the clinical target volume (CTV). RESULTS: While CTV coverage was maintained when the simulated pancreatic tumor drifted inside the PTV with magnitudes of 1.0 cm and 1.5 cm, the V95% of the PTV was reduced by 10% and 17%, respectively. We also found that the differences between the measurements and the static VDMs increased proportional to the amplitude of motion, while the agreement between the measurements and the motion-convolved VDMs was excellent for any magnitude of motion. CONCLUSIONS: When the 4D technique is not available, predetermined margins must be used carefully to avoid possible under-dose to the target. Additionally, the phantom results show that the kernel convolution method provides an accurate evaluation of the dosimetric impact due to tumor motion and it should be employed in the planning process.

[Information tool about labor and delivery designed by Delphi method]. / Élaboration d'un outil d'information sur l'accouchement : consensus par la méthode Delphi.

OBJECTIVE: The integration of couples in decision making in obstetrics is necessary to improve the experience of giving birth. The objective of this work is to elaborate a new tool to provide information to health professionals. METHODS: A 5-round Delphi method was used to define the information points. The 20 multi-disciplinary experts answered 5 surveys on the information to deliver concerning childbirth. The selected items were organized with mind mapping. RESULTS: 54 items were identified on the first round. 5 were retained after the second survey while the rest were reformulated and submitted for the third round. Amongst the 47 items submitted, 19 were retained, the rest were removed, merged or reworded. The fourth survey included 22 items of which 11 were retained. The fifth survey concerned the 11 remaining items and 2 new ones. During this round, 7 items were retained. This round made it possible to reach the consensus. In total, 42 items reached the consensus of the experts. They were then split into 5 mind maps allowing their visual organization to form the information tool. CONCLUSION: The tool elaborated in a multi-disciplinary manner offers complementary information to that already given during childbirth preparation courses. It is a framework for the information to be given that leaves the content up to each professional.

Toxicity data for preoperative concurrent chemoradiotherapy with oxaliplatin and continuous infusion 5-fluorouracil for locally advanced esophageal cancer.

The purpose of this retrospective analysis was to characterize the feasibility and tolerability of oxaliplatin/5-fluorouracil (5-FU) given concurrently with radiotherapy for patients with locally advanced esophageal cancer. Between July 2005 and March 2009, 15 patients with clinical stage T3/T4 and/or N1/M1a lower esophageal or gastroesophageal junction adenocarcinoma were treated with preoperative chemoradiotherapy using oxaliplatin every 2 weeks and continuous infusion 5-FU. The main treatment-related toxicities were oral mucositis and dysphagia. During the first 2 weeks of treatment, 20% of patients presented with grade 1-2 oral mucositis, and one patient developed grade 1 dysphagia. In weeks 3-4, 53% of the patients experienced grade 1-2 mucositis, and 40% experienced grade 1-2 dysphagia. One patient only experienced grade 3 mucositis in week 4. Three patients (20%) had grade 3-4 dysphagia in weeks 3-4 and were continued on intravenous fluids and pain medications. During the last 2 weeks of chemoradiotherapy, 53% of patients reported grade 1-2 oral mucositis, mostly grade 1 and 73% of patients experienced grade 1-2 dysphagia and 26% patients experienced grade 3-4 dysphagia. Other toxicities included fatigue, nausea, neuropathy, and diarrhea. Only one patient experienced > 10% weight loss. The whole group was treated with aggressive supportive care during radiotherapy. Five (33%) patients achieved a pathological complete response. No patients developed locoregional failure. Sixty percent of the patients developed distant metastases and the 2-year disease-free survival was 53%. The median survival was 3.2 years with the 2-year overall survival of 73%. Preoperative oxaliplatin/5-FU-based chemoradiotherapy for locally advanced esophageal cancer is feasible, but associated with substantial gastrointestinal toxicity. A careful attention to nutrition and hydration throughout the course of therapy is required.

Corrigendum: Zebrafish Models of Craniofacial Malformations: Interactions of Environmental Factors.

[This corrects the article DOI: 10.3389/fcell.2020.600926.].

Daphnia revisited: local stability and bifurcation theory for physiologically structured population models explained by way of an example.

