Altrenogest treatment reduces the stress response of three-year-old warmblood mares during their initial equestrian training.

Horse mares are frequently treated with the progestin altrenogest with the aim to suppress estrous behavior and its negative impact on equestrian performance. Progestogens, however, also have sedative effects in males, and females of different species. The aim of our study was therefore to investigate altrenogest-induced changes in the stress response of female horses during initial equestrian training. Three-yr-old Warmblood mares were randomly assigned to treatment with altrenogest (ALT; 0.044 mg/kg once daily; n = 6) or sunflower oil (CON; n = 5) for 12 wk during training. At predefined steps of the training program (free movement, lunging without and with side reins, lunging with saddle, mounting of a rider, free riding, riding by an unfamiliar rider) salivary cortisol concentration, and heart rate were determined from 60 min before to 120 min after training. The same procedures were performed during repeated gynecologic examinations and 2 novel object tests. Bodyweight and body condition scores (BCS) were assessed at 4-wk intervals. During all training units, salivary cortisol concentration and heart rate increased (P < 0.001), but the increase was smaller in group ALT mares (time x treatment P < 0.001). Gynecologic examinations and novel object tests induced a much smaller increase in cortisol and heart rate (P < 0.001) than equestrian training with no difference between groups ALT and CON. Initially, bodyweight, and BCS decreased during training. The subsequent increase was larger in group ALT vs CON (time x treatment P < 0.05). In conclusion, altrenogest reduced the stress response of 3-yr-old mares to equestrian training. The use of altrenogest during equestrian competitions should therefore be reconsidered.

Effects of blue monochromatic light directed at one eye of pregnant horse mares on gestation, parturition and foal maturity.

Blue light directed at 1 eye advances the equine ovulatory season but may also advance foaling. In this study, effects of blue LED light on pregnancy outcome were assessed. A total of 20 mares with singleton pregnancies were studied over 2 consecutive years in a cross-over design. In 1 year, mares received an extended photoperiod using 50 lux of blue LED light (468 nm) directed at a single eye from 08:00 until 23:00 daily via head-worn light masks starting mid-December and in the other year remained untreated as controls. Gestation was shorter in blue LED light-treated than in control pregnancies (median 333.0 vs 338.5 days, P = 0.036). Foals born to blue LED light-treated mares had lower wither heights (median 103.0 vs 104.5 cm, P = 0.023), similar weights (median 55.8 vs 54.8 kg, P = 0.732) and took less time to stand after birth than control foals (median 35.0 vs 53.5 min, P = 0.036). Foals born to blue LED light-treated mares had reduced hair length compared to controls (median 12.0 vs 20.0 mm, P = 0.009) and hair regrowth in treated mares was reduced (P = 0.036). In conclusion, blue LED light directed at 1 eye advanced foaling and influenced height and hair coat but not weight in foals.

[A definition of work-related asthma and its social and occupational consequences in adults and teenagers]. / Définition de l'asthme en relation avec le travail et ses conséquences sociales et professionnelles chez l'adulte et l'adolescent.

Work-related asthma (WRA) accounts for 10-25% of all adult asthma. It therefore seems important to raise questions regarding an asthmatic's approach to occupational or job training activities. WRA takes on two forms: work-exacerbated asthma (WEA) and occupational asthma (OA), which encompasses different subtypes of heterogeneous mechanisms. It currently represents a major challenge for occupational medicine in terms of detailed diagnosis, social care, the economic repercussions for workers and employers and, last but not least, social insurance. This review aims to sensitize health care practitioners to the peculiarities of WRA management in routine practice. More specifically, prognosis depends on early diagnosis, medical care and work adjustment measures. WEA and OA are explained in detail in view of identifying causative agents and at-risk occupations and defining adapted medical strategy. Relevant lines of questioning and complementary exams are presented. In addition, the key role of the occupational physician, especially as regards recognition and identification of occupational disease, is underlined, the objective being to facilitate optimal professional and social management. In future studies, the key role of counseling and orientation mechanisms should be highlighted as means of preventing WRA occurrence.

Transient suppression of ovulatory ovarian function in pony mares after treatment with slow-release deslorelin implants.

