Secretion and uptake of copper via a small copper carrier in blood fluid.

Studies with Wilson disease model mice that accumulate excessive copper, due to a dysfunctional ATP7B "copper pump" resulting in decreased biliary excretion, showed that the compensatory increase in urinary copper loss was due to a small copper carrier (∼1 kDa) (SCC). We show here that SCC is also present in the blood plasma of normal and Wilson disease model mice and dogs, as determined by ultrafiltration and size exclusion chromatography (SEC). It is secreted by cultured hepatic and enterocytic cells, as determined by pretreatment with 67Cu nitrilotriacetate (NTA) or nonradioactive 5-10 µM Cu-NTA, and collecting and examining 3 kDa ultrafiltrates of the conditioned media, where a single major copper peak is detected by SEC. Four different cultured cell types exposed to the radiolabeled SCC all took up the 67Cu at various rates. Rates differed somewhat when uptake was from Cu-NTA. Uptake of SCC-67Cu was inhibited by excess nonradioactive Cu(I) or Ag(I) ions, suggesting competition for uptake by copper transporter 1 (CTR1). Knockout of CTR1 in fibroblasts reduced uptake rates by 60%, confirming its participation, but also involvement of other transporters. Inhibitors of endocytosis, or an excess of metal ions taken up by divalent metal transporter 1, did not decrease SCC-67Cu uptake. The results imply that SCC may play a significant role in copper transport and homeostasis, transferring copper particularly from the liver (but also intestinal cells) to other cells within the mammalian organism, as well as spilling excess into the urine in copper overload-as an alternative means of copper excretion.

Quality of life assessment in core outcome sets: A position statement of the EADV Task Force on Quality of Life and Patient Oriented Outcomes.

Core outcome sets (COSs) are an agreed standardized collection of outcomes that should be measured and reported in all clinical trials for a specific clinical condition. Tsekhe aim of our position paper by the European Academy of Dermatology and Venereology (EADV) Task Force on Quality of Life and Patient Oriented Outcomes was to identify the challenges and Patient Oriented Outcomes advantages in the development of COSs within dermatological QoL research. Twelve EADV Task Force multidisciplinary team members presented a total of 101 items (51 advantages and 50 disadvantages). All participants considered that COS are beneficial for comparison between different studies, treatments, dermatological diseases, geographical location and ethnicities. In conclusion, the EADV Task Force on Quality of Life and Patient Oriented Outcomes has recognized the primacy of advantages of COS and deliberated that the disadvantages in COS are related to development process and use of COS.

Role of active nanoliposomes in the surface and bulk mechanical properties of hybrid hydrogels.

Nanoliposomes are widely used as delivery vehicles for active compounds. Nanoliposomes from rapeseed phospholipids were incorporated into interpenetrating polymer network hydrogels of gelatin methacryloyl and alginate. The multiscale physicochemical properties of the hydrogels are studied both on the surface and through the thickness of the 3D network. The obtained composite hydrogels exhibited strong mechanical properties and a highly porous surface. The blend ratio, as well as the concentration of nanoliposomes, affects the properties of the hydrogels. Nanofunctionalized hydrogels induced keratinocyte â€‹growth. These advantageous characteristics may open up many applications of the developed hydrogels in drug delivery and tissue engineering.

A case-control study of risk factors associated with Zoon balanitis in men.

BACKGROUND: Zoon balanitis (ZB) is a chronic inflammatory benign mucositis. Its etiopathogenesis still remains hypothetical and speculative. OBJECTIVES: To determine risk factors associated with genital ZB in men. METHODS: This is a case-control study including 30 patients diagnosed with ZB and 54 patients with dermatological diseases other than ZB enrolled in the Dermatological Clinic of the University of Padova, Italy, from September 2015 to June 2018. Univariate and multivariate logistic regression analyses were used for analysis of data collected. RESULTS: According to multivariate logistic regression analysis, risk factors for ZB were as follows: the mean daily cigarettes consumption (OR 1.065; 95% CI 1.8-11.4; P = 0.006) and the number of weekly foreskin retractions (OR 0.847; 95% CI 5.5-24.1; P = 0.003). There were no statistically significant differences between cases and controls according to age, presence of circumcision as well in number of sexual partners. CONCLUSIONS: To our knowledge, this is the first case-control study showing that smoking and poor genital hygiene are associated with being affected by ZB.

Simulating the life course of psoriasis patients: the interplay between therapy intervention and marital status.

