The Role of Ceramide in Inherited Retinal Disease Pathology.

Ceramide (Cer) plays an essential role in photoreceptor cell death in the retina. On the one hand, Cer accumulation emerges as a common feature during retina neurodegeneration, leading to the death of photoreceptors. On the other hand, Cer deficiency has also recently been associated with retinal dysfunction and degeneration. Although more and more evidence supports the importance of maintaining Cer homeostasis in the retina, mechanistic explanations of the observed phenotypes, especially in the context of Cer deficiency, are still lacking. An enhanced understanding of Cer's role in the retina will help us explore the underlying molecular basis for clinical phenotypes of retinal dystrophies and provide us with potential therapeutic targets.

Ceramide compensation by ceramide synthases preserves retinal function and structure in a retinal dystrophy mouse model.

Increasing evidence has supported the role of ceramide as a mediator of photoreceptor dysfunction or cell death in ceramide accumulation and deficiency contexts. TLCD3B, a non-canonical ceramide synthase, was previously identified in addition to the six canonical ceramide synthases (CerSs), and the Tlcd3b-/- mouse model exhibited both retinal dysfunction and degeneration. As previous canonical CerS-deficient mouse models failed to display retinal degeneration, the mechanisms of how TLCD3B interacts with CerSs have not been investigated. Additionally, as the ceramide profile of each CerS is distinct, it is unclear whether the overall level or the homeostasis of different ceramide species plays a critical role in photoreceptor degeneration. Interactions between TLCD3B with canonical CerSs expressed in the retina were examined by subretinally injecting recombinant adeno-associated virus 8 vectors containing the Cers2 (rAAV8-CerS2), Cers4 (rAAV8-CerS4) and Cers5 (rAAV8-CerS5) genes. Injection of all three rAAV8-CerS vectors restored retinal functions as indicated by improved electroretinogram responses, but only rAAV8-CerS5 successfully retained retinal morphology in Tlcd3b-/- mice. CerSs and TLCD3B played partially redundant roles. Additionally, rather than acting as an integral entity, different ceramide species had different impacts on retinal cells, suggesting that the maintenance of the overall ceramide profile is critical for retinal function.

The Role of Ambulatory Heart Failure Clinics to Avoid Heart Failure Admissions.

BACKGROUND: There is a complex relationship between heart failure (HF) clinic services and health outcomes. We hypothesized that ambulatory clinic activity may be associated with both hospital admission and also with avoidance of admission. METHODS: A retrospective comparative cohort study was conducted examining activity in an ambulatory HF Clinic. Consecutive clinic visits in 2013 were recorded (n = 1728) and periods of high-intensity utilization (HIU) were identified (n = 128). A HIU period was defined by ≥2 consecutive clinic visits within 30 days, ending after 30 days passed without an additional clinic visit. For each HIU period identified, patient characteristics (n = 107) and all clinic visits (n = 324) were examined. HIU periods were then classified by association with hospital admission (±30 days). RESULTS: In 2013, 18.8% of all clinic visits occurred during HIU periods, involving 13.7% of the clinic population. Thirty-eight percent of HIU periods were associated with 62 total hospital admissions (±30 days), of which 58% (n = 36) were for a primary diagnosis of HF. In addition,17 HIU periods met criteria for admission avoided, and 7 HIU periods occurring after hospital discharge also met criteria for admission avoided. CONCLUSIONS: We identified periods of intensive ambulatory clinic activity dedicated to patients with high burdens of comorbidities and both HF and non-HF-related admissions. These periods were also associated with episodes of successful decongestion with oral diuretics, resulting in avoidance of admission. Identifying HF patients who can be treated successfully or who are likely to require admission may be helpful for allocating clinic resources.

