Murine double minute 2 regulates Hu antigen R stability in human liver and colon cancer through NEDDylation

Hu antigen R (HuR) is a central RNA-binding protein regulating cell dedifferentiation, proliferation, and survival, which are well-established hallmarks of cancer. HuR is frequently overexpressed in tumors correlating with tumor malignancy, which is in line with a role for HuR in tumorigenesis. However, the precise mechanism leading to changes in HuR expression remains unclear. In the liver, HuR plays a crucial role in hepatocyte proliferation, differentiation, and transformation. Here, we unraveled a novel mean of regulation of HuR expression in hepatocellular carcinoma (HCC) and colon cancer. HuR levels correlate with the abundance of the oncogene, murine double minute 2 (Mdm2), in human HCC and colon cancer metastases. HuR is stabilized by Mdm2-mediated NEDDylation in at least three lysine residues, ensuring its nuclear localization and protection from degradation. Conclusion: This novel Mdm2/NEDD8/HuR regulatory framework is essential for the malignant transformation of tumor cells, which, in turn, unveils a novel signaling paradigm that is pharmacologically amenable for cancer therapy.     

No effect of menstrual cycle on LDL oxidizability and particle size

OBJECTIVES: Premenopausal women have a lower incidence of cardiovascular disease than men, but this female advantage disappears after menopause, suggesting that female sex hormones exert some cardioprotective effects. One of the mechanisms proposed to explain this cardioprotection is the antioxidant properties of estrogens. The aim of this work was to assess whether fluctuations in ovarian hormones, particularly 17beta-estradiol (E(2)), during the menstrual cycle were associated with changes in the low-density lipoprotein (LDL) particle size, fatty acyl composition, alpha-tocopherol content and in vitro oxidizability. METHODS: Twenty-eight healthy premenopausal women (mean age: 32.2 years) participated in the study. Blood was drawn on days 3 (menstrual phase), 14 (follicular phase) and 22 (luteal phase) of the menstrual cycle for plasma determinations and LDL isolation. Plasma E(2), progesterone, follicle-stimulating hormone and luteinizing hormone were determined by immunoassay. LDL oxidation by Cu(2+)- and 2,2'-azobis (2-amidinopropane) was measured by the formation of conjugated dienes, LDL particle size by quasi-elastic light scattering, fatty acyl composition by gas chromatography, alpha-tocopherol by reversed phase HPLC. A within-subjects analysis of variance was performed to determine significant differences of the variables over the course of a subject's menstrual cycle. RESULTS: The LDL oxidizability indices (lag time before the onset of propagation and the maximal oxidation rate) did not change during the menstrual cycle. The LDL particle size (24.8+/-1.7 nm diameter), alpha-tocopherol (11.7+/-3.7 nmol/mg LDL protein) and fatty acyl composition also remained constant. CONCLUSIONS: The LDL physicochemical properties and oxidizability are not affected by menstrual cycle phase.     

Enhancement of tioconazole ungual delivery: Combining nanocapsule formulation and nail poration approaches

This work investigated the impact of formulation including in vitro release profile, repeated dosing, and nail poration on the ex vivo nail delivery performance of antifungal formulations. Chitosan coated and uncoated tioconazole-loaded nanocapsules and a nano-based film-forming vehicle were assessed via in vitro release and in vitro permeation tests using an artificial membrane and human nail clippings, respectively. The later involved single and daily dosing experiments with intact and porated nails. Additional experiments with Nile Red-loaded formulations evaluated the depth of penetration of the fluorescent marker into the nail by laser scanning confocal microscopy. The nanocapsule formulations prolonged release of tioconazole for longer than the control solutions and this ability was related to an enhanced nail penetration of the drug. Further, the new film-forming formulation delivered its drug payload more efficiently than a marketed product. Daily dosing of the formulations doubled the amount of drug recovered from the nails. Porating the nails enhanced tioconazole delivery in single dose experiments only. The depth of penetration of Nile Red into the nails clippings ranged between 90–160?μm. This research suggests that ensuring prolonged release of a drug is fundamental to develop efficacious topical nail formulations.     