BACKGROUND: Psoriasis, a chronic relapsing inflammatory disease affecting primarily the skin, shows multiple comorbidities including depression, cardiovascular diseases and other relevant conditions. Psoriasis patients experience social isolation, job loss, financial difficulties and partnership problems. Inversely, psychosocial impairments may negatively influence the disease course. OBJECTIVE: To explore the feasibility of a model describing the interaction of psychosocial and clinical factors over the life course of patients. METHODS: We considered only seven states for members of a hypothetical population: single and healthy, single and having a psoriasis flare, single and 'cured', coupled and healthy, coupled and having a psoriasis flare, coupled and 'cured', and dead. Transition probabilities between states were taken from the Norwegian Population Register for the healthy population and from epidemiological research articles. Clinical experience allowed adjustments on the assumed parameters. RESULTS: Our macromodel, which simulates the effect of therapy intervention on patients' partnership status, yields a description of the transitions between the seven states. Treatment efficacy shows only a negligible effect on the chances of living with a partner. CONCLUSIONS: Mathematical modelling of interactions between social and health variables is in principle feasible. However, complex models, comprising more variables (for instance: employment status, depression level, obesity etc.), are needed for more realistic simulations for the interactions studied. As increasing the number of variables leads to an exponential increase of the model's state space, switching to micromodelling (representing each individual separately) may be necessary.

Mobilization of iron from ferritin: new steps and details.

Much evidence indicates that iron stored in ferritin is mobilized through protein degradation in lysosomes, but concerns about this process have lingered, and the mechanistic details of its aspects are lacking. In the studies presented here, 59Fe-labeled ferritin was induced by preloading hepatic (HepG2) cells with radiolabeled Fe. Placing these cells in a medium containing desferrioxamine resulted in the loss of ferritin-59Fe, but adding high concentrations of reducing agents or modulating the internal GSH concentration failed to alter the rates of ferritin-59Fe release. Confocal microscopy showed that Fe deprivation increased the movement of ferritin into lysosomes and hyperaccumulation was observed when lysosomal proteolysis was inhibited. It also resulted in the rapid movement of DMT1 to lysosomes, which was inhibited by bafilomycin. Ferrihydrite crystals isolated from purified rat liver/spleen ferritin were solubilized at pH 5 and 7 by GSH, ascorbate, citrate and lysosomal fluids obtained from livers and J774a.1 macrophages. The inhibition of DMT1/Nramp2 and siRNA knockdown of Nramp1 each reduced the transfer of 59Fe from lysosomes to the cytosol; and hepatocyte-specific knockout of DMT1 in mice prevented the release of Fe from the liver responding to EPO treatment, but did not inhibit lysosomal ferritin degradation. We conclude that ferritin-Fe mobilization does not occur through changes in cellular concentrations of reducing/chelating agents but by the coordinated movement of ferritin and DMT1 to lysosomes, where the ferrihydrite crystals exposed by ferritin degradation dissolve in the lysosomal fluid, and the reduced iron is transported back to the cytosol via DMT1 in hepatocytes, and by both DMT1 and Nramp1 in macrophages, prior to release into the blood or storage in ferritin.

Modification of carbon nanotubes by amphiphilic glycosylated proteins.

Precise organization of nanomaterials with functional biomolecules play a key role in many natural materials. In this work, single-walled carbon nanotubes were functionalized by a self-assembling amphiphilic protein that enabled their dispersion into nanofibrillated cellulose matrix. The protein contained a hydrophobic patch and a glycosylated domain and due to its dual functionality, it was able to assemble at the interface of the carbon nanotubes and the nanofibrillated cellulose and thus enhance the interactions between them. The electrical conductivity of the nanocellulose/carbon nanotube composites was improved by approximately 5-fold when the protein modified nanotubes where applied. Also improvement of the mechanical properties due to the proteins was observed.

Dissecting Pathway Disturbances Using Network Topology and Multi-platform Genomics Data.

Complex diseases such as cancers usually result from accumulated disturbance of pathways instead of the disruptions of one or a few major genes. As opposed to single-platform analyses, it is likely that integrating diverse molecular regulatory elements and their interactions can lead to more insights on pathway-level disturbances of biological systems and their potential consequences in disease development and progression. To explore the benefit of pathway-based analysis, we focus on mutli-platform genomics, epigenomics and transcriptomics (-omics, for short) from 11 cancer types collected by the Cancer Genome Atlas (TCGA) project. Specifically, we use a well-studied oncogenetic pathway, the BRAF pathway, to investigate the relevant copy number variants, methylations and gene expressions, and quantify their effects on discovering tumor-specific aberrations across multiple tumor lineages. We also perform simulation studies to further investigate the effects of network topology and multiple omics on dissecting pathway disturbances. Our analysis shows that adding molecular regulatory elements such as copy number variants (CNVs) and/or methylations to the baseline mRNA molecules can improve our power of discovering tumorous aberrances. Also, incorporating copy number variants with the baseline mRNA molecules can be more beneficial than incorporating methylations. Moreover, employing regulatory topologies can improve the discoveries of tumorous aberrances. Finally, our analysis reveals similarities and differences among diverse cancer types based on disturbance of the BRAF pathway.

