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.

[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.

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.

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.

ViralORFeome: an integrated database to generate a versatile collection of viral ORFs.

Large collections of protein-encoding open reading frames (ORFs) established in a versatile recombination-based cloning system have been instrumental to study protein functions in high-throughput assays. Such 'ORFeome' resources have been developed for several organisms but in virology, plasmid collections covering a significant fraction of the virosphere are still needed. In this perspective, we present ViralORFeome 1.0 (http://www.viralorfeome.com), an open-access database and management system that provides an integrated set of bioinformatic tools to clone viral ORFs in the Gateway(R) system. ViralORFeome provides a convenient interface to navigate through virus genome sequences, to design ORF-specific cloning primers, to validate the sequence of generated constructs and to browse established collections of virus ORFs. Most importantly, ViralORFeome has been designed to manage all possible variants or mutants of a given ORF so that the cloning procedure can be applied to any emerging virus strain. A subset of plasmid constructs generated with ViralORFeome platform has been tested with success for heterologous protein expression in different expression systems at proteome scale. ViralORFeome should provide our community with a framework to establish a large collection of virus ORF clones, an instrumental resource to determine functions, activities and binding partners of viral proteins.

[Impact of socioeconomic status on stage at diagnosis of breast cancer]. / Impact du statut socioéconomique sur la gravité du diagnostic initial de cancer du sein.

BACKGROUND: This study aimed to evaluate the potential impact of social inequalities on stage at diagnosis and long-term outcome of breast cancer patients attending the Institut Curie in Paris (France). METHODS: The study population included 14,610 breast cancer patients diagnosed and treated in the Institut Curie between 1981 and 2001. The socioeconomic status was determined from district of residence, median income for town of residence corrected by the consumption unit and body mass index. Logistic regression models adjusted on socioeconomic factors were used to evaluate clinical and pathologic features at diagnosis. Overall survival and distant metastasis were analysed with log-rank tests and Cox proportional hazards regression models. RESULTS: Patients living in lower income districts were more likely to be diagnosed with breast tumors size greater than 20 mm (P=0.01). Residents of high-income urban areas (>15,770 €) exhibited a significant overall survival and distant metastasis advantage (respectively HR=0.93 [0.86-0.99]; P=0.02 and HR=0.91 [0.85-0.98]; P=0.01). Breast cancer screening with mammography was independent of district of residence (P=0.61) or income (P=0.14). After adjusting for age at diagnosis and period, the risk of having breast cancer with unfavorable prognostic factors such as tumor size greater than 20 mm decreased with 1000 € increase in district income (OR=0.986 [0.98-0.99]; P<0.001). Similarly, the risk of cancer death decreased for patients residing in districts with median income greater than 15,770 € (HR=0.92 [0.86-0.98]; P=0.01). CONCLUSION: Despite the limitations of the study (aggregate data used to assess socioeconomic status, non representative cohort of French women), we observed that poorer breast cancer prognosis with advanced disease diagnosis and increased risk of breast cancer mortality was related to low socioeconomic status.

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.

Single-centre prospective comparison between contrast-enhanced ultrasound and computed tomography angiography after EVAR.

AIM: To evaluate contrast-enhanced ultrasound (CEUS) as an effective alternative to CT-angiography (CTA) for endoleak detection and aneurismal sac diameter measurement in the follow-up after endovascular abdominal aortic aneurysm repair (EVAR). METHODS: From January 2006 to December 2010, 395 patients underwent EVAR follow-up with both CTA and CEUS. The diameter of the aneurismal sac and the presence of endoleaks were evaluated in all the 395 paired examinations. RESULTS: Bland-Altman plots showed a good agreement in aneurismal sac diameter evaluation between the two imaging modalities. The mean diameter was 54.93 mm (standard deviation (SD) ±12.57) with CEUS and 56.01 mm (SD ± 13.23) with CTA. The mean difference in aneurismal sac diameter was -1.08 mm ± 3.3543 (95% confidence interval (CI), -0.75 to -1.41), in favour of CTA. The number of observed agreement in endoleak detection was 359/395 (90.89%). The two modalities detected the same type I and type III endoleaks. McNemar's χ(2) test confirmed that CTA and CEUS are equivalent in endoleak detection. CONCLUSIONS: CEUS demonstrated to be as accurate as CTA in endoleak detection and abdominal aortic aneurysm diameter measurements during EVAR follow-up, without carrying the risks of radiation exposure or nephrotoxicity. Even if it cannot be proposed as the sole imaging modality during follow-up, our analysis suggests that it should have a major role.

