Motor skill learning modulates striatal extracellular vesicles' content in a mouse model of Huntington's disease.

Huntington's disease (HD) is a neurological disorder caused by a CAG expansion in the Huntingtin gene (HTT). HD pathology mostly affects striatal medium-sized spiny neurons and results in an altered cortico-striatal function. Recent studies report that motor skill learning, and cortico-striatal stimulation attenuate the neuropathology in HD, resulting in an amelioration of some motor and cognitive functions. During physical training, extracellular vesicles (EVs) are released in many tissues, including the brain, as a potential means for inter-tissue communication. To investigate how motor skill learning, involving acute physical training, modulates EVs crosstalk between cells in the striatum, we trained wild-type (WT) and R6/1 mice, the latter with motor and cognitive deficits, on the accelerating rotarod test, and we isolated their striatal EVs. EVs from R6/1 mice presented alterations in the small exosome population when compared to WT. Proteomic analyses revealed that striatal R6/1 EVs recapitulated signaling and energy deficiencies present in HD. Motor skill learning in R6/1 mice restored the amount of EVs and their protein content in comparison to naïve R6/1 mice. Furthermore, motor skill learning modulated crucial pathways in metabolism and neurodegeneration. All these data provide new insights into the pathogenesis of HD and put striatal EVs in the spotlight to understand the signaling and metabolic alterations in neurodegenerative diseases. Moreover, our results suggest that motor learning is a crucial modulator of cell-to-cell communication in the striatum.

Alpha-secretase dependent nuclear localization of the amyloid-ß precursor protein-binding protein Fe65 promotes DNA repair.

Fe65 is a brain enriched adaptor protein involved in various cellular processes, including actin cytoskeleton regulation, DNA repair and transcription. A well-studied interacting partner of Fe65 is the transmembrane amyloid-ß precursor protein (APP), which can undergo regulated intramembrane proteolysis (RIP). Following ß- and γ-secretase-mediated RIP, the released APP intracellular domain (AICD) together with Fe65 can translocate to the nucleus and regulate transcription. In this study, we investigated if Fe65 nuclear localization can also be regulated by different α-secretases, also known to participate in RIP of APP and other transmembrane proteins. We found that in both Phorbol 12-myristate 13-acetate and all-trans retinoic acid differentiated neuroblastoma cells a strong negative impact on Fe65 nuclear localization, equal to the effect observed upon γ-secretase inhibition, could be detected following inhibition of all three (ADAM9, ADAM10 and ADAM17) α-secretases. Moreover, using the comet assay and analysis of Fe65 dependent DNA repair associated posttranslational modifications of histones, we could show that inhibition of α-secretase-mediated Fe65 nuclear translocation resulted in impaired capacity of the cells to repair DNA damage. Taken together this suggests that α-secretase processing of APP and/or other Fe65 interacting transmembrane proteins play an important role in regulating Fe65 nuclear translocation and DNA repair.

Predictive factors for anti-MDA5 antibody in patients with dermatomyositis: a retrospective multicenter study.

BACKGROUND AND OBJECTIVES: Melanoma differentiation-associated gene 5 antibody (anti-MDA5) in dermatomyositis (DM) is associated with rapidly progressive interstitial lung disease and poor prognosis. Early diagnosis is key to improving the prognosis of these patients. The aim was to confirm cutaneous characteristics in patients with anti-MDA5 dermatomyositis and to explore new diagnostic markers for the presence of anti-MDA5 (anti-MDA5+ ). PATIENTS AND METHODS: A multicenter cross-sectional retrospective cohort study of 124 patients diagnosed with DM, of which 37 were anti-MDA5+ . Demographic data, laboratory data, and clinical manifestations were collected. RESULTS: Anti-MDA5+ DM is characterized by a distinct mucocutaneous phenotype that includes oral lesions, alopecia, mechanic's hands, palmar and dorsal papules, palmar erythema, vasculopathy, and skin ulceration. We found vasculopathy and digit tip involvement very frequently in anti-MDA5+ patients (p <0.001), being a diagnostic marker of anti-MDA5+ (OR, 12.355; 95% CI 2.850-79.263; p  =  0.012 and OR, 7.447; 95% CI 2.103-46.718; p  =  0.004, respectively). The presence of ulcers deserves special mention, especially in anti-MDA5+ patients, because in our cohort, up to 97% of the anti-MDA5+ patients had ulcers. CONCLUSIONS: In patients with suspected DM with digit tip involvement or vasculopathy, the presence of anti-MDA5 antibodies must be ruled out, as it may be a clinical predictor.