Behavior during the estrous cycle of mares can affect their performance and therefore inhibition of cyclical ovarian activity is indicated. We hypothesized that implants containing the GnRH analog deslorelin downregulate GnRH receptors and inhibit ovulation in mares. The estrous cycles of Shetland mares were synchronized with 2 injections of a PGF2α analog. One day after the second injection (day 0), mares received 9.4 (group D1, n = 6) and 4.7 mg deslorelin (D2, n = 5) as slow-release implants or 1.25 mg short-acting deslorelin as a control (C, n = 5). Ultrasonography of the reproductive tract and ovaries and observation of estrous behavior and collection of blood samples for analysis of progesterone and LH concentrations were performed every second day until day 10 and thereafter at 5-d intervals. Stimulation tests with the GnRH-agonist buserelin were performed on days 10 and 45. Until day 50, there were less spontaneous ovulations in group D1 (P < 0.01) and estrous behavior was reduced in groups D1 and D2 compared with group C (P < 0.05). The time until first ovulation (D1 62.0 ± 8.6, D2 44.2 ± 14.1, C 22.2 ± 3.1 d, P < 0.05) and the number of days with estrous behavior (P < 0.05) differed among groups. On day 10 after treatment, a GnRH stimulation test revealed interactions between group and time (P < 0.001) in plasma LH concentration that were no longer detectable on day 45 after treatment. In conclusion, long-acting deslorelin implants result in a transient downregulation of pituitary GnRH receptors that is associated with inhibition of ovulation and estrous behavior in Shetland mares.

The evaluation of intracranial bypass patency in neurosurgical practice.

BACKGROUND: The patency of cranial bypasses must be carefully evaluated during and after the microsurgical procedure. Although, several imaging techniques are used to evaluate the patency of bypasses, their findings are sometimes difficult to interpret. PURPOSE: The goal of this study was to assess the consistency of different diagnostic modalities for evaluating intracranial bypass patency. PATIENTS AND METHOD: This prospective study included 19 consecutive patients treated with EC-IC or IC-IC bypass for MoyaMoya disease (MMD) or complex/giant aneurysms between June 2016 and June 2018. In the early postoperative period (<7 days), all patients had transcranial Doppler (TCD), CT angiography (CTA) and MRA to demonstrate patency of anastomoses and to confirm exclusion of the aneurysm. When findings of anastomosis patency differed between these techniques, conventional angiography was performed. RESULTS: All anastomoses were patent on indocyanine green videoangiography at the end of microsurgical procedure. The results of noninvasive postoperative exams were consistent to demonstrate the patency of anastomoses in 13 patients. In 4 patients, a discrepancy in patency of anastomoses arose between TCD, CTA and MRI in the early postoperative period. In 2 other patients, the interpretation of bypass patency remained inconclusive before the decision to occlude the aneurysm. In these 6 patients, a significant edema was noted in 2 cases, a postoperative subdural hematoma in 1 case, a low flow in the anastomosis in 1 case and vasospasm in 2 cases. The anastomosis was patent on the conventional angiography in five patients. CONCLUSION: Noninvasive imaging techniques provide useful data about the patency but their findings should be carefully interpreted due to local anatomical, physiological, and pathological factors. In case of discrepant findings, conventional angiography including supraselective catheterization of the donor vessel is suggested.

The PINK1 kinase-driven ubiquitin ligase Parkin promotes mitochondrial protein import through the presequence pathway in living cells.

Most of over a thousand mitochondrial proteins are encoded by nuclear genes and must be imported from the cytosol. Little is known about the cytosolic events regulating mitochondrial protein import, partly due to the lack of appropriate tools for its assessment in living cells. We engineered an inducible biosensor for monitoring the main presequence-mediated import pathway with a quantitative, luminescence-based readout. This tool was used to explore the regulation of mitochondrial import by the PINK1 kinase-driven Parkin ubiquitin ligase, which is dysfunctional in autosomal recessive Parkinson's disease. We show that mitochondrial import was stimulated by Parkin, but not by disease-causing Parkin variants. This effect was dependent on Parkin activation by PINK1 and accompanied by an increase in the abundance of K11 ubiquitin chains on mitochondria and by ubiquitylation of subunits of the translocase of outer mitochondrial membrane. Mitochondrial import efficiency was abnormally low in cells from patients with PINK1- and PARK2-linked Parkinson's disease and was restored by phosphomimetic ubiquitin in cells with residual Parkin activity. Altogether, these findings uncover a role of ubiquitylation in mitochondrial import regulation and suggest that loss of this regulatory loop may underlie the pathophysiology of Parkinson's disease, providing novel opportunities for therapeutic intervention.