The sooty moulds

Sooty moulds are a remarkable, but poorly understood group of fungi. They coat fruits and leaves superficially with black mycelia, which reduces photosynthesis rates of host plants. Few researchers have, however, tried to quantify their economic importance. Sooty moulds have been well-studied at the morphological level, but they are poorly represented in a natural classification based on phylogeny. Representatives are presently known in Antennulariellaceae, Capnodiaceae, Chaetothyriaceae, Coccodiniaceae, Euantennariaceae, Metacapnodiaceae and Trichomeriaceae and several miscellaneous genera. However, molecular data is available for only five families. Most sooty mould colonies comprise numerous species and thus it is hard to confirm relationships between genera or sexual and asexual states. Future studies need to obtain single spore isolates of species to test their phylogenetic affinities and linkages between morphs. Next generation sequencing has shown sooty mould colonies to contain many more fungal species than expected, but it is not clear which species are dominant or active in the communities. They are more common in tropical, subtropical and warm temperate regions and thus their prevalence in temperate regions is likely to increase with global warming. Sooty moulds are rarely parasitized by fungicolous taxa and these may have biocontrol potential. They apparently grow in extreme environments and may be xerophilic. This needs testing as xerophilic taxa may be of interest for industrial applications. Sooty moulds grow on sugars and appear to out-compete typical “weed” fungi and bacteria. They may produce antibiotics for this purpose and their biochemical potential for obtaining novel bioactive compounds for medical application is underexplored.     

Long-Term Follow-up Assessment After the Arterial Switch Operation for Correction of Dextro-Transposition of the Great Arteries by Means of Exercise Myocardial Perfusion-Gated SPECT

The arterial switch operation (ASO) is the preferred technique for correcting transposition of the great arteries, but translocation and reimplantation of the coronary arteries can produce myocardial ischemia. This report aims to describe the authors’ experience with exercise single-photon emission computed tomography (SPECT) used to evaluate myocardial perfusion. Exercise-rest gated-myocardial perfusion SPECT was performed for 69 patients (49 boys; median age, 9 years; 5th percentile [6.4 years] to 95th percentile [15.6 years]), 64 of whom were asymptomatic 9.98 ± 3.20 years after ASO. During exercise testing, the patients reached 9.85 ± 3.05 metabolic equivalents (METs) and a median heart rate of 160 beats per minute (bpm), 5th percentile (106 bpm) to 95th percentile (196 bpm). Whereas 61 patients (88.41 %) had normal myocardial perfusion, 2 patients (2.9 %) had reversible defects, and 6 patients (8.7 %) had fixed defects. All the patients with perioperative ischemic complications (4/4, 100 %) had myocardial perfusion defects, whereas four patients (4/65, 6.15 %) without ischemic complications had abnormal perfusion (p = 0.0005). Age at the time of surgery did not differ significantly (p = 0.234) between the patients with perfusion defects and those with normal study results. No significant difference was observed between the patients who had an A coronary pattern (left coronary artery originating from the left sinus and the right coronary artery originating from the right sinus, n = 47) and those who had a non-A coronary pattern (n = 22) (p = 1). The high rate for normality of exercise myocardial perfusion in our study suggests that myocardial perfusion gated-SPECT should be reserved for patients who have experienced perioperative ischemic complications or those with symptoms, at least during the first 10 years after the surgery.     

Prosthodontic Considerations in the Implant‐Supported All‐Ceramic Restoration of Congenitally Missing Maxillary Lateral Incisor: A Clinical Report

The congenitally missing maxillary lateral incisor is the most common agenesis in the anterior region. There are several treatment options for this anomaly, which causes severe deficiencies: orthodontic space closure, tooth‐supported restoration, or single‐tooth implant. Each of these solutions has a high degree of success if used in the correct situation. An implant‐supported restoration with an interdisciplinary approach provides a predictable outcome. This article describes the treatment of a patient with agenesis of the maxillary left lateral incisor. After orthodontic space management, it was decided to restore the tooth with an all‐ceramic crown cemented on a zirconia custom abutment, which fractured after only 6 weeks of service. Fractographic analysis revealed that the failure was due to over‐reduction of the buccal wall to correct the labial emergence of the implant. Zirconia abutments should be designed with even wall thicknesses of at least 0.8 mm to avoid areas that may compromise functional success.     

