[Grisel's syndrome : about two cases of a atlantoaxial (C1-C2) subluxation]. / Le syndrome de Grisel : à propos de deux cas de subluxation C1-C2.

Grisel's syndrome is a non-traumatic atlantoaxial (C1-C2) subluxation and one of the causes of torticollis in children. The subluxation occurs in the context of an infection in the ENT ("Ear Nose and Throat") region or following surgery. Diagnosis is based on clinical examination and radiological assessment. Treatment is typically medical and conservative, with surgical interventions reserved for recurrences and late presentations. We discuss here two cases of C1-C2 subluxation. The first case involves a 10-year-old child with subluxation following a rhinopharyngitis. This presentation is the classical manifestation of Grisel's syndrome. Prompt management led to correction of the subluxation using medical treatment and a soft Philadelphia collar. The second case involves a 34-year-old adult who developed posterior headaches after sphenoidotomy surgery. Grisel's syndrome is less common in adults, leading to clinical challenges and delayed diagnosis (> 1 month). Reduction combined with a halo vest treatment failed, and the patient required cervical arthrodesis.

Le syndrome de Grisel est une subluxation atlanto-axoïdienne (C1-C2) non traumatique et l'une des causes de torticolis chez l'enfant. La subluxation survient dans le cadre d'une infection de la sphère ORL ou à la suite d'une chirurgie. Le diagnostic est basé sur la clinique et l'examen radiologique. Le traitement est le plus souvent médical et conservateur. Les prises en charge chirurgicales sont limitées aux récidives et aux présentations tardives.Nous discutons ici deux cas de subluxation C1-C2. La première chez un enfant de 10 ans faisait suite à une rhinopharyngite. Cette présentation correspond à la présentation typique du syndrome de Grisel. Une prise en charge rapide a permis une correction de cette subluxation à l'aide d'un traitement médical et d'une minerve souple de type Philadelphia. Le second cas concerne une adulte de 34 ans qui a présenté des céphalées postérieures à la suite d'une chirurgie de sphénoïdotomie. Le syndrome Grisel est moins fréquent chez l'adulte, ce qui a engendré une errance clinique et un diagnostic retardé (> 1 mois). La réduction associée à un traitement par haloveste a échoué et la patiente a nécessité une arthrodèse cervicale.

Ciliary Functional Analysis in Chronic Rhinosinusitis with Polyps after Multimodal Intervention: Oral Corticosteroid, Functional Endoscopic Sinus Surgery, and Omalizumab Injection.

In her late 50 s, a woman with a medical history of endoscopic sinus surgery for chronic rhinosinusitis with nasal polyps (CRSwNP) experienced a relapse of nasal polyps, significantly impacting her breathing and sense of smell. She underwent a multifaceted treatment approach, including oral corticosteroids, functional endoscopic sinus surgery, and omalizumab injections. Digital high-speed videomicroscopy (DHSV) revealed only partial improvement in ciliary beat pattern and ciliary beat frequency with oral corticosteroid treatment, while significant improvement in these ciliary parameters was observed with omalizumab injections. Furthermore, administration of omalizumab resulted in a decrease in her SNOT-22 (Sinonasal Outcome Test 22) score. Notably, this case report represents the first study investigating ciliary function using DHSV in a patient treated with omalizumab.

Factors Predictive of Binaural Hearing Restoration by Cochlear Implant in Single-Sided Deafness.

INTRODUCTION: Cochlear implants (CIs) can restore binaural hearing in cases of single-sided deafness (SSD). However, studies with a high level of evidence in support of this phenomenon are lacking. The aim of this study is to analyze the effectiveness of CIs using several spatialized speech-in-noise tests and to identify potential predictors of successful surgery. METHODS: Ten cases underwent standard CI surgery (MEDEL-Flex24). The speech-in-noise test was used in three different spatial configurations. The noise was presented from the front (N0), toward the CI (NCI), and toward the ear (Near), while the speech was always from the front (S0). For each test, the speech-to-noise ratio at 50% intelligibility (SNR50) was evaluated. Seven different effects were assessed (summation, head shadow [HS], speech released of masking [SRM], and squelch for the CI and for the ear). RESULTS: A significant summation effect of 1.5 dB was observed. Contralateral PTA was positively correlated with S0N0-B and S0NCI-B (CIon and unplugged ear). S0N0-B results were positively correlated with S0N0-CIoff (p < 0.0001) and with S0Near-CIoff results (p = 0.004). A significant positive correlation was found between delay post-activation and HS gain for the CI (p = 0.005). Finally, the HS was negatively correlated with the squelch effect for the ear. CONCLUSION: CI benefits patients with SSD in noise and can improve the threshold for detecting low-level noise. Contralateral PTA could predict good postoperative results. Simple tests performed preoperatively can predict the likelihood of surgical success in reversing SSD.