A neuroimaging comparative study of changes in a cellist's brain when playing contemporary and Baroque styles.

The emergence of different styles of Contemporary concert music in the 20th century led to a marked modification of the foundations built on previous styles. This work investigates whether these modifications, which include procedures and technical resources different to those used in the interpretation of previous musical styles, require different encephalic controls to those used in tonal music and if the experience of the musician in these styles influences them. Functional magnetic resonance images of encephalic regions from 13 professional cellists while interpreting Baroque and Contemporary excerpts inside an MRI scanner were acquired. Activation and connectivity encephalic maps show common cortical motor and sensorial regions (Precentral, Postcentral and Supramarginal Gyri) in both interpretation styles, but with different hemispheric intensity levels. However, certain auditory and motor regions only activate during Baroque. Connectivity maps show some exclusive seed-regions; thus, the Heschl's and Superior Frontal Gyri, Planum-Temporal and Caudate appear as prominent seeds when playing Baroque, whereas when playing Contemporary, the main seeds appear in the Cerebellar-Vermis, Insular cortex and Parietal Operculum. The discrepancies found are attributed to different cognitive, sensory and motor demands underlying the musical interpretation of each style, as well as to the musicians' learning of and training in these styles.

Gas exchange, biomass and non-structural carbohydrates dynamics in vines under combined drought and biotic stress.

BACKGROUND: Intensity of drought stress and pest attacks is forecasted to increase in the near future posing a serious threat to natural and agricultural ecosystems. Knowledge on potential effects of a combined abiotic-biotic stress on whole-plant physiology is lacking. We monitored the water status and carbon metabolism of a vine rootstock with or without scion subjected to water shortening and/or infestation with the sucking insect phylloxera (Daktulosphaira vitifoliae Fitch). We measured non-structural carbohydrates and biomass of different plant organs to assess the stress-induced responses at the root, stem, and leaf level. Effects of watering on root infestation were also addressed. RESULTS: Higher root infestation was observed in drought-stressed plants compared to well-watered. The drought had a significant impact on most of the measured functional traits. Phylloxera further influenced vines water and carbon metabolism and enforced the sink strength of the roots by stimulating photosynthates translocation. The insect induced carbon depletion, reprogramed vine development, while preventing biomass compensation. A synergic effect of biotic-abiotic stress could be detected in several physiological and morphological traits. CONCLUSIONS: Our results indicate that events of water shortage favour insects' feeding damage and increase the abundance of root nodosities. Root phylloxera infestation imposes a considerable stress to the plants which might exacerbate the negative effects of drought.

Desmoplastic Trichoepithelioma: An Infrequent Entity not to be Missed: Report of Two Cases.

Desmoplastic trichoepitheliomas are rare benign tumors with follicular differentiation. They have rarely been described in children. We report two children with this uncommon condition.

Topical hesperidin prevents glucocorticoid-induced abnormalities in epidermal barrier function in murine skin.