Superficial temporal artery-middle cerebral artery anastomosis patency correlates with cerebrovascular reserve in adult moyamoya syndrome patients.

OBJECTIVES: To evaluate the effectiveness of superficial temporal artery-middle cerebral artery (STA-MCA) bypass in improving cerebrovascular reserve (CVR) in Moyamoya syndrome. PATIENTS AND METHODS: This prospective study included 10 consecutive patients treated for Moyamoya syndrome by STA-MCA bypass in our institution between June 2016 and January 2018. Perfusion MRI, transcranial Doppler and 99m Tc-HMPAO SPECT with acetazolamide challenge were performed before and after treatment to evaluate perfusion and cerebrovascular reserve. STA-MCA bypass was indicated for patients with history of ischemic or hemorrhagic stroke and when CVR was diminished on both transcranial Doppler and 99m Tc-HMPAO SPECT with acetazolamide challenge or brain perfusion was deteriorated on MRI. RESULTS: Bypass anastomosis was patent in all patients at end of surgery. One patient presented partial postoperative sensorimotor deficit related to an ischemic lesion in the frontal cortical area. One patient presented regressive chronic subdural hematoma without neurological deficit. Three months after treatment, CVR was significantly improved in 8 patients and unchanged in 2, probably related to low flow. Further follow-up found CVR deterioration in 1 patient, with anastomosis occlusion at 1 year. CONCLUSION: Our data suggest that improvement in cerebral perfusion and CVR depends on flow in the STA-MCA anastomosis in patients with Moyamoya syndrome. Systematic long-term follow-up of anastomosis flow, brain perfusion and CVR improves quantification of the benefit of STA-MCA anastomosis in terms of disease progression.

Respiratory impairment in Niemann-Pick B disease: Two case reports and review for the pulmonologist.

Acid sphingomyelinase deficiency (ASMD), also called Niemann-Pick disease, is a storage disorder with pulmonary involvement but few respiratory symptoms in adults. However, the disease may evolve towards clinically relevant respiratory symptoms with referral to the pulmonologist for management and care. Based on two case reports illustrating respiratory impairment, the aim of this work was to review clinical features, diagnosis, respiratory prognostic and therapeutics for the pulmonologist. Overall, storage disorder should be suspected in the presence of hepatosplenomegaly and interstitial lung disease. Concomitant thrombopenia or hyperlipidemia should also draw attention. Following recent consensus guidelines, diagnosis is based on enzyme assay for ASM activity in blood, with subsequent gene sequencing once the biochemical diagnosis has been confirmed. Disease is slowly progressive and the main causes of death are respiratory and liver failure. Presence of emphysema lesions or worsening of respiratory symptoms should call for the intensification of treatment. Though enzyme replacement therapy is a promising way of development, lung transplantation might be considered for these patients in the absence of contraindication.

Isavuconazole MIC distribution of 29 yeast species responsible for invasive infections (2015-2017).

OBJECTIVES: Isavuconazole is a recent extended-spectrum triazole with activity against yeasts. However, few data are available about the in vitro activity of rare yeast species. We report the MIC distribution of isavuconazole compared with fluconazole for a large collection of common or rare yeasts. METHODS: Isavuconazole and fluconazole MICs were determined using the EUCAST method for 1457 clinical isolates, mainly recovered from invasive infections, belonging to 29 species. They were sent to the National Reference Centre for Invasive Mycoses & Antifungals between January 2015 and October 2017 and species identification was performed using a polyphasic approach (matrix-assisted laser desorption/ionization time of flight analysis and a molecular method). RESULTS: Isavuconazole had effective in vitro activity against Cryptococcus neoformans (MIC90 < 0.25 mg/L), the five most common Candida spp. (MIC90 ≤ 0.5 mg/L for Candida albicans, Candida glabrata, Candida tropicalis, Candida parapsilosis, and Candida krusei) and also against the majority of rare species, including Candida kefyr and Candida lusitaniae. A few isolates of C. albicans (0.7%, 3/404), C. glabrata (2.7%, 5/184), C. tropicalis (1.0%, 1/96) and C. parapsilosis (0.8%, 1/127) exhibited MIC ≥4 mg/L. All were also resistant to fluconazole according to the EUCAST breakpoints. Some isolates with isavuconazole MIC ≥4 mg/L were also observed among rarer species: Meyerozyma guilliermondii (8.7%, 2/23), Wickerhamomyces anomalus (10.0%, 1/10). Other rare species Saprochaete clavata, Magnusiomyces capitatus, and Rhodotorula mucilaginosa had high MIC50 (≥1 mg/L) and MIC90 (≥4 mg/L) and could be considered as resistant to isavuconazole. CONCLUSIONS: We confirmed the good in vitro activity of isavuconazole against common Candida, Cryptococcus species and the majority of the rare yeast species studied.

