RNA Foci Formation in a Retinal Glial Model for Spinocerebellar Ataxia Type 7.

Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder characterized by cerebellar ataxia and retinopathy. SCA7 is caused by a CAG expansion in the ATXN7 gene, which results in an extended polyglutamine (polyQ) tract in the encoded protein, the ataxin-7. PolyQ expanded ataxin-7 elicits neurodegeneration in cerebellar Purkinje cells, however, its impact on the SCA7-associated retinopathy remains to be addressed. Since Müller glial cells play an essential role in retinal homeostasis, we generate an inducible model for SCA7, based on the glial Müller MIO-M1 cell line. The SCA7 pathogenesis has been explained by a protein gain-of-function mechanism, however, the contribution of the mutant RNA to the disease cannot be excluded. In this direction, we found nuclear and cytoplasmic foci containing mutant RNA accompanied by subtle alternative splicing defects in MIO-M1 cells. RNA foci were also observed in cells from different lineages, including peripheral mononuclear leukocytes derived from SCA7 patient, suggesting that this molecular mark could be used as a blood biomarker for SCA7. Collectively, our data showed that our glial cell model exhibits the molecular features of SCA7, which makes it a suitable model to study the RNA toxicity mechanisms, as well as to explore therapeutic strategies aiming to alleviate glial dysfunction.

Screening for depression in psoriasis patients during a dermatological consultation: A first step towards treatment.

BACKGROUND AND OBJECTIVES: Depression is a highly prevalent comorbidity in psoriatic patients. The aim of this prospective study was to follow up psoriasis patients at risk for depression and to evaluate individual pathways to mental health care and the efficacy of depression screening in a real-life setting. PATIENTS AND METHODS: In this prospective multicenter study, 355 patients with psoriasis were screened for depressive symptoms with the revised Beck Depression Inventory (BDI-II). General practitioners of patients at risk for depression were asked for further evaluation. One year later, information on mental health care provision was gathered. RESULTS: 130 patients were screened positive for depressive symptoms, and 71 patients were followed-up (follow-up rate: 54.6 %). Psychiatric treatment was recommended for 28.2 % and accepted by 23.9 % of patients. Parameters of disease activity of psoriasis (PASI: 3.1, ∆: -1.7, P = 0.018), quality of life (Dermatology Life Quality Index [DLQI]: 6.5, ∆: -2.8, P = 0.005), and depressive symptoms (BDI-II: 13.2, ∆: -8.3, P < 0.001) improved significantly. Decrease of the BDI-II score was more pronounced in patients with higher PASI decrease. CONCLUSIONS: Screening for depressive symptoms led to increased utilization of mental health care and improvement of psoriasis, depressive symptoms, and quality of life. Thus, such screening should be implemented in routine care to optimize patient management.

Dermatophyte infections in children compared to adults in Germany: a retrospective multicenter study in Germany.

BACKGROUND AND OBJECTIVE: Dermatophyte infections of the skin and nails are common worldwide and vary between geographical areas and over time. The aim of this study was to determine the epidemiological profile of dermatophytes in Germany with a focus on comparing children with adults. PATIENTS AND METHODS: In this retrospective multicenter study, mycological dermatophyte culture results in the period 01/2014 to 12/2016 were analyzed according to identified pathogen, age and gender of patients, and type of disease. RESULTS: Of 1,136 infections (children: n = 88, adults: n = 1,048), 50.8 % were clinically classified as onychomycosis, followed by tinea pedis (34.6 %), tinea corporis (16.2 %), tinea manus (16.2 %), tinea capitis (2.5 %), and tinea faciei (1.2 %). The most frequent pathogen was Trichophyton (T.) rubrum (78.6 %), followed by T. interdigitale (14.3 %), T. benhamiae (3.2 %), T. mentagrophytes (2.1 %), and Microsporum canis (1.7 %). The fungal spectrum differed particularly in tinea corporis and tinea capitis between children and adults with a more diverse pathogen spectrum in children. Trichophyton tonsurans was rarely identified as cause for tinea corporis (2.7 %) or tinea capitis (3.3 %). CONCLUSIONS: Differences in pathogens and frequency of fungal infections between age groups should be considered for optimal selection of the appropriate therapeutic regimen.