Systemic and topical glucocorticoids (GC) can cause significant adverse effects not only on the dermis, but also on epidermal structure and function. In epidermis, a striking GC-induced alteration in permeability barrier function occurs that can be attributed to an inhibition of epidermal mitogenesis, differentiation and lipid production. As prior studies in normal hairless mice demonstrated that topical applications of a flavonoid ingredient found in citrus, hesperidin, improve epidermal barrier function by stimulating epidermal proliferation and differentiation, we assessed here whether its topical applications could prevent GC-induced changes in epidermal function in murine skin and the basis for such effects. When hairless mice were co-treated topically with GC and 2% hesperidin twice-daily for 9 days, hesperidin co-applications prevented the expected GC-induced impairments of epidermal permeability barrier homoeostasis and stratum corneum (SC) acidification. These preventive effects could be attributed to a significant increase in filaggrin expression, enhanced epidermal ß-glucocerebrosidase activity and accelerated lamellar bilayer maturation, the last two likely attributable to a hesperidin-induced reduction in stratum corneum pH. Furthermore, co-applications of hesperidin with GC largely prevented the expected GC-induced inhibition of epidermal proliferation. Finally, topical hesperidin increased epidermal glutathione reductase mRNA expression, which could counteract multiple functional negative effects of GC on epidermis. Together, these results show that topical hesperidin prevents GC-induced epidermal side effects by divergent mechanisms.

Reducing CLABSI through a quality strategy for the implementation of the aseptic non-touch technique in a pediatric ward.

BACKGROUND: Central line-associated bloodstream infections (CLABSIs) are among the most epidemiologically relevant health care-associated infections. The aseptic non-touch technique (ANTT) is a standardized practice used to prevent CLABSIs. In a pediatric hospital, the overall CLABSI rate was 1.92/1000 catheter days (CD). However, in one unit, the rate was 5.7/1000 CD. METHODS: Nurses were trained in ANTT. For the implementation, plan-do-study-act (PDSA) cycles were completed. Adherence monitoring of the ANTT and epidemiological surveillance were performed. RESULTS: ANTT adherence of 95% was achieved after 6 PDSA cycles. Hand hygiene and general cleaning reached 100% adherence. Port disinfection and material collection had the lowest adherence rates, with 76.2% and 84.7%, respectively. The CLABSI rate decreased from 5.7 to 1.26/1000 CD. CONCLUSION: The implementation of ANTT helped reduce the CLABSI rate. Training and continuous monitoring are key to maintaining ANTT adherence.

INTRODUCCIÓN: Las infecciones relacionadas con catéteres venosos centrales son unas de las infecciones asociadas a la atención de salud con mayor relevancia epidemiológica. La técnica aséptica «no tocar¼ es una práctica estandarizada que se utiliza para prevenir estas infecciones. En un hospital pediátrico, la tasa de infecciones relacionadas con catéteres venosos centrales fue de 1.92/1000 días de catéter. Sin embargo, en una de las unidades la tasa fue de 5.7/1000 días de catéter. MÉTODO: Se capacitaron enfermeras en la técnica aséptica «no tocar¼. Para la implementación se cumplieron ciclos de planificar-hacer-estudiar-actuar (PHEA). Se realizaron seguimiento de la adherencia a la técnica y vigilancia epidemiológica. RESULTADOS: Se logró una adherencia a la técnica aséptica «no tocar¼ del 95% después de seis ciclos. La higiene de manos y la limpieza general alcanzaron un 100% de cumplimiento. La desinfección de los puertos y la recolección de material alcanzaron la menor adherencia, con un 76.2% y un 84.7%, respectivamente. La tasa de infecciones relacionadas con catéteres venosos centrales disminuyó de 5.7 a 1.26 por 1000 días de catéter. CONCLUSIONES: La implementación de la técnica aséptica «no tocar¼ ayudó en la reducción de infecciones relacionadas con catéteres venosos centrales. La capacitación y el seguimiento continuo son clave para mantener el cumplimiento de la técnica.

Eosinophilic pustular folliculitis of infancy: a series of 15 cases and review of the literature.