The Molecular Circadian Clock Is a Target of Anti-cancer Translation Inhibitors.

Circadian-paced biological processes are key to physiology and required for metabolic, immunologic, and cardiovascular homeostasis. Core circadian clock components are transcription factors whose half-life is precisely regulated, thereby controlling the intrinsic cellular circadian clock. Genetic disruption of molecular clock components generally leads to marked pathological events phenotypically affecting behavior and multiple aspects of physiology. Using a transcriptional signature similarity approach, we identified anti-cancer protein synthesis inhibitors as potent modulators of the cardiomyocyte molecular clock. Eukaryotic protein translation inhibitors, ranging from translation initiation (rocaglates, 4-EGI1, etc.) to ribosomal elongation inhibitors (homoharringtonine, puromycin, etc.), were found to potently ablate protein abundance of REV-ERBα, a repressive nuclear receptor and component of the molecular clock. These inhibitory effects were observed both in vitro and in vivo and could be extended to PER2, another component of the molecular clock. Taken together, our observations suggest that the activity spectrum of protein synthesis inhibitors, whose clinical use is contemplated not only in cancers but also in viral infections, must be extended to circadian rhythm disruption, with potential beneficial or iatrogenic effects upon acute or prolonged administration.

Time-of-day-dependent variation of the human liver transcriptome and metabolome is disrupted in MASLD.

Background & Aims: Liver homeostasis is ensured in part by time-of-day-dependent processes, many of them being paced by the molecular circadian clock. Liver functions are compromised in metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), and clock disruption increases susceptibility to MASLD progression in rodent models. We therefore investigated whether the time-of-day-dependent transcriptome and metabolome are significantly altered in human steatotic and MASH livers. Methods: Liver biopsies, collected within an 8 h-window from a carefully phenotyped cohort of 290 patients and histologically diagnosed to be either normal, steatotic or MASH hepatic tissues, were analyzed by RNA sequencing and unbiased metabolomic approaches. Time-of-day-dependent gene expression patterns and metabolomes were identified and compared between histologically normal, steatotic and MASH livers. Results: Herein, we provide a first-of-its-kind report of a daytime-resolved human liver transcriptome-metabolome and associated alterations in MASLD. Transcriptomic analysis showed a robustness of core molecular clock components in steatotic and MASH livers. It also revealed stage-specific, time-of-day-dependent alterations of hundreds of transcripts involved in cell-to-cell communication, intracellular signaling and metabolism. Similarly, rhythmic amino acid and lipid metabolomes were affected in pathological livers. Both TNFα and PPARγ signaling were predicted as important contributors to altered rhythmicity. Conclusion: MASLD progression to MASH perturbs time-of-day-dependent processes in human livers, while the differential expression of core molecular clock components is maintained. Impact and implications: This work characterizes the rhythmic patterns of the transcriptome and metabolome in the human liver. Using a cohort of well-phenotyped patients (n = 290) for whom the time-of-day at biopsy collection was known, we show that time-of-day variations observed in histologically normal livers are gradually perturbed in liver steatosis and metabolic dysfunction-associated steatohepatitis. Importantly, these observations, albeit obtained across a restricted time window, provide further support for preclinical studies demonstrating alterations of rhythmic patterns in diseased livers. On a practical note, this study indicates the importance of considering time-of-day as a critical biological variable which may significantly affect data interpretation in animal and human studies of liver diseases.

An extended transcription factor regulatory network controls hepatocyte identity.