Transcriptome Analysis Reveals Altered Inflammatory Pathway in an Inducible Glial Cell Model of Myotonic Dystrophy Type 1.

Myotonic dystrophy type 1 (DM1), the most frequent inherited muscular dystrophy in adults, is caused by the CTG repeat expansion in the 3'UTR of the DMPK gene. Mutant DMPK RNA accumulates in nuclear foci altering diverse cellular functions including alternative splicing regulation. DM1 is a multisystemic condition, with debilitating central nervous system alterations. Although a defective neuroglia communication has been described as a contributor of the brain pathology in DM1, the specific cellular and molecular events potentially affected in glia cells have not been totally recognized. Thus, to study the effects of DM1 mutation on glial physiology, in this work, we have established an inducible DM1 model derived from the MIO-M1 cell line expressing 648 CUG repeats. This new model recreated the molecular hallmarks of DM1 elicited by a toxic RNA gain-of-function mechanism: accumulation of RNA foci colocalized with MBNL proteins and dysregulation of alternative splicing. By applying a microarray whole-transcriptome approach, we identified several gene changes associated with DM1 mutation in MIO-M1 cells, including the immune mediators CXCL10, CCL5, CXCL8, TNFAIP3, and TNFRSF9, as well as the microRNAs miR-222, miR-448, among others, as potential regulators. A gene ontology enrichment analyses revealed that inflammation and immune response emerged as major cellular deregulated processes in the MIO-M1 DM1 cells. Our findings indicate the involvement of an altered immune response in glia cells, opening new windows for the study of glia as potential contributor of the CNS symptoms in DM1.

Two questions may be enough - screening for depression in patients with psoriasis: a multicenter study.

BACKGROUND: Depression is frequently underdiagnosed and insufficiently treated in psoriatic patients in their daily routine. The aim of this study was to screen and analyze the impact of patient and disease characteristics on depression scores. PATIENTS AND METHODS: In this cross-sectional multicenter cohort study, adult psoriasis patients were screened for depression with two validated tools: the Whooley questions and the revised Beck Depression Inventory (BDI-II). RESULTS: Overall, 538 patients (median PASI 3.0, mean DLQI 5.3) were screened for depressive symptoms (mean BDI-II score 8.3). 24.2 % of all participants reached a BDI-II score ≥ 13, suggesting a depression that was at least mild. The results of the Whooley questions were positive for 28.2 % of the patients. There was a strong correlation between the two tools (p < 0.001). In the subgroup with a BDI-II score ≥ 13, disease activity (median PASI 3.8 vs. 2.8, p = 0.06) and DLQI scores (mean 10.1 vs. 3.7, p < 0.0001) were higher, and psoriatic arthritis and diabetes were more prevalent (52.6 % vs. 37.8 %, p = 0.002, and 16.2 % vs. 10.0 %, p = 0.04, respectively) than in the subgroup with a BDI-II score < 13. CONCLUSIONS: In specialized psoriatic outpatient clinics, a BDI-II score ≥ 13 was present in almost every fourth patient despite a low median PASI. The Whooley questions might be easy to use as a screening tool for depression in psoriasis patients.

Treatment of acrodermatitis continua of Hallopeau: A case series of 39 patients.

Acrodermatitis continua of Hallopeau (ACH) is a rare chronic inflammatory skin disease. Treatment is extremely challenging and mostly based on empirics as there is only scarce evidence from case reports and few small case series. In this retrospective study, patients with ACH treated at five university medical centers were analyzed according to patient and disease characteristics and treatment experience. We identified 39 patients with ACH with a mean age of 54.4 years at onset, of whom 22 (56.4%) were female. A total of 115 systemic treatment courses were analyzed with methotrexate as the most common therapy (27.0%). Overall, effectiveness of systemic treatments was low (excellent response rate: 14.8%). Among non-biologics, excellent response was noted in 21.1% (4/19) of treatment courses with methotrexate, followed by acitretin (13.3%; 2/15). Among biologics, guselkumab (excellent response: 100%; 2/2), secukinumab (excellent response: 42.9%; 3/7) and adalimumab (excellent response: 20.0%; 2/10) were most efficacious. The median drug survival was 7.0 months and did not differ significantly between the subgroup of non-biologic and biologic therapies. To our knowledge, this is the largest case series in ACH investigating patient characteristics and treatment outcomes. Based on our treatment experience, we suggest a treatment algorithm starting with acitretin or methotrexate as first-line therapy, followed by biologics. Cyclosporin may be used for short-term control. However, none of the applied systemic therapies yielded satisfying efficacy in our cohort. In patients with primary non-response, switch of treatment should be evaluated timely on an individual basis, considering possible irreversible disease complications such as nail loss. More research with prospective design is needed to further evaluate traditional and also particularly newer antipsoriatic drugs in ACH.