We consider the interaction between a general size-structured consumer population and an unstructured resource. We show that stability properties and bifurcation phenomena can be understood in terms of solutions of a system of two delay equations (a renewal equation for the consumer population birth rate coupled to a delay differential equation for the resource concentration). As many results for such systems are available (Diekmann et al. in SIAM J Math Anal 39:1023-1069, 2007), we can draw rigorous conclusions concerning dynamical behaviour from an analysis of a characteristic equation. We derive the characteristic equation for a fairly general class of population models, including those based on the Kooijman-Metz Daphnia model (Kooijman and Metz in Ecotox Env Saf 8:254-274, 1984; de Roos et al. in J Math Biol 28:609-643, 1990) and a model introduced by Gurney-Nisbet (Theor Popul Biol 28:150-180, 1985) and Jones et al. (J Math Anal Appl 135:354-368, 1988), and next obtain various ecological insights by analytical or numerical studies of special cases.

Zebrafish Models of Craniofacial Malformations: Interactions of Environmental Factors.

The zebrafish is an appealing model organism for investigating the genetic (G) and environmental (E) factors, as well as their interactions (GxE), which contribute to craniofacial malformations. Here, we review zebrafish studies on environmental factors involved in the etiology of craniofacial malformations in humans including maternal smoking, alcohol consumption, nutrition and drug use. As an example, we focus on the (cleft) palate, for which the zebrafish ethmoid plate is a good model. This review highlights the importance of investigating ExE interactions and discusses the variable effects of exposure to environmental factors on craniofacial development depending on dosage, exposure time and developmental stage. Zebrafish also promise to be a good tool to study novel craniofacial teratogens and toxin mixtures. Lastly, we discuss the handful of studies on gene-alcohol interactions using mutant sensitivity screens and reverse genetic techniques. We expect that studies addressing complex interactions (ExE and GxE) in craniofacial malformations will increase in the coming years. These are likely to uncover currently unknown mechanisms with implications for the prevention of craniofacial malformations. The zebrafish appears to be an excellent complementary model with high translational value to study these complex interactions.

[Focus on the Odon Device™: Technical improvements, mechanical principles and progress of the clinical research program]. / Mise au point sur l'Odon Device™ : amélioration technique, fonctionnement et avancée du programme de recherche clinique.

The Odon Device™ has been described in the literature since 2013 and the World Health Organization supports its development through the Human Reproduction Program. This innovative device could be easier to use than usual instruments and could be an alternative to caesarean section during the second stage of labor, especially in countries where access to obstetric care is limited. The aim of the Odon Device™ is to position an air cuff over the fetal head, past its widest point (around the level of the fetal mouth anteriorly and the nape of the fetal neck posteriorly). Three mechanical principles favor the progression of the fetal head with the Odon Device™: partial propulsion, limited flexion and traction. Preliminary clinical studies on animals and simulators are reassuring and show that an appropriate use is no more at risk than the vaccum or forceps. A phase 1 study was conducted in Argentina and South Africa between 2011 and 2017. The reported failure rate was 29%, of which 77% was secondary to a mechanical failure of one of the components of the device. Improvements concerning the applicator, the handles and the inflatable air cuff have been made to the device. Phase II of the clinical research program began in 2018 and includes two studies in two different centers: The ASSIST Study in Bristol, England, and The BESANCON ASSIST Study, Besançon, France.

Feasibility of two-dimensional ultrasound shear wave elastography of human fetal lungs and liver: A pilot study.