The wearable cardioverter defibrillator as a bridge to reimplantation in patients with ICD or CRT-D-related infections.

BACKGROUND: The approach to treat device infection in patients with implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy defibrillator (CRT-D) is a challenging procedure. Optimal treatment is complete extraction of the infected device. To protect these patients from sudden cardiac arrest while waiting for reimplantation and to avoid recurrent infection, a wearable cardioverter defibrillator (WCD) seems to be a valuable solution. Therefore, we investigated the management and outcome of patients with ICD or CRT-D infections using the WCD as a bridge to re-implantation after lead extraction procedures. METHODS: We conducted a retrospective study on consecutive patients who underwent ICD or CRT-D removal due to device-related local or systemic infections. All patients were prescribed a WCD at our center between 01/2012 and 10/2015. All patients returned to our outpatient clinic for regular ICD or CRT-D monitoring initially 1 and 3 months after reimplantation followed by 6-months intervals. RESULTS: Twenty-one patients (mean age 65.0 ± 8.0 years, male 76.2%) were included in the study. Complete lead extraction was achieved in all patients. While waiting for reimplantation one patient experienced a symptomatic episode of sustained ventricular tachycardia. This episode was converted successfully into sinus rhythm by a single 150 J shock. Mean follow-up time 392 ± 206 days, showing survival rate of 100% and freedom from reinfection in all patients. CONCLUSION: The WCD seems to be a valuable bridging option for patients with ICD or CRT-D infections, showing no recurrent device infection.

EWS-FLI1 perturbs MRTFB/YAP-1/TEAD target gene regulation inhibiting cytoskeletal autoregulatory feedback in Ewing sarcoma.

Ewing sarcoma (EWS) is a paediatric bone cancer with high metastatic potential. Cellular plasticity resulting from dynamic cytoskeletal reorganization, typically regulated via the Rho pathway, is a prerequisite for metastasis initiation. Here, we interrogated the role of the Ewing sarcoma driver oncogene EWS-FLI1 in cytoskeletal reprogramming. We report that EWS-FLI1 strongly represses the activity of the Rho-F-actin signal pathway transcriptional effector MRTFB, affecting the expression of a large number of EWS-FLI1-anticorrelated genes including structural and regulatory cytoskeletal genes. Consistent with this finding, chromatin immunoprecipitation sequencing (ChIP-seq) revealed strong overlaps in myocardin-related transcription factor B (MRTFB) and EWS-FLI1 chromatin occupation, especially for EWS-FLI1-anticorrelated genes. Binding of the transcriptional co-activator Yes-associated protein (YAP)-1, enrichment of TEAD-binding motifs in these shared genomic binding regions and overlapping transcriptional footprints of MRTFB and TEAD factors led us to propose synergy between MRTFB and the YAP/TEAD complex in the regulation of EWS-FLI1-anticorrelated genes. We propose that EWS-FLI1 suppresses the Rho-actin pathway by perturbation of a MRTFB/YAP-1/TEAD transcriptional module, which directly affects the actin-autoregulatory feedback loop. As spontaneous fluctuations in EWS-FLI1 levels of Ewing sarcoma cells in vitro and in vivo, associated with a switch between a proliferative, non-migratory EWS-FLI1-high and a non-proliferative highly migratory EWS-FLI1-low state, were recently described, our data provide a mechanistic basis for the underlying EWS-FLI1-dependent reversible cytoskeletal reprogramming of Ewing sarcoma cells.

The dynamics of multimer formation of the amphiphilic hydrophobin protein HFBII.

Hydrophobins are surface-active proteins produced by filamentous fungi. They have amphiphilic structures and form multimers in aqueous solution to shield their hydrophobic regions. The proteins rearrange at interfaces and self-assemble into films that can show a very high degree of structural order. Little is known on dynamics of multimer interactions in solution and how this is affected by other components. In this work we examine the multimer dynamics by stopped-flow fluorescence measurements and Förster Resonance Energy Transfer (FRET) using the class II hydrophobin HFBII. The half-life of exchange in the multimer state was 0.9s at 22°C with an activation energy of 92kJ/mol. The multimer exchange process of HFBII was shown to be significantly affected by the closely related HFBI hydrophobin, lowering both activation energy and half-life for exchange. Lower molecular weight surfactants interacted in very selective ways, but other surface active proteins did not influence the rates of exchange. The results indicate that the multimer formation is driven by specific molecular interactions that distinguish different hydrophobins from each other.