The role of aggressions suffered by healthcare workers as predictors of burnout

Aims and objectives. To examine the prevalence of aggression against healthcare professionals and to determine the possible impact that violent episodes have on healthcare professionals in terms of loss of enthusiasm and involvement towards work. The objective was to analyse the percentage of occupational assault against professionals’ aggression in different types of healthcare services, differentiating between physical and verbal aggression as a possible variable in detecting burnout in doctors and nursing professionals. Background. Leiter and Maslach have explored a double process model of burnout not only based on exhaustion by overload, but also based on personal and organisational value conflicts (community, rewards or values). Moreover, Whittington has obtained conclusive results about the possible relationship between violence and burnout in mental health nurses. Design. A retrospective study was performed in three hospitals and 22 primary care centres in Spain (n = 1·826). Methods. Through different questionnaires, we have explored the relationship between aggression suffered by healthcare workers and burnout. Results. Eleven percent of respondents had been physically assaulted on at least one occasion, whilst 34·4% had suffered threats and intimidation on at least one occasion and 36·6% had been subjected to insults. Both forms of violence, physical and non‐physical aggression, showed significant correlations with symptoms of burnout (emotional exhaustion, depersonalisation and inefficacy). Conclusions. The survey showed evidence of a double process: (1) by which excess workload helps predict burnout, and (2) by which a mismatch in the congruence of values, or interpersonal conflict, contributes in a meaningful way to each of the dimensions of burnout, adding overhead to the process of exhaustion–cynicism–lack of realisation. Relevance to clinical practice. Studies indicate that health professionals are some of the most exposed to disorders steaming from psychosocial risks and a high comorbidity: anxiety, depression, etc. There is a clear need for accurate instruments of evaluation to detect not only the burnout but also the areas that cause it. Professional exhaustion caused by aggression or other factors can reflect a deterioration in the healthcare relationship.     

Outcome in obscure gastrointestinal bleeding after capsule endoscopy

AIM: To investigate the clinical impact of capsule endoscopy (CE) after an obscure gastrointestinal bleeding (OGIB) episode, focusing on diagnostic work-up, follow-up and predictive factors of rebleeding.METHODS: Patients who were referred to Hospital del Mar (Barcelona, Spain) between 2007 and 2009 for OGIB who underwent a CE were retrospectively analyzed. Demographic data, current treatment with non-steroid anti-inflammtory drugs or anticoagulant drugs, hemoglobin levels, transfusion requirements, previous diagnostic tests for the bleeding episode, as well as CE findings (significant or non-significant), work-up and patient outcomes were analyzed from electronic charts. Variables were compared by χ² analysis and Student t test. Risk factors of rebleeding were assessed by Log-rank test, Kaplan-Meier curves and Cox regression model.RESULTS: There were 105 patients [45.7% women, median age of 72 years old (interquartile range 56-79)] and a median follow-up of 326 d (interquartile range 123-641) included in this study. The overall diagnostic yield of CE was 58.1% (55.2% and 63.2%, for patients with occult OGIB and overt OGIB, respectively). In 73 patients (69.5%), OGIB was resolved. Multivariate analysis showed that hemoglobin levels lower than 8 g/dL at diagnosis [hazard ratios (HR) = 2.7, 95%CI: 1.9-6.3], patients aged 70 years and above (HR = 2.1, 95%CI: 1.2-6.1) and significant findings in CE (HR = 2.4, 95%CI: 1.1-5.8) were independent predictors of rebleeding.CONCLUSION: One third of the patients presented with rebleeding after CE; risk factors were hemoglobin levels < 8 g/dL, age ≥ 70 years or the presence of significant lesions.