Evaluación de la respuesta inflamatoria en ratas Wistar a TheraCalTM LC implantado vía subcutánea / Evaluation of the inflammatory response in Wistar rats to TheraCalTM LC implanted subcutaneously

El Theracal TM LC es un cemento silicato de calcio (Ca) modificado con resina (SMCR) que ha demostrado ser un material ideal para el tratamiento dentino-pulpar por su alta tasa de formación de calcio. Los biomateriales por su contenido de Ca tienden a tener un aumento en su biodisponibilidad, estimulando la formación del puente dentario atreves de las células involucradas en la formación de tejidos mineralizados, promoviendo la diferenciación de fibroblastos en odontoblastos y aumentando la actividad de la enzima pirofostasa responsable en la mineralización de la dentina. El presente estudio con el objetivo de evaluar la respuesta inflamatoria a Theracal TM LC subcutáneamente en ratas Wistar. Fueron usados seis ratas cepa Wistar en las cuales se realizaron cuatro bolsillos quirúrgicos subcutáneos. Cada uno de estos bolsillos se determinó como cuadrante distinto, conteniendo los siguientes implantes: 1 Theracal TM LC en tubo polietileno, 2 tubo de polietileno, 3 Theracal TM LC directo y 4 como control. Las muestras histológicas se procesaron y se evaluaron distintos tipos celulares mediante conteo a microscopio de luz a 100X utilizando las tinciones H&E y AT pH 2.3. Los resultados mostraron que existen diferencias significativas en todos los tipos celulares observados durante los diferentes tiempos de exposición. Las diferencias en los tipos celulares observados podrían ser debido al tiempo de exposición al Theracal TM LC, al tubo polietileno y a ambos. El tejido evaluado del implante del tubo polietileno y al tubo polietileno con Theracal TM LC, presentan mayor respuesta inflamatoria, a diferencia en el tejido implantado con Theracal TM LC directamente.

TheraCalTM LC is a resin-modified calcium silicate (Ca) resin (SMCR) that has proven to be an ideal material for dentin-pulp treatment due to its high rate of calcium formation. Biomaterials due to their Ca content tend to have an increase in their bioavailability, stimulating the formation of the dental bridge through the cells involved in the formation of mineralized tissues, promoting the differentiation of fibroblasts in odontoblasts and increasing the activity of the pyrophosphate enzyme responsible in dentin mineralization. The present study aimed to evaluate the inflammatory response to TheracalTM LC subcutaneously in Wistar rats. Six Wistar strain rats were used in which four subcutaneous surgical pockets were made. Each of these pockets was determined as a different quadrant, containing the following implants: 1 TheracalTM LC in polyethylene tube, 2 polyethylene tubes, 3 TheracalTM LC direct and 4 as control. The histological samples were processed, and different cell types were evaluated by light microscopy at 100X using the H&E and AT pH 2.3 stains. The results showed that there are significant differences in all cell types observed during the different exposure times. The differences in the cell types observed could be due to the exposure time to TheracalTM LC, to the polyethylene tube and to both. The evaluated tissue of the polyethylene tube implant and the polyethylene tube with TheracalTM LC present a greater inflammatory response, unlike in the tissue implanted with TheracalTM LC directly.

Systemic therapies of pityriasis rubra pilaris: a systematic review.

