Search

Objective: Steatotic liver disease (SLD) is frequent in individuals with obesity. In this study, type 2 diabetes (T2D), sex, and menopausal status were combined to refine the stratification of obesity regarding the risk of advanced SLD and gain further insight into disease physiopathology. Methods: This study enrolled 1446 participants with obesity from the ABOS cohort (NCT01129297), who underwent extensive phenotyping, including liver histology and transcriptome profiling. Hierarchical clustering was applied to classify participants. The prevalence of metabolic disorders associated with steatohepatitis (NASH) and liver fibrosis (F ≥ 2) was determined within each identified subgroup and aligned to clinical and biological characteristics. Results: The prevalence of NASH and F ≥ 2 was, respectively, 9.5% (N = 138/1446) and 11.7% (N = 159/1365) in the overall population, 20.3% (N = 107/726) and 21.1% (N = 106/502) in T2D patients, and 3.4% (N = 31/920) and 6.1% (N = 53/863) in non‐T2D patients. NASH and F ≥ 2 prevalence was 15.4% (33/215) and 15.5% (32/206) among premenopausal women with T2D vs. 29.5% (33/112) and 30.3% (N = 36/119) in postmenopausal women with T2D (p < 0.01); and 21.0% (21/100) / 27.0% (24/89) in men with T2D ≥ age 50 years and 17.9% (17/95) / 18.5% (17/92) in men with T2D < age 50 years (NS). The distinct contribution of menopause was confirmed by the interaction between sex and age with respect to NASH among T2D patients (p = 0.048). Finally, several NASH‐associated biological traits (lower platelet count; higher serum uric acid; gamma‐glutamyl transferase; aspartate aminotransferase) and liver expressed genes AKR1B10 and CCL20 were significantly associated with menopause in women with T2D but not with age in men with T2D. Conclusions: This study unveiled a remarkably high prevalence of advanced SLD after menopause in women with T2D, associated with a dysfunctional biological liver profile. [ABSTRACT FROM AUTHOR]

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. Synopsis: Hepatocyte identity is controlled by interconnected transcription factors (TFs) extending beyond the core regulatory TF network (CoRC). The extended network comprises thyroid hormone receptor beta whose activation resets CoRC TFs expression and hepatocyte identity in dedifferentiated hepatocytes. Hepatocyte identity TFs of the CoRC are tightly connected to a large set of non‐hepatocyte‐specific TFs that we call Hep‐IDCONNECT TFsHep‐IDCONNECT TFs fine tune hepatocyte identity TF expression in homeostatic basal conditionsIn dedifferentiated hepatocytes, Hep‐IDCONNECT TFs can reset hepatocyte identity as shown for the thyroid hormone receptor beta whose activation induces expression of the CoRC TFs in hepatocarcinoma and in hepatocytes subjected to inflammation‐induced loss of identity. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Highlights: [•] Nur77 promoter activity is regulated by palmitate in MIN6 cells. [•] Palmitate treatment modulates the balance between ZBP89 and Sp1 binding to the Nur77 promoter. [•] Activation of Nur77 promoter by palmitate is modulated by ZBP89 and Sp1. [Copyright &y& Elsevier]

Abstract: Nuclear receptors (NRs) are molecular transducers of endocrine and dietary signals allowing tissues to adapt their transcriptional responses to endogenous or exogenous cues. These signals act in many cases as specific ligands, converting of NRs into transcriptionally active molecules. This on-off mechanism needs, however, to be finely tuned with respect to the tissue environment and adjusted to the organism needs. These subtle adjustments of NR transcriptional activity are brought about by post-translational modifications (PTMs), which can be, in the case of orphan NRs, the sole regulatory mechanism. The role of PTMs, with a more specific focus on phosphorylation, affecting the functions of NR controlling metabolic events is described in this review. [Copyright &y& Elsevier]

J. Neurochem. (2010) 114, 1827–1839. The cochleo-vestibular ganglion contains neural crest-derived glial cells and sensory neurons that are derived from the neurogenic otic placode. Little is known about the molecular mechanisms that regulate the tightly orchestrated development of this structure. Here, we report that Sox10, a high-mobility group DNA-binding domain transcription factor that is required for the proper development of neural crest cell derivatives, is specifically expressed in post-migratory neural crest cells in the cochleo-vestibular ganglion. Using Sox10-deficient mice, we demonstrate that this transcription factor is essential for the survival, but not the generation, of the post-migratory neural crest cells within the inner ear. In the absence of these neural crest-derived cells, we have investigated the survival of the otocyst-derived auditory neurons. Surprisingly, auditory neuron differentiation, sensory target innervation and survival are conserved despite the absence of glial cells. Moreover, brain-derived neurotrophic factor expression is increased in the hair cells of Sox10-deficient mice, a compensatory mechanism that may prevent spiral ganglion neuronal cell death. Taken together, these data suggest that in the absence of neural crest-derived glial cells, an increase trophic support from hair cells promotes the survival of spiral ganglion neurons in Sox10 mutant mice. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which discusses the characterization of hepatitis C virus caused by remodelling of nasal nucosa.