Cell identity is specified by a core transcriptional regulatory circuitry (CoRC), typically limited to a small set of interconnected cell-specific transcription factors (TFs). By mining global hepatic TF regulons, we reveal a more complex organization of the transcriptional regulatory network controlling hepatocyte identity. We show that tight functional interconnections controlling hepatocyte identity extend to non-cell-specific TFs beyond the CoRC, which we call hepatocyte identity (Hep-ID)CONNECT TFs. Besides controlling identity effector genes, Hep-IDCONNECT TFs also engage in reciprocal transcriptional regulation with TFs of the CoRC. In homeostatic basal conditions, this translates into Hep-IDCONNECT TFs being involved in fine tuning CoRC TF expression including their rhythmic expression patterns. Moreover, a role for Hep-IDCONNECT TFs in the control of hepatocyte identity is revealed in dedifferentiated hepatocytes where Hep-IDCONNECT TFs are able to reset CoRC TF expression. This is observed upon activation of NR1H3 or THRB in hepatocarcinoma or in hepatocytes subjected to inflammation-induced loss of identity. Our study establishes that hepatocyte identity is controlled by an extended array of TFs beyond the CoRC.

Roux-en-Y gastric bypass induces hepatic transcriptomic signatures and plasma metabolite changes indicative of improved cholesterol homeostasis.

BACKGROUND & AIMS: Roux-en-Y gastric bypass (RYGB), the most effective surgical procedure for weight loss, decreases obesity and ameliorates comorbidities, such as non-alcoholic fatty liver (NAFLD) and cardiovascular (CVD) diseases. Cholesterol is a major CVD risk factor and modulator of NAFLD development, and the liver tightly controls its metabolism. How RYGB surgery modulates systemic and hepatic cholesterol metabolism is still unclear. METHODS: We studied the hepatic transcriptome of 26 patients with obesity but not diabetes before and 1 year after undergoing RYGB. In parallel, we measured quantitative changes in plasma cholesterol metabolites and bile acids (BAs). RESULTS: RYGB surgery improved systemic cholesterol metabolism and increased plasma total and primary BA levels. Transcriptomic analysis revealed specific alterations in the liver after RYGB, with the downregulation of a module of genes implicated in inflammation and the upregulation of three modules, one associated with BA metabolism. A dedicated analysis of hepatic genes related to cholesterol homeostasis pointed towards increased biliary cholesterol elimination after RYGB, associated with enhancement of the alternate, but not the classical, BA synthesis pathway. In parallel, alterations in the expression of genes involved in cholesterol uptake and intracellular trafficking indicate improved hepatic free cholesterol handling. Finally, RYGB decreased plasma markers of cholesterol synthesis, which correlated with an improvement in liver disease status after surgery. CONCLUSIONS: Our results identify specific regulatory effects of RYGB on inflammation and cholesterol metabolism. RYGB alters the hepatic transcriptome signature, likely improving liver cholesterol homeostasis. These gene regulatory effects are reflected by systemic post-surgery changes of cholesterol-related metabolites, corroborating the beneficial effects of RYGB on both hepatic and systemic cholesterol homeostasis. IMPACT AND IMPLICATIONS: Roux-en-Y gastric bypass (RYGB) is a widely used bariatric surgery procedure with proven efficacy in body weight management, combatting cardiovascular disease (CVD) and non-alcoholic fatty liver disease (NAFLD). RYGB exerts many beneficial metabolic effects, by lowering plasma cholesterol and improving atherogenic dyslipidemia. Using a cohort of patients undergoing RYGB, studied before and 1 year after surgery, we analyzed how RYGB modulates hepatic and systemic cholesterol and bile acid metabolism. The results of our study provide important insights on the regulation of cholesterol homeostasis after RYGB and open avenues that could guide future monitoring and treatment strategies targeting CVD and NAFLD in obesity.

Use of Vandenberg and Kuse Mental Rotation Test to Predict Practical Performance of Sinus Endoscopy.

OBJECTIVES: The aim of this study was to assess the predictive value of the Vandenberg and Kuse Mental Rotation Test (MRT) on performance of novice medical students for manipulation of a nasal endoscope on a cadaveric model. MATERIAL AND METHOD: We randomly selected 39 medical students who had never handled a nasal endoscope and subjected them to the MRT. General information including experience in manual, technical, or surgical activities and testing of anatomical knowledge were collected to exclude possible confounding factors. They were then asked to perform series of cadaveric model exercises using a nasal endoscope. Their cadaver performance was evaluated by 2 blinded observers, using a standardized scale. RESULTS: We found that medical students with higher mental rotation skills had significantly increased endoscopic sinus performance (P = .0002 using multivariate regression adjusted for specialty choice, previous surgical exposure, and anatomy knowledge). Higher anatomy knowledge was also associated with better endoscopic sinus performance (P = .0141). Other parameters had no impact on endoscopic sinus performance measured by the endoscopic scale (P > .05). CONCLUSION: The score obtained on the MRT was correlated with the practical performance of manipulating the nasal endoscope in cadaver. It could therefore be a useful spatial ability tool for directing targeted training in rhinology.