Attachment Styles of Dermatological Patients in Europe: A Multi-centre Study in 13 Countries.

Attachment styles of dermatological outpatients and satisfaction with their dermatologists were investigated within the framework of a multicentre study conducted in 13 European countries, organized by the European Society for Dermatology and Psychiatry. Attachment style was assessed with the Adult Attachment Scale. Patient satisfaction with the dermatologist was assessed with an 11-degree scale. A total of 3,635 adult outpatients and 1,359 controls participated in the study. Dermatological outpatients were less able to depend on others, were less comfortable with closeness and intimacy, and experienced similar rates of anxiety in relationships as did the controls. Participants who had secure attachment styles reported stressful life events during the last 6 months significantly less often than those who had insecure attachment styles. Patients with secure attachment styles tended to be more satisfied with their dermatologist than did insecure patients. These results suggest that secure attachment of dermatological outpatients may be a protective factor in the management of stress.

Self-Inflicted Lesions in Dermatology: A Management and TherapeuticApproach - A Position Paper From the European Society for Derma-tology and Psychiatry.

The classification of self-inflicted skin lesions proposed by the European Society for Dermatology and Psychiatry (ESDaP) group generated questions with regard to specific treatments that could be recommended for such cases. The therapeutic guidelines in the current paper integrate new psychotherapies and psychotropic drugs without forgetting the most important relational characteristics required for dealing with people with these disorders. The management of self-inflicted skin lesions necessitates empathy and a doctor-patient relationship based on trust and confidence. Cognitive behavioural therapy and/or psychodynamic and psychoanalytic psychotherapy (alone, or combined with the careful use of psychotropic drugs) seem to achieve the best results in the most difficult cases. Relatively new therapeutic techniques, such as habit reversal and mentalization-based psychotherapy, may be beneficial in the treatment of skin picking syndromes.

Impairment of Sexual Life in 3,485 Dermatological Outpatients From a Multicentre Study in 13 European Countries.

Skin conditions may have a strong impact on patients' sexual life, and thus influence personal relationships. Sexual issues are difficult to discuss directly in clinical practice, and a mediated instrument may be useful to capture such information. In this study item 9 of the Dermatology Life Quality Index was used to collect information on sexual impact of several skin conditions in 13 European countries. Among 3,485 patients, 23.1% reported sexual problems. The impairment was particularly high in patients with hidradenitis suppurativa, prurigo, blistering disorders, psoriasis, urticaria, eczema, infections of the skin, or pruritus. Sexual impact was strongly associated with depression, anxiety, and suicidal ideation. It was generally more frequent in younger patients and was positively correlated with clinical severity and itch. It is important to address the issue of sexual well-being in the evaluation of patients with skin conditions, since it is often linked to anxiety, depression, and even suicidal ideation.

Ceruloplasmin and other copper binding components of blood plasma and their functions: an update.

We know that blood plasma contains many proteins and also other components that bind copper. The largest contributor to copper in the plasma is ceruloplasmin, which accounts for 40-70 percent. Apart from ceruloplasmin and albumin, most of these components have not been studied extensively, and even for ceruloplasmin and albumin, much remains to be discovered. New components with new functions, and new functions of known components are emerging, some warranting reconsideration of earlier findings. The author's laboratory has been actively involved in research on this topic. This review summarizes and updates our knowledge of the nature and functions of ceruloplasmin and the other known and emerging copper-containing molecules (principally proteins) in this fluid, to better understand how they contribute to copper homeostasis and consider their potential significance to health and disease.

The Psychoanalytic Interpretation of Symptoms - Evidence and Benefits.

Dermatological symptoms are explained in medicine in biological terms. Nevertheless, exploring the life history of dermatological patients can lead to seductive, but non-rigorously scientific interpretations which are of associative, or even symbolic nature. Moreover, associations of physical signs and life events, suggest us to consider our patients as subjects pervaded by the will to communicate not only through language, but also through their body and all its functions and malfunctions. Interpreting symptoms and eventually finding a meaning to the disease must not imply a causative attribution, because the very signification of cause and effect is probably beyond our grasp. Hence, aware of our limits, we should know whether we wish to treat the disease as a whole, considering that the observer (the doctor, the patient or the medicine as a theoretical corpus) is not only an observer from outside, but part of the disease that will be treated or described.