[Non-allergenic impact of indoor mold exposure]. / Effets non allergiques des moisissures domestiques sur la santé.

The proportion of moldy housing in France is around 20%. It is not simple to establish that a health impact of mold is not allergic, because the identification of allergy is itself difficult. Moreover, exposure to molds and their metabolites may have a protective effect. Non-allergic health impacts may occur due to the multiple aerocontaminants found in damp or mold-containing dwellings: glucans, microbial volatile organic compounds, mycotoxins, bacteria and endotoxins. The heath impacts of indoor mold have been addressed by numerous toxicologic and epidemiologic investigations, the results of which have been summarized in three notable reports. These conclude that mold exposure is linked to a risk of ENT and bronchial symptoms, both the genesis and exacerbation of asthma and, lastly, hypersensitivity pneumonitis. Finally, other studies highlight the protective role of fungal metabolites with respect to asthma and allergy. Pulmonologists should be aware of these data, which can be useful in clinical practice and also in legal work.

Maternal obesity increases insulin resistance, low-grade inflammation and osteochondrosis lesions in foals and yearlings until 18 months of age.

INTRODUCTION: Obesity is a growing concern in horses. The effects of maternal obesity on maternal metabolism and low-grade inflammation during pregnancy, as well as offspring growth, metabolism, low-grade inflammation, testicular maturation and osteochondrotic lesions until 18 months of age were investigated. MATERIAL AND METHODS: Twenty-four mares were used and separated into two groups at insemination according to body condition score (BCS): Normal (N, n = 10, BCS ≤4) and Obese (O, n = 14, BCS ≥4.25). BCS and plasma glucose, insulin, triglyceride, urea, non-esterified fatty acid, serum amyloid A (SAA), leptin and adiponectin concentrations were monitored throughout gestation. At 300 days of gestation, a Frequently Sampled Intravenous Glucose Tolerance Test (FSIGT) was performed. After parturition, foals' weight and size were monitored until 18 months of age with plasma SAA, leptin, adiponectin, triiodothyronine (T3), thyroxine (T4) and cortisol concentrations measured at regular intervals. At 6, 12 and 18 months of age, FSIGT and osteoarticular examinations were performed. Males were gelded at one year and expression of genes involved in testicular maturation analysed by RT-qPCR. RESULTS: Throughout the experiment, maternal BCS was higher in O versus N mares. During gestation, plasma urea and adiponectin were decreased and SAA and leptin increased in O versus N mares. O mares were also more insulin resistant than N mares with a higher glucose effectiveness. Postnatally, there was no difference in offspring growth between groups. Nevertheless, plasma SAA concentrations were increased in O versus N foals until 6 months, with O foals being consistently more insulin resistant with a higher glucose effectiveness. At 12 months of age, O foals were significantly more affected by osteochondrosis than N foals. All other parameters were not different between groups. CONCLUSION: In conclusion, maternal obesity altered metabolism and increased low-grade inflammation in both dams and foals. The risk of developing osteochondrosis at 12 months of age was also higher in foals born to obese dams.

Maternal parity affects placental development, growth and metabolism of foals until 1 year and a half.