A targeted multi-omics approach reveals paraoxonase-1 as a determinant of obesity-associated fatty liver disease.

BACKGROUND: The multifactorial nature of non-alcoholic fatty liver disease cannot be explained solely by genetic factors. Recent evidence revealed that DNA methylation changes take place at proximal promoters within susceptibility genes. This emphasizes the need for integrating multiple data types to provide a better understanding of the disease's pathogenesis. One such candidate gene is paraoxonase-1 (PON1). Substantial interindividual differences in PON1 are apparent and could influence disease risk later in life. The aim of this study was therefore to determine the different regulatory aspects of PON1 variability and to examine them in relation to the predisposition to obesity-associated fatty liver disease. RESULTS: A targeted multi-omics approach was applied to investigate the interplay between PON1 genetic variants, promoter methylation, expression profile and enzymatic activity in an adult patient cohort with extensive metabolic and hepatic characterisation including liver biopsy. Alterations in PON1 status were shown to correlate with waist-to-hip ratio and relevant features of liver pathology. Particularly, the regulatory polymorphism rs705379:C > T was strongly associated with more severe liver disease. Multivariable data analysis furthermore indicated a significant association of combined genetic and epigenetic PON1 regulation. This identified relationship postulates a role for DNA methylation as a mediator between PON1 genetics and expression, which is believed to further influence liver disease progression via modifications in PON1 catalytic efficiency. CONCLUSIONS: Our findings demonstrate that vertical data-integration of genetic and epigenetic regulatory mechanisms generated a more in-depth understanding of the molecular basis underlying the development of obesity-associated fatty liver disease. We gained novel insights into how NAFLD classification and outcome are orchestrated, which could not have been obtained by exclusively considering genetic variation.

The Use of a Robot to Insert an Electrode Array of Cochlear Implants in the Cochlea: A Feasibility Study and Preliminary Results.

INTRODUCTION: Cochlear implants (CIs) are commonly used for the rehabilitation of profound bilateral hearing loss. However, patients with substantial residual acoustic hearing are potential CI candidates. Because of both improvements in technology and advancements in surgical techniques, it may be possible to preserve hearing to some extent. For more than a decade, it has been suggested that robots are used to perform middle ear surgery. We evaluated the use of the RobOtol® otologic robot specifically to insert CI electrodes into the inner ear. METHODS: CI surgery with the conventional approach was performed under general anesthesia. The MED-El Flex 24-electrode array was inserted using RobOtol®. Video recordings were used to calculate the speed of insertion. The positions of the electrodes were evaluated using a cone beam CT. All subjects underwent pure-tone audiometry tests before and after surgery, and the pure-tone average (PTA) was calculated from 250 to 4,000 Hz. RESULTS: The robot inserted implants in 5 patients, and complete insertion of the electrode array was achieved. The speed of insertion of the electrode array was 0.88 ± 0.12 mm/s. The mean loss of the PTA for 5 frequencies (250, 500, 1,000, 2,000, and 4,000 Hz) was 13.60 ± 7.70 dB. Only 1 patient showed a loss of the PTA by >20 dB. For these 5 patients, the cone beam CT findings showed that all the electrode arrays were in the tympanic ramp and had a grade of 0. The results were compared with those obtained from a cohort of 17 patients who underwent manual implantation of a MED-El Flex 24-electrode array. CONCLUSION: To minimize disturbance to the cochlea while atraumatic electrode arrays are inserted, electrodes can be inserted at a constant, slow speed in the inner ear with the assistance of the RobOtol® robot in a normal clinical surgical setting.

CDKN2A/p16INK4a suppresses hepatic fatty acid oxidation through the AMPKα2-SIRT1-PPARα signaling pathway.