Pityriasis rubra pilaris (PRP) is a rare papulosquamous disorder. Treatment is challenging; the armamentarium consists of topical corticosteroids, phototherapy, classic systemic treatments such as retinoids or immunosuppressive drugs, and most recently biologicals. However, the relative effectiveness of therapies is unclear. Our objective was to review the published literature on systemic treatment of PRP. A systematic review was conducted on PubMed and the Cochrane Library up to 5 September 2017. Studies evaluating any systemic treatments of PRP (except for historical treatments) were included. Overall, 182 studies met the predefined inclusion criteria, and reported on 475 patients and 652 courses of treatment. 42.0 % (225/514) of all patients treated with retinoids achieved an excellent response (isotretinoin: 61.1 % [102/167], etretinate: 47 % [54/115], and acitretin: 24.7 % [43/174]) compared to an excellent response rate of 33.1 % (53/160) with methotrexate. Therapy with biologicals was successful in 51.0 % of patients (71/133) (ustekinumab: 62.5 % [10/16], infliximab: 57.1 % [28/49], etanercept: 53.3 % [16/30], and adalimumab: 46.4 % [13/28]). This review balances effectiveness, side effects, experience, and drug costs in order to suggest a treatment regimen starting with isotretinoin as first-line, methotrexate as second-line and biologicals as third-line treatment for this difficult-to-treat dermatosis.

Evaluación de la actividad antioxidante de Cnidoscolus chayamansa (Chaya), Euphorbia prostrata (Hierba de la Golondrina) y Jatropha dioica (Sangre de Drago) en ratas Wistar inducidas a hiperglicemia / Evaluation of the antioxidant activity of Cnidoscolus chayamansa (Chaya), Euphorbia prostrata (Herb of the Swallow) and Jatropha dioica (Drago blood) in Wistar rats induced to hyperglycemia

RESUMEN: Estudios recientes han demostrado que los compuestos activos presentes en extractos de C. chayamansa, E. prostrata y J. dioica tienen propiedades antioxidantes. Los resultados obtenidos en nuestro estudio fueron compuestos fenólicos solubles mostraron en C. chayamansa 6,34, E. prostrata 10,67, J. dioica 1,83 mg equiv de ácido gálico/gm BS respectivamente. Los antioxidantes solubles en agua por el método ABTS fueron para C. chayamansa 5.9, E. prostrata 12.7 y para J. dioica 2.5 mM equiv. de trolox/gr BS. Los resultados histopatológicos muestran una mejoría en los tejidos tratados con los extractos después de la inducción a hiperglicemia.

SUMMARY: Recent studies have shown that the active compounds present in extracts of C. chayamansa, E. prostrata and J. dioica have antioxidant properties. The results obtained in our study were soluble phenolic compounds showed in C. chayamansa 6.34, E. prostrata 10.67, J. dioica 1.83 mg equiv of gallic acid/gm BS respectively. The antioxidants soluble in water by the ABTS method were for C. chayamansa 5.9, E. prostrata 12.7 and for J. dioica 2.5 mM equiv. of trolox/gr BS. The histopathological results show an improvement in the tissues treated with the extracts after the induction to hyperglycemia.

Biologicals and small molecules in psoriasis: A systematic review of economic evaluations.

Biological therapy for moderate-to-severe psoriasis is highly effective but cost-intensive. This systematic review aimed at analyzing evidence on the cost-effectiveness of biological treatment of moderate-to-severe psoriasis. A literature search was conducted until 30/06/2017 in PubMed, Cochrane Library, LILACS, and EconLit. The quality of identified studies was assessed with the checklist by the Centre for Reviews and Dissemination guidance. Out of 482 records, 53 publications were eligible for inclusion. Half of the studies met between 20 and 25 of the quality checklist items, displaying moderate quality. Due to heterogeneity of studies, a qualitative synthesis was conducted. Cost ranges per outcome were enormous across different studies due to diversity in assumptions and model design. Pairwise comparisons of biologicals revealed conflicting results. Overall, adalimumab appeared to be most cost-effective (100% of all aggregated pairwise comparisons), followed by ustekinumab (66.7%), and infliximab (60%). However, in study conclusions most recent publications favored secukinumab and apremilast (75% and 60% of the studies investigating these medications). Accepted willingness-to-pay thresholds varied between 30,000 and 50,000 USD/Quality-Adjusted Life Year (QALY). Three-quarters of studies were financially supported, and in 90% of those, results were consistent with the funder's interest. Economic evaluation of biologicals is crucial for responsible allocation of health care resources. In addition to summarizing the actual evidence this review highlights gaps and needs for future research.