Nurr1 (NR4A2) is an atypical nuclear receptor (NR) because of its inability to bind a ligand and to activate transcription following canonical NR rules. An affinity chromatography-based screen identified the glucocorticoid receptor (GR) as an interactant of Nurr1. The co-localization of these two NRs in the hippocampus and the substantia nigra, as well as their involvement in similar neurological processes led us to investigate the functional consequences of such a physical interaction. GR interfered with Nurr1 transcriptional activity, and Nurr1 association to GR confers glucocorticoid regulation to this orphan receptor. The N-terminal domain of Nurr1 interacts directly with GR, whereas several domains of GR can associate to Nurr1. The GR-mediated increase in Nurr1 transcriptional activity requires the N-terminal domain of GR, but not a functional DNA binding domain. Finally, SMRT and SRC2, two co-regulators of GR, modulated the transcriptional activity of the Nurr1-GR complex, but not that of Nurr1 alone. Our results therefore establish GR as a transcriptional regulator of Nurr1, and open new opportunities in the pharmacological regulation of Nurr1 by glucocorticoids in the CNS. [ABSTRACT FROM AUTHOR]

Ligand-dependent transcriptional activation of retinoic acid receptors (RARs) is a multistep process culminating in the formation of a multimeric co-activator complex on regulated promoters. Several co-activator complexes harbor an acetyl transferase activity, which is required for retinoid-induced transcription of reporter genes. Using murine P19 embryonal carcinoma cells, we examined the relationship between histone post-translational modifications and activation of the endogenous RARβJ32 promoter, which is under the control of a canonical retinoic acid response element and rapidly induced upon retinoid treatment. While histones H3 and H4 were constitutively acetylated at this promoter, retinoid agonists induced a rapid phosphorylation at Ser10 of histone H3. A retinoid antagonist, whose activity was independent of co-repressor binding to RAR, could oppose this agonist-induced H3 phosphorylation. Since such post-translational modifications were not observed at several other promoters, we conclude that histone H3 phosphorylation may be a molecular signature of the activated, retinoid-controlled mRARβ32 gene promoter. [ABSTRACT FROM AUTHOR]

The cytosolic untransformed molybdate-stabilized glucocorticoid-receptor complex from rat liver was eluted as a heterogenous peak containing two components with Stokes radii (Rs) of 8.3 nm and 7.1 nm when analyzed by size-exclusion HPLC even in the absence of molybdate. In contrast, the highly purified glucocorticoid receptor yielded a sharp symmetrical peak of Rs = 7.1 nm. We demonstrate that the 7.1-nm component could not result from a proteolytic degradation of the 8.3-nm receptor form. The same receptor heterogeneity was observed in thymus cytosol which contains less proteases than liver. After labeling with [³H]dexamethasone 21-mesylate and SDS/PAGE the same 94-kDa receptor band was revealed in both the 8.3-nm and 7.1-nm forms. Immunoblotting experiments showed that both the 94-kDa hormone-binding subunit and the 90-kDa heat-shock protein were present in the two different receptor forms. The 8.3-nm receptor form was converted to the 7.1-nm receptor form after treatment by ribonuclease A in the presence of molybdate and this effect was dose-dependent, being completely prevented by placental ribonuclease inhibitor (RNasin). In contrast, in the presence of molybdate, the 7.1-nm receptor form was ribonuclease-insensitive. Treatment of cytosol with RNase A in the absence of molybdate, partially shifted the untransformed receptor towards the 5.2-nm transformed receptor form. This effect was abolished by placental ribonuclease inhibitor. RNase S protein, an enzymatically inactive proteolytic fragment of RNase A, or S1 nuclease, which is specific for single-stranded nucleic acids, were ineffective when used instead of RNase A. In contrast, cobra venom endonuclease, which preferentially attacks double-stranded regions of small RNAs, caused a complete conversion of the 7-8-nm untransformed receptor to the 5.2-nm transformed receptor form. These results were not observed in the presence of molybdate. Addition of RNasin prior to heating cytosol in the absence of molybdate did not prevent the receptor from dissociating to the 5.2-nm form, suggesting that an endogenous RNase is not involved in the transformation process. The 7.1-nm receptor form was shifted to a 9.2-nm complex when incubated with an excess of GR 49 antireceptor antibody, whereas the 8.3-nm receptor form did not bind to the antibody. Furthermore, both these receptor forms were shifted when incubated with the monoclonal AC 88 anti-(heat-shock protein) antibody. These results domonstrate that a ribonuclease-sensitive cytosolic factor is closely associated to the receptor protein inside the heteromeric untransformed glucocorticoid receptor. To identify the receptor-associated RNA, the untransformed receptor was purified by protamine sulfate precipitation, affinity chromatography and size-exclusion HPLC. Samples were extracted with phenol and RNA was end-labeled with 32P. Receptor purification led to a specific enrichment in a 120-nucleotide RNA band which could not be detected when a mock purification was performed. Taken together these results suggest that a highly structured small RNA molecule is associated with the untransformed glucocorticoid-receptor complex. [ABSTRACT FROM AUTHOR]