In addition to their well-known role in the control of cellular proliferation and cancer, cell cycle regulators are increasingly identified as important metabolic modulators. Several GWAS have identified SNPs near CDKN2A, the locus encoding for p16INK4a (p16), associated with elevated risk for cardiovascular diseases and type-2 diabetes development, two pathologies associated with impaired hepatic lipid metabolism. Although p16 was recently shown to control hepatic glucose homeostasis, it is unknown whether p16 also controls hepatic lipid metabolism. Using a combination of in vivo and in vitro approaches, we found that p16 modulates fasting-induced hepatic fatty acid oxidation (FAO) and lipid droplet accumulation. In primary hepatocytes, p16-deficiency was associated with elevated expression of genes involved in fatty acid catabolism. These transcriptional changes led to increased FAO and were associated with enhanced activation of PPARα through a mechanism requiring the catalytic AMPKα2 subunit and SIRT1, two known activators of PPARα. By contrast, p16 overexpression was associated with triglyceride accumulation and increased lipid droplet numbers in vitro, and decreased ketogenesis and hepatic mitochondrial activity in vivo Finally, gene expression analysis of liver samples from obese patients revealed a negative correlation between CDKN2A expression and PPARA and its target genes. Our findings demonstrate that p16 represses hepatic lipid catabolism during fasting and may thus participate in the preservation of metabolic flexibility.

Auditory function and dysfunction: estrogen makes a difference.

Estrogen is the major female hormone involved in reproductive functions, but it also exerts a variety of additional roles in non-reproductive organs. In this review, we highlight the preclinical and clinical studies that have pointed out sex differences and estrogenic influence on audition. We also describe the experimental evidences supporting a protective role of estrogen towards acquired forms of hearing loss. Although a high level of endogenous estrogen is associated with a better hearing function, hormonal treatments at menopause have provided contradictory outcomes. The various factors that are likely to explain these discrepancies include the treatment regimen as well as the hormonal status and responsiveness of the patients. The complexity of estrogen signaling is being untangled and many downstream effectors of its genomic and non-genomic actions have been identified in other systems. Based on these advances and on the common physio-pathological events that underlie age-related, drug or noise-induced hearing loss, we discuss potential mechanisms for their protective actions in the cochlea.

Responsiveness of acoustic rhinometry to septorhinoplasty by comparison with rhinomanometry and subjective instruments.

OBJECTIVES: Nose patency measures and instruments assessing subjective health are increasingly being used in rhinology. However, there is very little evidence of comparing existing methods' responsiveness to change. We evaluated the responsiveness of acoustic rhinometry to nasal valve surgery by comparison with rhinomanometry and patient-reported outcome instruments. DESIGN: Prospective case-control study. SETTING: Tertiary referral University Hospital. PARTICIPANTS: Sixty consecutive patients with internal nasal valve dysfunction and 20 healthy volunteers as control group were enrolled. Prospectively collected data included acoustic rhinometry, rhinomanometry, NOSE scale, SNOT-23 questionnaire, visual analogue scale and demographics. MAIN OUTCOME MEASURES: Primary endpoint was the responsiveness of acoustic rhinometry to functional septorhinoplasty surgery at 3 months. Secondary endpoints were ability of acoustic rhinometry to reflect "known group" differences and correlation to subjective symptoms. RESULTS: Acoustic rhinometry was highly responsive to septorhinoplasty (P < 0.0001) while anterior rhinomanometry was not (P = 0.08). Based on the quartiles of the postoperative change in NOSE score, patients were classified as, respectively, non-responders, mild, moderate and good responders to surgery. Logistic regression model showed that acoustic rhinometry was able to discriminate non-responders to responders to surgery (P = 0.019), while anterior rhinomanometry failed (P = 0.611). Sensitivity and specificity of acoustic rhinometry were significantly higher (ROC area = 0.76) than rhinomanometry (ROC area = 0.48). Acoustic rhinometry was also superior than rhinomanometry to discriminate patients from control subjects and agreed better with patients-based subjective questionnaires. CONCLUSIONS: Our study confirms and quantifies the responsiveness of acoustic rhinometry to nasal valve surgery, with a higher sensitivity and specificity than rhinomanometry.

Hepatocyte-specific loss of GPS2 in mice reduces non-alcoholic steatohepatitis via activation of PPARα.