PURPOSE: The first aim was to evaluate feasibility and reproducibility of 2-dimensional ultrasound (2D) shear wave elastography (SWE) of human fetal lungs and liver between 24 and 34weeks of gestation. The second aim was to model fetal lung-to-liver elastography ratio (LLE ratio) and to assess its variations according to gestational age and maternal administration of corticosteroids. MATERIAL AND METHODS: 2D-SWE examinations were prospectively performed in fetuses of women with an uncomplicated pregnancy (group 1) and fetuses of women with a threatened preterm labor requiring administration of corticosteroids (group 2). Two 2D-SWE examinations were performed at "day 0" and "day 2" in group 1; before and 24hours after a course of corticosteroid in group 2. Three operators performed 2 cycles of 3 measurements on the lung (regions A1, A2, A3) and the liver (regions IV, V, VI). Repeatability and reproducibility of measurements were calculated. The fetal LLE ratio was modeled from the most reproducible regions. RESULTS: Fifty-five women were enrolled in group 1 and 48 in group 2. For the lung, 8.6% of measurements were considered invalid and 6.9% for the liver. The most reproducible region for the lung was A3 [ICC between 0.70 (95% CI: 0.42-0.85) and 0.78 (95% CI: 0.48-0.90)] and region VI for the liver [ICC between 0.70 (95% CI: 0.40-0.85) and 0.84 (95% CI: 0.60-0.94)]. According to gestational age, a moderate positive linear correlation was found for stiffness values of A3 (R=0.56), V (R=0.46) and VI (R=0.44). LLE ratio values at "day 0" were not different between the two groups but decreased at "day 2" in group 2 (0.2; 95% CI: 0.07-0.34; P<0.001). CONCLUSION: Quantitative fetal lung and liver stiffness measurements are possible with 2D-SWE with acceptable reproducibility.

The anti-epileptic drug valproic acid causes malformations in the developing craniofacial skeleton of zebrafish larvae.

Valproic acid (VPA) is an anti-epileptic drug known to cause congenital craniofacial abnormalities, including orofacial clefts (OFC). The exact mechanisms by which VPA leads to craniofacial skeletal malformations are poorly understood. In this study, we investigated the effects of VPA on cartilage and bone formation in the zebrafish larval head during 1-13 hpf (early) and 25-37 hpf (late) development in which cranial neural crest cells (CNCCs) arise and then proliferate and differentiate, respectively. Double-staining for cartilage and bone at 5 dpf revealed that VPA reduced cartilage and bone formation in a dose-dependent manner after both early or late exposure. Several different CNCC-derived cartilage and bone elements were affected in both groups. In the early group (100 µM VPA), the posterior head length and the ethmoid plate were reduced in length (both p < 0.01), while mineralization of 4 out of 9 bone elements was often lacking (all p < 0.01). In the late group (100 µM VPA), also the posterior head length was reduced as well as the length of the ceratohyals (both p < 0.01). Similar to early exposure, mineralization of 3 out of 9 bone elements was often lacking (all p < 0.01). These results indicate that both CNCC formation (early) and differentiation (late) are hampered by VPA treatment, of which the consequences for bone and cartilage formation are persistent at 5 dpf. Indeed, we also found that the expression of several genes related to cartilage and bone was upregulated at 5 dpf. These data indicate a compensatory reaction to the lack of cartilage and bone. Altogether, VPA seems to induce craniofacial malformations via disturbed CNCC function leading to defects in cartilage and bone formation.

Theory and modeling of stereoselective organic reactions.

Theoretical investigations of the transition structures of additions and cycloadditions reveal details about the geometries of bond-forming processes that are not directly accessible by experiment. The conformational analysis of transition states has been developed from theoretical generalizations about the preferred angle of attack by reagents on multiple bonds and predictions of conformations with respect to partially formed bonds. Qualitative rules for the prediction of the stereochemistries of organic reactions have been devised, and semi-empirical computational models have also been developed to predict the stereoselectivities of reactions of large organic molecules, such as nucleophilic additions to carbonyls, electrophilic hydroborations and cycloadditions, and intramolecular radical additions and cycloadditions.

Production of polyunsaturated fatty acids by polyketide synthases in both prokaryotes and eukaryotes.

Polyunsaturated fatty acids (PUFAs) are essential membrane components in higher eukaryotes and are the precursors of many lipid-derived signaling molecules. Here, pathways for PUFA synthesis are described that do not require desaturation and elongation of saturated fatty acids. These pathways are catalyzed by polyketide synthases (PKSs) that are distinct from previously recognized PKSs in both structure and mechanism. Generation of cis double bonds probably involves position-specific isomerases; such enzymes might be useful in the production of new families of antibiotics. It is likely that PUFA synthesis in cold marine ecosystems is accomplished in part by these PKS enzymes.

The effect of digital lesions and floor type on locomotion score in Dutch dairy cows.