CONTEXTE: Il existe un lien complexe entre les services cliniques relatifs à l'insuffisance cardiaque (IC) et les résultats liés à la santé. Nous avons posé l'hypothèse que l'activité dans les unités de soins ambulatoires pourrait avoir une influence à la fois sur les hospitalisations et sur l'évitement des hospitalisations. MÉTHODOLOGIE: Une étude de cohorte comparative rétrospective a été menée afin d'examiner l'activité dans une unité de soins ambulatoires auprès de patients atteints d'IC. Les visites consécutives effectuées à l'unité de soins en 2013 ont été compilées (n = 1728) et les périodes d'utilisation intensive des services (UIS) ont été relevées (n = 128). Une période d'UIS était définie par au moins 2 visites consécutives à l'unité de soins ambulatoires en l'espace de 30 jours; la période était considérée comme terminée après 30 jours sans nouvelle visite. Pour chaque période d'UIS relevée, les caractéristiques des patients (n = 107) et toutes les visites à l'unité de soins (n = 324) ont été examinées. Les périodes d'UIS ont ensuite été classées en fonction de leur association avec une hospitalisation (± 30 jours). RÉSULTATS: En 2013, 18,8 % de toutes les visites à l'unité de soins ambulatoires étaient rattachées à une période d'UIS et concernaient 13,7 % des patients de l'unité. Au total, 38 % des périodes d'UIS ont été associées à 62 hospitalisations (± 30 jours), dont 58 % (n = 36) étaient liées à un diagnostic primaire d'IC. En outre, 17 périodes d'UIS répondaient aux critères définissant une hospitalisation évitée, et 7 périodes d'UIS survenues après que le patient soit sorti de l'hôpital répondaient aussi aux critères définissant une hospitalisation évitée. CONCLUSIONS: Nous avons relevé des périodes d'activité intensive de l'unité de soins ambulatoires consacrées à des patients présentant un lourd fardeau de comorbidité, ainsi que les hospitalisations liées à l'IC et non liées à l'IC. Ces périodes étaient aussi associées à des épisodes de congestion soulagée grâce à des diurétiques oraux, ce qui a permis d'éviter des hospitalisations. Le repérage des patients atteints d'IC qui peuvent être traités efficacement en consultation externe et de ceux qui risquent de devoir être hospitalisés pourrait permettre d'optimiser l'affectation des ressources des unités de soins.

The effect of time interval of vaginal ring pessary replacement for pelvic organ prolapse on complications and patient satisfaction: A randomised controlled trial.

OBJECTIVES: Limited data are available on the effect of the time interval of vaginal ring pessary replacement for pelvic organ prolapse (POP). This study investigated the effect of different replacement intervals on complications and patient satisfaction. STUDY DESIGN: A double-blinded, randomized controlled trial was conducted in a tertiary urogynecology center. Women with a vaginal ring pessary for POP (stage I to IV) were randomly allocated to two groups: 3-monthly or 6-monthly ring pessary replacement. All women were blinded to the replacement interval. Investigators were blinded during outcome assessment. Subjects were followed up for 6 months. MAIN OUTCOME MEASURES: The primary outcomes were the complication rates and patient satisfaction scores at 6 months. Secondary outcomes were the change in patient-reported symptoms and staging of POP. RESULTS: Of 101 women were screened from June 2016 to November 2017, 60 were recruited and randomly allocated: 30 to the 3-monthly replacement group and 30 to the 6-monthly replacement group. The overall complication rate in the 6-monthly group was higher than that in the 3-monthly group at the third visit (9 [30%] vs. 3[10.3%]; OR 3.71; 95%CI 0.89-15.58), but the difference was not statistically significant (p = 0.061). There were no statistically significant differences between groups in patient satisfaction scores, other prolapse-related symptoms or staging of POP. CONCLUSIONS: We provide evidence on the effect of replacement interval for a vaginal pessary on complications and patient satisfaction. A higher complication rate was found in the 6-monthly group than in the 3-monthly group, although the difference was not statistically significant. Patient satisfaction scores were similar in both groups.

Coordination of Myeloid Differentiation with Reduced Cell Cycle Progression by PU.1 Induction of MicroRNAs Targeting Cell Cycle Regulators and Lipid Anabolism.

During macrophage development, myeloid progenitor cells undergo terminal differentiation coordinated with reduced cell cycle progression. Differentiation of macrophages from myeloid progenitors is accompanied by increased expression of the E26 transformation-specific transcription factor PU.1. Reduced PU.1 expression leads to increased proliferation and impaired differentiation of myeloid progenitor cells. It is not understood how PU.1 coordinates macrophage differentiation with reduced cell cycle progression. In this study, we utilized cultured PU.1-inducible myeloid cells to perform genome-wide chromatin immunoprecipitation sequencing (ChIP-seq) analysis coupled with gene expression analysis to determine targets of PU.1 that may be involved in regulating cell cycle progression. We found that genes encoding cell cycle regulators and enzymes involved in lipid anabolism were directly and inducibly bound by PU.1 although their steady-state mRNA transcript levels were reduced. Inhibition of lipid anabolism was sufficient to reduce cell cycle progression in these cells. Induction of PU.1 reduced expression of E2f1, an important activator of genes involved in cell cycle and lipid anabolism, indirectly through microRNA 223. Next-generation sequencing identified microRNAs validated as targeting cell cycle and lipid anabolism for downregulation. These results suggest that PU.1 coordinates cell cycle progression with differentiation through induction of microRNAs targeting cell cycle regulators and lipid anabolism.