Obesity triggers the development of non-alcoholic fatty liver disease (NAFLD), which involves alterations of regulatory transcription networks and epigenomes in hepatocytes. Here we demonstrate that G protein pathway suppressor 2 (GPS2), a subunit of the nuclear receptor corepressor (NCOR) and histone deacetylase 3 (HDAC3) complex, has a central role in these alterations and accelerates the progression of NAFLD towards non-alcoholic steatohepatitis (NASH). Hepatocyte-specific Gps2 knockout in mice alleviates the development of diet-induced steatosis and fibrosis and causes activation of lipid catabolic genes. Integrative cistrome, epigenome and transcriptome analysis identifies the lipid-sensing peroxisome proliferator-activated receptor α (PPARα, NR1C1) as a direct GPS2 target. Liver gene expression data from human patients reveal that Gps2 expression positively correlates with a NASH/fibrosis gene signature. Collectively, our data suggest that the GPS2-PPARα partnership in hepatocytes coordinates the progression of NAFLD in mice and in humans and thus might be of therapeutic interest.

Combinatorial regulation of hepatic cytoplasmic signaling and nuclear transcriptional events by the OGT/REV-ERBα complex.

The nuclear receptor REV-ERBα integrates the circadian clock with hepatic glucose and lipid metabolism by nucleating transcriptional comodulators at genomic regulatory regions. An interactomic approach identified O-GlcNAc transferase (OGT) as a REV-ERBα-interacting protein. By shielding cytoplasmic OGT from proteasomal degradation and favoring OGT activity in the nucleus, REV-ERBα cyclically increased O-GlcNAcylation of multiple cytoplasmic and nuclear proteins as a function of its rhythmically regulated expression, while REV-ERBα ligands mostly affected cytoplasmic OGT activity. We illustrate this finding by showing that REV-ERBα controls OGT-dependent activities of the cytoplasmic protein kinase AKT, an essential relay in insulin signaling, and of ten-of-eleven translocation (TET) enzymes in the nucleus. AKT phosphorylation was inversely correlated to REV-ERBα expression. REV-ERBα enhanced TET activity and DNA hydroxymethylated cytosine (5hmC) levels in the vicinity of REV-ERBα genomic binding sites. As an example, we show that the REV-ERBα/OGT complex modulates SREBP-1c gene expression throughout the fasting/feeding periods by first repressing AKT phosphorylation and by epigenomically priming the Srebf1 promoter for a further rapid response to insulin. Conclusion: REV-ERBα regulates cytoplasmic and nuclear OGT-controlled processes that integrate at the hepatic SREBF1 locus to control basal and insulin-induced expression of the temporally and nutritionally regulated lipogenic SREBP-1c transcript.

Circulating PCSK9 levels are not associated with the severity of hepatic steatosis and NASH in a high-risk population.

BACKGROUND AND AIMS: Some studies suggested that proprotein convertase subtilisin kexin type 9 (PCSK9) is linked to liver steatosis severity and non-alcoholic steatohepatitis (NASH). We aimed to assess whether circulating PCSK9 levels are associated with either liver fat content (LFC) or histological markers of NASH in high-risk patients. METHODS: We present results from three cross-sectional studies from two French Hospitals: Dijon and Numevox (departments of Endocrinology) and Angers (department of Hepatology). Only patients without lipid-lowering therapy were included. All 132 patients had type 2 diabetes in Dijon, compared to 55/224 in Numevox (25%) and 39/122 in Angers (32%). LFC was assessed on MRI (Dijon and Numevox), and NASH lesion on liver biopsy (Angers). Additionally, we included mRNA results from 138 overweight patients of a Belgian Hospital (Antwerp). RESULTS: While circulating levels of PCSK9 were positively correlated with total cholesterol, LDL-C, triglycerides and non-HDL-C in all 3 cohorts, no significant association was found between PCSK9 and transaminases. Furthermore, no association was found between plasma PCSK9 levels and LFC in both Numevox (ßadjusted = 0.71 ±â€¯1.33, p = 0.60) and Dijon (ßadjusted = -1.03 ±â€¯0.90, p = 0.25). There was no correlation between circulating PCSK9 and histological liver lesions: steatosis severity (ßadjusted = -3.95 ±â€¯2.75, p = 0.15), NASH activity score (ßadjusted = -0.31 ±â€¯0.17, p = 0.082), lobular (ß = -0.067 ±â€¯0.055, p = 0.22) or portal inflammation (ß = -0.088 ±â€¯0.079, p = 0.27), ballooning (ß = -0.025 ±â€¯0.065, p = 0.70) and fibrosis (ß = -0.17 ±â€¯0.11, p = 0.12). Finally, hepatic PCSK9 mRNA levels were not correlated with NASH histological severity. CONCLUSIONS: Circulating PCSK9 concentrations are not associated with the severity of liver steatosis or histological markers of NASH. These data are reassuring regarding the clinical use of PCSK9 inhibitors in cardiovascular diseases.