This study describes the effects of floor system, digital dermatitis (DD) and interdigital dermatitis and heel-horn erosion (IDHE) on locomotion performance in 225 dairy cows of 12 commercial dairy herds. Nine herds were kept in cubicle houses with concrete passageways (either solid, slatted, or grooved concrete) and three herds were kept in straw yards. Animals were at most five times examined at monthly intervals for lesion severity of DD and IDHE and for locomotion score. Locomotion score was rated on a scale ranging from 1 to 5 (from normal to severe) and disturbed locomotion (lameness) was defined as a score > or =3. A logistic regression model was used to analyze the 943 observations using lameness (yes/no) as outcome variable. The proportion of observations scored as lame (locomotion score > or =3) increased from 18% 1 month after trimming to 29% at 4 months after trimming. Severe lesions of DD and IDHE were associated with a significantly higher proportion of lame cows. The proportion of animals with disturbed locomotion increased from 16% to 40% as the severity of DD increased and from 17% to 30% with increasing severity of IDHE lesions. Locomotion performance highly differed between the cubicle house and straw yard group. Only 1% of all gaits in straw yard cows were scored as lame, while in cubicle housed cows these percentages varied from 24% to 46% with grooved floors showing the highest average locomotion score. Due to the extreme low incidence of lameness in straw yards, the statistical analysis had to be restricted to observations on concrete floors (n=744). The logistic regression model with lameness (yes/no) as dependent variable and random effects of cow and herd resulted in Odds Ratios for severe DD and IDHE of, respectively, 3.2 and 3.2, both significantly larger than unity. Cows housed at grooved concrete floors showed the highest OR of 6.5 compared to solid concrete floors. Recovery of lameness was poor as disturbance in gait lasted several months.

[Manual rotation in occiput posterior position: A systematic review in 2019]. / Rotation manuelle des variétés postérieures : état des lieux de la littérature en 2019.

OBJECTIVE: The aim of our study was to evaluate the safety and the benefits of manual rotation in the management of Occiput-posterior positions in 2019. METHODS: A systematic review of literature was performed using the MEDLINE and COCHRANE LIBRARY databases, in order to identify articles concerning maternal and neonatal outcomes after a manual rotation, through January 2019. Information on study characteristics (review, author, year of publication), population, objectives and main neonatal and maternal outcomes were extracted. RESULTS: A total of 51 articles were identified and 12 articles were selected for the systematic review. The rate of successful manual rotation were about 47 to 90%. There were more success if systematic manual rotation, multiparity, engagement, spontaneous labour and maternal age<35. The 2nd stage of labour was shorter after an attempt of manual rotation. The randomised controlled trials did not find any statistical difference concerning operative deliveries or neonatal and maternal outcomes. CONCLUSION: The manual rotation is an obstetrical manoeuvre which must be regulated and only practiced by trained operators. Currently, the state of science is not sufficient to recommend the manual rotation as a systematic practice in 2019.

Fgf8a mutation affects craniofacial development and skeletal gene expression in zebrafish larvae.

Craniofacial development is tightly regulated and therefore highly vulnerable to disturbance by genetic and environmental factors. Fibroblast growth factors (FGFs) direct migration, proliferation and survival of cranial neural crest cells (CNCCs) forming the human face. In this study, we analyzed bone and cartilage formation in the head of five dpf fgf8ati282 zebrafish larvae and assessed gene expression levels for 11 genes involved in these processes. In addition, in situ hybridization was performed on 8 and 24 hours post fertilization (hpf) larvae (fgf8a, dlx2a, runx2a, col2a1a). A significant size reduction of eight out of nine craniofacial cartilage structures was found in homozygous mutant (6-36%, P<0.01) and heterozygous (7-24%, P<0.01) larvae. Also, nine mineralized structures were not observed in all or part of the homozygous (0-71%, P<0.0001) and heterozygous (33-100%, P<0.0001) larvae. In homozygote mutants, runx2a and sp7 expression was upregulated compared to wild type, presumably to compensate for the reduced bone formation. Decreased col9a1b expression may compromise cartilage formation. Upregulated dlx2a in homozygotes indicates impaired CNCC function. Dlx2a expression was reduced in the first and second stream of CNCCs in homozygous mutants at 24 hpf, as shown by in situ hybridization. This indicates an impairment of CNCC migration and survival by fgf8 mutation.