Primiparous mares are known to produce smaller foals than multiparous mares. This difference seems to be partly explained by the reduced exchange surface and volume of the placental villi in primiparous compared to multiparous placentas. The effect of maternal parity on foals' post-natal growth, metabolism and sexual maturation, however, has been given little consideration. The objectives of this work were to analyse placental biometry and structure at term, growth of foals and yearlings, their metabolism and testicular maturation at one year of age. Twenty multiparous mares (M), aged over 6 years and 12 primiparous mares (P), aged up to 5 years were artificially inseminated with the same stallion and monitored the same way until foaling. At birth, foals and placentas were measured and placentas were sampled above at the umbilical cord insertion, as well as in the pregnant and the non-pregnant horn to perform stereological analyses. Foals were weighed and measured until 540 days of age. At 120 and 360 days of age, an Intravenous Glucose Tolerance Test was performed on foals and yearlings. At 360 days of age, the males were castrated and testicular maturation analysed by RT-qPCR. At birth, P dams produced lighter and smaller foals and placentas. The foal birth weight to placental surface ratio was lower in the P compared to the M group. P Foals remained lighter than M foals until 360 days of age and smaller until at least 540 days of age. At 120 days of age, P foals had a higher glucose tolerance than M foals, and then may be less mature than M foals in terms of the control of their glucose homeostasis. At 360 days of age, the testicles of prepubertal P stallions were less mature in the P vs the M group. In conclusion, primiparous dams produce intrauterine growth restricted, less mature and smaller foals compared to multiparous dams with altered metabolism and growth until at least 540 days of age. These differences could affect the sport career of these foals, especially if it begins at an early age.

[Contribution of contrast enhanced ultrasonography in the characterization of carotid lesions]. / Apport de l'échographie de contraste dans la caractérisation des lésions carotidiennes.

Harmonic mode ultrasound with injection of a contrast enhancement agent allows visualization of mobile microbubbles in the carotid plaque corresponding to neovessels secondary to an inflammation or hypoxia. These neovessels could be considered "precursor" markers of the vulnerable plaque. The aim of this work was to give an update on ultrasound contrast imaging acquisition in the exploration of carotid artery both for atheromatous lesions and for large vessel vasculitis. A precise description of the material to be used, the image acquisition methodology and the environmental conditions is discussed, emphasizing the pitfalls to be avoided as well as proper image interpretation. Microbubbles in a plaque are significantly associated with an increase in cardiovascular events (infarction and acute coronary syndrome) and ipsilateral cerebral ischemic events. Wall irregularities, microfissures and ulcer plaque detection are facilitated by the use of contrast compared to the CT scan. No studies have yet validated contrast enhanced ultrasound in the exploration of asymptomatic carotid stenosis. Contrast enhanced ultrasound also allows to detect vasculitis of the large vessels active phases by the presence of microbubbles in the carotid wall thickening and to monitor the regression under appropriate medical treatment. Future validation studies or even registries are needed to allow better use of this tool in everyday clinical practice.

[MODen: Psychoeducationnal therapeutic group program for schizophrenic patients, based on nutritional balance and pleasure, using cognitive functions: A pilot study]. / MODen : programme d'éducation thérapeutique dans la schizophrénie centré sur l'équilibre alimentaire et le plaisir, sollicitant les fonctions cognitives : étude pilote.

INTRODUCTION: Schizophrenia causes psychological difficulties (with positive and/or negative symptoms) as well as cognitive disabilities (attention, memory, executive functions and social cognition). Moreover, 40 to 60% of patients suffer from an excess of weight or obesity (due to bad eating habits, eating disorders or medication). All these difficulties impair their autonomy and their insertion into the society. In this context, setting-up a therapeutic tool, which may have cognitive benefits seems relevant. Thus, MODen is a therapeutic educational tool whose aim is to improve cognitive functions and the symptoms by using "nutritional balance" as an aid. METHOD: In this treatment program, two therapists lead a group of 5 to 8 patients which group meets once a week during two to four hours for 16 weeks, divided in 4 cycles. The first three weeks of each cycle consists of theoretical instruction: patients talk about their eating habits, information is given about nutritional balance and preparation of meals. In the different cycles, flexibility, planning, memory and attention are trained. For instance, the work on categorisation of foods and nutritional balance allow enhancing flexibility abilities. Writing down the lists of different ingredients needed for one week's meals and preparation of meals train planning abilities. MODen also takes into account ecological issues such as the limited budget of patients to do their shopping (this budget is around 4 euros per meal in France). The budget is also linked to planning abilities and reasoning. Finally, during the last session of each cycle the group prepares a meal (from the shopping to cooking). This last session is all about sharing and social cognition abilities. By the end of the program, patients will have prepared four meals together. Also "homework" has to be done each week in order to facilitate memorisation of what has been learned during the last session and to prepare the beginning of the next session. RESULTS: In a pilot study with 8 patients with schizophrenia (DSM-IV), improvements in PANSS negative symptoms and disorganization (respectively P<0.02; P<0.02) were observed. An underlying improvement at BECS scores was also observed (P<0.08). Regarding those preliminary results as well as the ecological qualities of this program, this therapeutic tool could be relevant in the treatment of patients with schizophrenia.