Stapes Surgery for Otosclerosis in Patients Presenting with Mixed Hearing Loss.

OBJECTIVES: To evaluate the efficacy of stapes surgery in patients presenting with a preoperative mixed hearing loss (bone conduction thresholds ≥40 dB; 40 < air conduction thresholds (AC) < 85 dB). PATIENTS AND METHODS: A total of 30 patients (32 ears) with mixed hearing loss who underwent primary stapedotomy were evaluated. Audiometric parameters were assessed before and after surgery. Contralateral thresholds were also reported. The need for a hearing aid (HA) after surgery and its impact on quality of life were also measured. RESULTS: AC and word recognition at 40, 55 and 70 dB were significantly improved after stapes surgery. Only 16.6% of the patients needed an HA after surgery and reported being satisfied with the aid. CONCLUSION: Stapes surgery improved auditory function in patients with mixed hearing loss, allowing most patients to delay the need for an HA without worsening their quality of life.

The nuclear bile acid receptor FXR is a PKA- and FOXA2-sensitive activator of fasting hepatic gluconeogenesis.

BACKGROUND & AIMS: Embedded into a complex signaling network that coordinates glucose uptake, usage and production, the nuclear bile acid receptor FXR is expressed in several glucose-processing organs including the liver. Hepatic gluconeogenesis is controlled through allosteric regulation of gluconeogenic enzymes and by glucagon/cAMP-dependent transcriptional regulatory pathways. We aimed to elucidate the role of FXR in the regulation of fasting hepatic gluconeogenesis. METHODS: The role of FXR in hepatic gluconeogenesis was assessed in vivo and in mouse primary hepatocytes. Gene expression patterns in response to glucagon and FXR agonists were characterized by quantitative reverse transcription PCR and microarray analysis. FXR phosphorylation by protein kinase A was determined by mass spectrometry. The interaction of FOXA2 with FXR was identified by cistromic approaches and in vitro protein-protein interaction assays. The functional impact of the crosstalk between FXR, the PKA and FOXA2 signaling pathways was assessed by site-directed mutagenesis, transactivation assays and restoration of FXR expression in FXR-deficient hepatocytes in which gene expression and glucose production were assessed. RESULTS: FXR positively regulates hepatic glucose production through two regulatory arms, the first one involving protein kinase A-mediated phosphorylation of FXR, which allowed for the synergistic activation of gluconeogenic genes by glucagon, agonist-activated FXR and CREB. The second arm involves the inhibition of FXR's ability to induce the anti-gluconeogenic nuclear receptor SHP by the glucagon-activated FOXA2 transcription factor, which physically interacts with FXR. Additionally, knockdown of Foxa2 did not alter glucagon-induced and FXR agonist enhanced expression of gluconeogenic genes, suggesting that the PKA and FOXA2 pathways regulate distinct subsets of FXR responsive genes. CONCLUSIONS: Thus, hepatic glucose production is regulated during physiological fasting by FXR, which integrates the glucagon/cAMP signal and the FOXA2 signal, by being post-translationally modified, and by engaging in protein-protein interactions, respectively. LAY SUMMARY: Activation of the nuclear bile acid receptor FXR regulates gene expression networks, controlling lipid, cholesterol and glucose metabolism, which are mostly effective after eating. Whether FXR exerts critical functions during fasting is unknown. The results of this study show that FXR transcriptional activity is regulated by the glucagon/protein kinase A and the FOXA2 signaling pathways, which act on FXR through phosphorylation and protein-protein interactions, respectively, to increase hepatic glucose synthesis.

Development and implementation of a cell-based assay to discover agonists of the nuclear receptor REV-ERBα.