Whooping cough is resurgent in the developed world. Systematic vaccination has changed its epidemiology, with the majority of cases now primarily affecting adolescents and adults. A 46-year-old male physiotherapist presented with a 1-week history of bothersome cough and respiratory difficulties, and a 51-year-old man was admitted to the emergency department with a 4-week history of increasing cough and dyspnea. Polymerase chain reaction of nasopharyngeal swab were positive for Bordetella pertussis. These cases illustrate pertussis in adulthood. We review the clinical features, the prevalence, the diagnostic tools, and the management of the patients and their relatives to increase awareness of this highly contagious disease. Laryngoscope, 2009 [ABSTRACT FROM AUTHOR]

Molecular cues that drive the generation of the highly organized organ of Corti with intricated hair cells (HCs) and supporting cells (SCs) remain broadly unknown. We wanted to assess whether the activity of cyclin-dependent kinases (CDKs) could control cell fate, differentiation, or proliferation in embryonic and neonatal organs of Corti. [ABSTRACT FROM AUTHOR]

Whooping cough is resurgent in the developed world. Systematic vaccination has changed its epidemiology, with the majority of cases now primarily affecting adolescents and adults. A 46-year-old male physiotherapist presented with a 1-week history of bothersome cough and respiratory difficulties, and a 51-year-old man was admitted to the emergency department with a 4-week history of increasing cough and dyspnea. Polymerase chain reaction of nasopharyngeal swab were positive for Bordetella pertussis. These cases illustrate pertussis in adulthood. We review the clinical features, the prevalence, the diagnostic tools, and the management of the patients and their relatives to increase awareness of this highly contagious disease.

Objective: In this pilot study are presented the first clinical experiences of the use of a resorbable bioimplant made of esterified hyaluronic acid inserted in the microdissected superficial layer of the lamina propria (SLLP), also called Reinke's space, after a flap excision procedure for a benign vocal fold lesion. Laryngeal and vocal evolution of implanted patients are depicted and discussed., Study Design: Eleven bio-implants have been inserted in microdissected SLLP of 11 cases presenting with benign vocal fold lesions. The surgical procedure consisted of the excision of primary lesion by a microflap technique immediately followed by implantation of esterified hyaluronic acid in Reinke's space., Methods: All patients underwent rigid laryngoscopy and a microsurgical procedure under general anesthesia. The cordal lesion was treated with cold instrumentation of Bouchayer (7 cases) or with a mixed technique using CO(2) laser (4 cases). After the classical freeing-up of Reinke's space and the creation of a mucosal flap, a few fibers of esterified hyaluronic bioimplant are gently arranged in Reinke's space before redraping the ligament and closing the cordal incision with a few drops of fibrin glue. Laryngeal and vocal assessments were performed pre- and postoperatively in all patients using videostroboscopy as well as perceptual and objective voice evaluation. All patients were followed in a longitudinal manner: between two and five postoperative evaluations were performed. The longest follow-up was 19 months and the shortest 2 months., Results: All cases exhibited postsurgical improvement of the pliability of the SLLP. None of them developed an adverse scarring process. Improvement of SLLP's pliability was maintained in time in all cases. Vocal improvement was observed in all. Temporary inflammation was noted in one case. There were no serious adverse effects apparent during the follow-up period., Conclusion: Bio-implantation of esterified hyaluronic acid in Reinke's space is technically easy and well tolerated. All treated cases exhibited postoperative good pliability of the SLLP compared with their preoperative evaluation.