NF-κB pathway controls mitochondrial dynamics.

The Optic atrophy 1 protein (OPA1) is a key element in the dynamics and morphology of mitochondria. We demonstrated that the absence of IκB kinase-α, which is a key element of the nonclassical NF-κB pathway, has an impact on the mitochondrial network morphology and OPA1 expression. In contrast, the absence of NF-κB essential modulator (NEMO) or IκB kinase-ß, both of which are essential for the canonical NF-κB pathway, has no impact on mitochondrial dynamics. Whereas Parkin has been reported to positively regulate the expression of OPA1 through NEMO, herein we found that PARK2 overexpression did not modify the expression of OPA1. PARK2 expression reduced the levels of Bax, and it prevented stress-induced cell death only in Bak-deficient mouse embryonic fibroblast cells. Collectively, our results point out a role of the nonclassical NF-κB pathway in the regulation of mitochondrial dynamics and OPA1 expression.

Benefits of Completion 3D Angiography Associated with Contrast Enhanced Ultrasound to Assess Technical Success after EVAR.

OBJECTIVES: This study evaluated a new strategy to assess technical success after standard and complex endovascular aortic repair (EVAR), combining completion contrast enhanced cone beam computed tomography (ceCBCT) and post-operative contrast enhanced ultrasound (CEUS). METHODS: Patients treated with bifurcated or fenestrated and branched endografts in the hybrid room during the study period were included. From December 2012 to July 2013, a completion angiogram (CA) was performed at the end of the procedure, and computed tomography angiography (CTA) before discharge (group 1). From October 2013 to April 2014, a completion ceCBCT was performed, followed by CEUS during the 30 day post-operative period (group 2). The rate of peri-operative events (type I or III endoleaks, kinks, occlusion of target vessels), need for additional procedures or early secondary procedures, total radiation exposure (mSv), and total volume of contrast medium injected were compared. RESULTS: Seventy-nine patients were included in group 1 and 54 in group 2. Peri-operative event rates were respectively 8.9% (n = 7) and 33.3% (n = 18) (p = .001). Additional procedures were performed in seven patients (8.9%) in group 1 versus 17 (31.5%) in group 2 (p = .001). Two early secondary procedures were performed in group 2 (3.7%), and three (3.8%) in group 1 (p = .978). Median radiation exposure due to CBCT was 7 Gy cm(2) (5.25-8) (36%, 27%, and 9% of the total procedure exposure, respectively for bifurcated, fenestrated, and branched endografts). CEUS did not diagnose endoleaks or any adverse events not diagnosed by ceCBCT. Overall radiation and volume of contrast injected during the patient hospital stay in groups 1 and 2 were 34 (25.8-47.3) and 11 (5-20.5) mSv, and 184 (150-240) and 91 (70-132.8) mL respectively (reduction of 68% and 50%, p < .001). CONCLUSIONS: Completion ceCBCT is achievable in routine practice to assess technical success after EVAR. Strategies to evaluate technical success combining ceCBCT and CEUS can reduce total in hospital radiation exposure and contrast medium volume injection.

Parkin maintains mitochondrial levels of the protective Parkinson's disease-related enzyme 17-ß hydroxysteroid dehydrogenase type 10.

Mutations of the PARK2 and PINK1 genes, encoding the cytosolic E3 ubiquitin-protein ligase Parkin and the mitochondrial serine/threonine kinase PINK1, respectively, cause autosomal recessive early-onset Parkinson's disease (PD). Parkin and PINK1 cooperate in a biochemical mitochondrial quality control pathway regulating mitochondrial morphology, dynamics and clearance. This study identifies the multifunctional PD-related mitochondrial matrix enzyme 17-ß hydroxysteroid dehydrogenase type 10 (HSD17B10) as a new Parkin substrate. Parkin overproduction in cells increased mitochondrial HSD17B10 abundance by a mechanism involving ubiquitin chain extension, whereas PARK2 downregulation or deficiency caused mitochondrial HSD17B10 depletion in cells and mice. HSD17B10 levels were also found to be low in the brains of PD patients with PARK2 mutations. Confocal and Förster resonance energy transfer (FRET) microscopy revealed that HSD17B10 recruited Parkin to the translocase of the outer membrane (TOM), close to PINK1, both in functional mitochondria and after the collapse of mitochondrial membrane potential (ΔΨm). PD-causing PARK2 mutations impaired interaction with HSD17B10 and the HSD17B10-dependent mitochondrial translocation of Parkin. HSD17B10 overproduction promoted mitochondrial elongation and mitigated CCCP-induced mitochondrial degradation independently of enzymatic activity. These effects were abolished by overproduction of the fission-promiting dynamin-related protein 1 (Drp1). By contrast, siRNA-mediated HSD17B10 silencing enhanced mitochondrial fission and mitophagy. These findings suggest that the maintenance of appropriate mitochondrial HSD17B10 levels is one of the mechanisms by which Parkin preserves mitochondrial quality. The loss of this protective mechanism may contribute to mitochondrial dysfunction and neuronal degeneration in autosomal recessive PD.