[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.

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.

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.

[Hypofractionated breast radiotherapy in 13 fractions, perfect tolerance or delayed early reaction? Prospective study of Curie Institute]. / La radiothérapie mammaire hypofractionnée en 13 séances, parfaite tolérance ou réaction cutanée décalée ? Etude prospective de l'institut Curie.

PURPOSE: To assess the skin toxicity of this scheme and the time to its appearance. PATIENTS AND METHODS: Eighty-one prospectively recorded patients (pts), treated in Radiotherapy Department for Breast Cancer (BC) with radiotherapy (RT) to the whole breast at the dose of 42.9Gy per 13 fractions (F) per 5 weeks have been studied. Skin reactions were monitored weekly using the National Cancer Institute-Common Toxicity Criteria scoring system, version 3. All risk factors as tobacco smoking, diabetes, obesity were also recorded. RESULTS: All 81 pts, aged from 40 to 83 years (median: 70 years) received whole breast RT 42.9Gy per 13 F without lymph node irradiation after breast conserving surgery. There were no pts with concurrent chemo- and/or hormonal therapy. Seventeen patients (21%) have been treated using decubitus dorsal (DD) technique and 64 (79%) using the previously described isocentric decubitus lateral (IDL) technique. During the RT, only 34 pts (42%) experienced grade I skin reactions and 47 pts (58%) were without. At the last day of the breast irradiation, there were 66 (81%) grade I (N=59) and II (N=7) skin reactions and 15 pts (19%) without. The early skin tolerance of this scheme was considered to be excellent. But in the 2 weeks after the RT, 20 pts (25%) asked for new clinics with their radiation oncologist as a matter of urgency due to worsening of their skin condition. All of them have been seen by their physician and/or the nurse. Of them, nine presented grade I and 11 presented grade II skin reactions, with necessity of special skin care. The analysis of these results was realized and delayed clinics were organized for all pts treated with this scheme 10-14 days after the end of the radiation treatment. CONCLUSIONS: The breast RT 42.9Gy/13 F have been previously described as an efficacious and well tolerated scheme. This prospective homogeneous group of patients showed that delayed early skin reactions could appear in some cases. Therefore complementary clinics are needed to detect and treat these reactions.

[Follow up of endovascular abdominal aortic anevrysm repair with contrast ultrasound]. / Intérêt de l'échographie de contraste dans la surveillance des endoprothèses aortiques.

Endovascular aortic aneurysm repair (EVAR) is a widely accepted treatment for anatomically fitted abdominal aortic aneurysms. The increasing use of this procedure has prompted the need for close surveillance and reliable post-operative imaging. The current tool for assessing EVAR technical success is to perform computed tomography angiography (CTA) in order to exclude endoleaks and to confirm the exclusion of the aneurysm sac. Contrast enhanced ultrasound with low mechanical index is a promising method for follow-up of patients after EVAR. It seems to allow better identification and characterization of endoleaks than unenhanced ultrasound and even than CTA for very low flow endoleaks.

[Cytological study of 191 women with invasive cancer of the uterine cervix in Brittany, France]. / Histoire cytologique de 191 patientes atteintes d'un cancer invasif du col de l'utérus en région Bretagne.

INTRODUCTION: The cancer of the cervix annually occurs in 150 women in Brittany in the absence of organized screening. MATERIAL AND METHODS: Retrospective study concerning 191 patients treated for an invasive cancer of the uterine cervix between 2000 and 2005 analyzing their cytological past. The average age of the patients was 52 years (22-87 years). The socioeconomic level of the patients was recorded. The distribution of under histological types was: squamous, 73% (54 years average age) and adenocarcinoma, 22% (average age 47 years). All the stages were represented: stage I 46%, II 32%, III 9% and stage IV 13%. RESULTS: Cancer was symptomatic in 89% of the cases and 72% of the patients had not profited from cytological screening according to French recommendations (50% no follow-up, 22% follow-up between three and 10 years), while 28% of the patients had a smear in the three years. The socioeconomic level of the patients strongly influenced the participation in screening. The proportion of patients having an invasive adenocarcinom was 31% in the patients with a smear going back to less than three years (versus 22% in our total population) and this histological subtype was mainly represented in patients less than 35 years old (35%). Lastly, 2,6% of the patients were lost after realization of a pathological smear. CONCLUSION: The extension of screening and its organization remain a priority in our area. The average sensitivity of the smear is illustrated by the on-representation of the adenocarcinoma, in particular among young women.

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.

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.

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.

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.