BACKGROUND: Eosinophilic pustular folliculitis (EPF) of infancy is characterized by the presence of pustular lesions containing eosinophils. It is the least well-characterized of the EPF diseases. OBJECTIVES: We sought to define the clinical and histopathologic features of the condition. METHODS: We conducted a retrospective review of the clinical data and histologic findings of 15 patients given the diagnosis of EPF of infancy at the Hospital Niño Jesús, Madrid, Spain, from 1995 to 2011, and of patient data published in MEDLINE with such a diagnosis from the disease description (1984-2011). RESULTS: A total of 61 cases were collected. The disease was more common in males than females (ratio 4:1), and presented before 14 months of life in 95% of cases (mean 6.1 months; median 5 months). All patients had recurrent outbreaks and scalp involvement, and 65% had lesions on areas of the body other than the scalp. Tissue eosinophilia was present in all cases; however, true follicular involvement was observed only in 62% of cases in which histologic study was available. More than 80% of the patients were cured by 3 years of age (mean 25.3 months; median 18 months). Topical steroids were effective in 90% of cases. LIMITATIONS: This was a retrospective study. CONCLUSIONS: EPF of infancy presents most often in the first 14 months of life and usually resolves by 3 years of age. All patients showed scalp involvement, tissue eosinophilia, and recurrent outbreaks. The condition does not require aggressive treatment, as it is benign and self-limiting.

Effects of probiotics in periodontal diseases: a systematic review.

OBJECTIVES: This study was designed to determine the effects of probiotics in prevention and/or treatment of periodontal diseases. MATERIALS AND METHODS: We performed broad searches in the MEDLINE, Embase, and Cochrane databases and selected articles that satisfied the description of randomized clinical trials comparing the administration of probiotics versus placebo or another intervention to prevent or treat periodontal diseases in adult patients. RESULTS: Four randomized clinical trials were analyzed in the final review process. For the primary outcome, probing pocket depth, there would be no clinical beneficial effect of probiotics. For secondary outcomes, probiotics have shown small benefits on plaque index and gingival inflammation. CONCLUSIONS: Based on the results of this review, the effectiveness of probiotics on the prevention and treatment of periodontal diseases is questionable. There is currently insufficient evidence demonstrating the benefits of systematic preventative use of probiotics in patients with periodontal diseases. CLINICAL RELEVANCE: The use of probiotics are described to prevent or treat periodontal diseases in some clinical trials; therefore, a systematic review of the evidence for the effect of periodontal diseases is needed.

Tofacitinib Is an Effective Treatment for Refractory Scleromyositis Associated With Anti-PM/Scl.

Scleromyositis is a rare autoimmune disease characterized by overlapping scleroderma and myositis. This case report discusses the presentation and management of a 28-year-old male with scleromyositis presenting with myositis, arthritis, Raynaud's phenomenon, refractory calcinosis, interstitial lung disease, and myocarditis. This case highlights key points in the systematic approach to immunosuppressive treatment and proposes a novel therapeutic option.

RTP801 mediates transneuronal toxicity in culture via extracellular vesicles.

Extracellular vesicles (EVs) play a crucial role in intercellular communication, participating in the paracrine trophic support or in the propagation of toxic molecules, including proteins. RTP801 is a stress-regulated protein, whose levels are elevated during neurodegeneration and induce neuron death. However, whether RTP801 toxicity is transferred trans-neuronally via EVs remains unknown. Hence, we overexpressed or silenced RTP801 protein in cultured cortical neurons, isolated their derived EVs (RTP801-EVs or shRTP801-EVs, respectively), and characterized EVs protein content by mass spectrometry (MS). RTP801-EVs toxicity was assessed by treating cultured neurons with these EVs and quantifying apoptotic neuron death and branching. We also tested shRTP801-EVs functionality in the pathologic in vitro model of 6-Hydroxydopamine (6-OHDA). Expression of RTP801 increased the number of EVs released by neurons. Moreover, RTP801 led to a distinct proteomic signature of neuron-derived EVs, containing more pro-apoptotic markers. Hence, we observed that RTP801-induced toxicity was transferred to neurons via EVs, activating apoptosis and impairing neuron morphology complexity. In contrast, shRTP801-EVs were able to increase the arborization in recipient neurons. The 6-OHDA neurotoxin elevated levels of RTP801 in EVs, and 6-OHDA-derived EVs lost the mTOR/Akt signalling activation via Akt and RPS6 downstream effectors. Interestingly, EVs derived from neurons where RTP801 was silenced prior to exposing them to 6-OHDA maintained Akt and RPS6 transactivation in recipient neurons. Taken together, these results suggest that RTP801-induced toxicity is transferred via EVs, and therefore, it could contribute to the progression of neurodegenerative diseases, in which RTP801 is involved.