Cophylogeny reconstruction via an approximate Bayesian computation.

Despite an increasingly vast literature on cophylogenetic reconstructions for studying host-parasite associations, understanding the common evolutionary history of such systems remains a problem that is far from being solved. Most algorithms for host-parasite reconciliation use an event-based model, where the events include in general (a subset of) cospeciation, duplication, loss, and host switch. All known parsimonious event-based methods then assign a cost to each type of event in order to find a reconstruction of minimum cost. The main problem with this approach is that the cost of the events strongly influences the reconciliation obtained. Some earlier approaches attempt to avoid this problem by finding a Pareto set of solutions and hence by considering event costs under some minimization constraints. To deal with this problem, we developed an algorithm, called Coala, for estimating the frequency of the events based on an approximate Bayesian computation approach. The benefits of this method are 2-fold: (i) it provides more confidence in the set of costs to be used in a reconciliation, and (ii) it allows estimation of the frequency of the events in cases where the data set consists of trees with a large number of taxa. We evaluate our method on simulated and on biological data sets. We show that in both cases, for the same pair of host and parasite trees, different sets of frequencies for the events lead to equally probable solutions. Moreover, often these solutions differ greatly in terms of the number of inferred events. It appears crucial to take this into account before attempting any further biological interpretation of such reconciliations. More generally, we also show that the set of frequencies can vary widely depending on the input host and parasite trees. Indiscriminately applying a standard vector of costs may thus not be a good strategy.

Mitochondrial dysfunctions in Parkinson's disease.

Neurodegenerative disorders (ND) include a wide spectrum of diseases characterized by progressive neuronal dysfunctions or degeneration. With an estimated cost of 135 billion € in 2010 in the European Union (Olesen et al., 2012), they put an enormous economic as well as social burden on modern societies. Hence, they have been the subject of a huge amount of research for the last fifty years. For many of these diseases, our understanding of their profound causes is incomplete and this hinders the discovery of efficient therapies. ND form a highly heterogeneous group of diseases affecting various neuronal subpopulations reflecting different origins and different pathological mechanisms. However, some common themes in the physiopathology of these disorders are emerging. There is growing evidence that mitochondrial dysfunctions play a pivotal role at some point in the course of neurodegeneration. In some cases (e.g. Alzheimer's disease, amyotrophic lateral sclerosis), impairment of mitochondrial functions probably occurs late in the course of the disease. In a subset of ND, current evidence suggests that mitochondrial dysfunctions play a more seminal role in neuronal demise. Parkinson's disease (PD) presents one of the strongest cases based in part on post-mortem studies that have shown mitochondrial impairment (e.g. reduced complex I activity) and oxidative damage in idiopathic PD brains. The occurrence of PD is largely sporadic, but clinical syndromes resembling sporadic PD have been linked to specific environmental insults or to mutations in at least 5 distinct genes (α-synuclein, parkin, DJ-1, PINK1 and LRRK2). It is postulated that the elucidation of the pathogenic mechanisms underlying the selective dopaminergic degeneration in familial and environmental Parkinsonism should provide important clues to the pathogenic mechanisms responsible for idiopathic PD. Hence, numerous cellular and animal models of the disease have been generated that mimic these environmental or genetic insults. The study of these models has yielded valuable information regarding the pathogenic mechanisms underlying dopaminergic degeneration in PD, many of which point towards an involvement of mitochondrial dysfunction. In this short review we will analyze critically the experimental evidence for the mitochondrial origin of PD and evaluate its relevance for our general understanding of the disease.