The nuclear receptors are transcription factors involved in the regulation of a variety of physiological processes whose activity can be modulated by binding to relevant small molecule ligands. Their dysfunction has been shown to play a role in disease states such as diabetes, cancer, inflammatory diseases, and hormonal resistance ailments, which makes them interesting targets for drug discovery. The nuclear receptor REV-ERBα is involved in regulating the circadian rhythm and metabolism. Its natural ligand is heme and there is significant interest in identifying novel synthetic modulators to serve as tools to characterize its function and to serve as drugs in treating metabolic disorders. To do so, we established a mammalian cell-based two-hybrid assay system capable of measuring the interaction between REV-ERBα and its co-repressor, nuclear co-repressor 1. This assay was validated to industry standard criteria and was used to screen a subset of the LOPAC®1280 library and 29568 compounds from a diverse compound library. Profiling of the primary hits in a panel of counter and selectivity assays confirmed that REV-ERBα activity can be modulated pharmacologically and chemical scaffolds have been identified for optimization.

Daytime variation of perioperative myocardial injury in cardiac surgery and its prevention by Rev-Erbα antagonism: a single-centre propensity-matched cohort study and a randomised study.

BACKGROUND: On-pump cardiac surgery provokes a predictable perioperative myocardial ischaemia-reperfusion injury which is associated with poor clinical outcomes. We determined the occurrence of time-of-the-day variation in perioperative myocardial injury in patients undergoing aortic valve replacement and its molecular mechanisms. METHODS: We studied the incidence of major adverse cardiac events in a prospective observational single-centre cohort study of patients with severe aortic stenosis and preserved left ventricular ejection fraction (>50%) who were referred to our cardiovascular surgery department at Lille University Hospital (Lille, France) for aortic valve replacement and underwent surgery in the morning or afternoon. Patients were matched into pairs by propensity score. We also did a randomised study, in which we evaluated perioperative myocardial injury and myocardial samples of patients randomly assigned (1:1) via permuted block randomisation (block size of eight) to undergo isolated aortic valve replacement surgery either in the morning or afternoon. We also evaluated human and rodent myocardium in ex-vivo hypoxia-reoxygenation models and did a transcriptomic analysis in myocardial samples from the randomised patients to identify the signalling pathway(s) involved. The primary objective of the study was to assess whether myocardial tolerance of ischaemia-reperfusion differed depending on the timing of aortic valve replacement surgery (morning vs afternoon), as measured by the occurrence of major adverse cardiovascular events (cardiovascular death, myocardial infarction, and admission to hospital for acute heart failure). The randomised study is registered with ClinicalTrials.gov, number NCT02812901. FINDINGS: In the cohort study (n=596 patients in matched pairs who underwent either morning surgery [n=298] or afternoon surgery [n=298]), during the 500 days following aortic valve replacement, the incidence of major adverse cardiac events was lower in the afternoon surgery group than in the morning group: hazard ratio 0·50 (95% CI 0·32-0·77; p=0·0021). In the randomised study, 88 patients were randomly assigned to undergo surgery in the morning (n=44) or afternoon (n=44); perioperative myocardial injury assessed with the geometric mean of perioperative cardiac troponin T release was significantly lower in the afternoon group than in the morning group (estimated ratio of geometric means for afternoon to morning of 0·79 [95% CI 0·68-0·93; p=0·0045]). Ex-vivo analysis of human myocardium revealed an intrinsic morning-afternoon variation in hypoxia-reoxygenation tolerance, concomitant with transcriptional alterations in circadian gene expression with the nuclear receptor Rev-Erbα being highest in the morning. In a mouse Langendorff model of hypoxia-reoxygenation myocardial injury, Rev-Erbα gene deletion or antagonist treatment reduced injury at the time of sleep-to-wake transition, through an increase in the expression of the ischaemia-reperfusion injury modulator CDKN1a/p21. INTERPRETATION: Perioperative myocardial injury is transcriptionally orchestrated by the circadian clock in patients undergoing aortic valve replacement, and Rev-Erbα antagonism seems to be a pharmacological strategy for cardioprotection. Afternoon surgery might provide perioperative myocardial protection and lead to improved patient outcomes compared with morning surgery. FUNDING: Fondation de France, Fédération Française de Cardiologie, EU-FP7-Eurhythdia, Agence Nationale pour la Recherche ANR-10-LABX-46, and CPER-Centre Transdisciplinaire de Recherche sur la Longévité.