Risks of low vaccination coverage and strategies to prevent the resurgence of vaccine-preventable diseases in infants in the COVID-19 pandemic scenario: recommendations for Latin America and the Caribbean by the group of experts on infant immunization for Latin America.

INTRODUCTION: The WHO 2030 Immunization Agenda (IA-2030) harmonizes immunization activity plans at community, national, regional and global levels. Additionally, medical societies play an important role. The Latin American Group of Experts on Infant Immunization, established in 2018, advises on the harmonization, update, and optimization of infant vaccination programs in Latin America and the Caribbean (LAC). In September 2021, 41 such experts from 13 LAC countries met to develop recommendations for increasing regional vaccination coverage to avoid the reemergence of vaccine-preventable diseases and/or the occurrence of outbreaks. AREAS COVERED: The following items were evaluated: (i) immunization challenges before and during the COVID-19 pandemic; (ii) the status of current immunization programs, particularly infant pertussis and polio vaccination; (iii) possible solutions for overcoming vaccination challenges and achieving regional vaccination coverage targets. EXPERT OPINION/COMMENTARY: Medical societies provide valuable recommendations to guide and update vaccination schedules. In the LAC region, possible strategies to achieve target vaccination rates include the use of combination vaccines, strengthening surveillance systems, improving school attendance, advancing vaccine education and confidence, striving for vaccination equity, widening operational capacity, creating strategic alliances, and strengthening the role of medical groups. It is hoped that these recommendations will be implemented in the LAC region.

CD300f immune receptor contributes to healthy aging by regulating inflammaging, metabolism, and cognitive decline.

Emerging evidence suggests that immune receptors may participate in many aging-related processes such as energy metabolism, inflammation, and cognitive decline. CD300f, a TREM2-like lipid-sensing immune receptor, is an exceptional receptor as it integrates activating and inhibitory cell-signaling pathways that modulate inflammation, efferocytosis, and microglial metabolic fitness. We hypothesize that CD300f can regulate systemic aging-related processes and ultimately healthy lifespan. We closely followed several cohorts of two strains of CD300f-/- and WT mice of both sexes for 30 months and observed an important reduction in lifespan and healthspan in knockout mice. This was associated with systemic inflammaging, increased cognitive decline, reduced brain glucose uptake observed by 18FDG PET scans, enrichment in microglial aging/neurodegeneration phenotypes, proteostasis alterations, senescence, increased frailty, and sex-dependent systemic metabolic changes. Moreover, the absence of CD300f altered macrophage immunometabolic phenotype. Taken together, we provide strong evidence suggesting that myeloid cell CD300f immune receptor contributes to healthy aging.

The use of cyclosporine in dermatology.

Cyclosporine is an immunosuppressive drug that acts selectively on T-cells by inhibiting calcineurin phosphorylase. It has been used in dermatology since its approval for US Food and Drug Administration in 1997 for the use in psoriasis. While indicated only for the treatment of moderate to severe psoriasis, cyclosporine has also been used as an off-label drug for the treatment of various inflammatory skin conditions, including atopic dermatitis, blistering disorders, and connective tissue diseases. In this article, we review the use of cyclosporine in dermatology.

An unusual adverse effect of nadroparin injections: Calcinosis cutis.

In 1988, Tumiati et al described the first case of calcinosis cutis related to a calcium-containing heparin. Since then, only 18 cases have been reported in the literature; they usually have an altered calcium-phosphate product, an elevated parathyroid hormone (PTH), or both. We report a 33-year-old patient who developed calcinosis cutis at sites of nadroparin injections without any disturbance of calcium-phosphate product, PTH, or vitamin D. The pathogenesis of calcinosis cutis secondary to nadroparin injections remains controversial; Proposed causes included metastatic, dystrophic, iatrogenic, or multifactorial etiologies. This is the first case of multiple nodules of calcinosis cutis without alterations of calcium-phosphate product, PTH, or vitamin D, which supports an iatrogenic mechanism. We also suggest that calcinosis cutis could be more frequent than we thought and is probably an underdiagnosed entity.