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Abstract We report the evolution of the superconducting properties of a commercial coated conductor during deoxygenation and reoxygenation processes. By analyzing the changes on the critical temperature, T c, and critical current density, J c, at 4 and 77 K, we have identified the conditions that cause a complete deoxygenation of the coated conductor and, also, the reoxygenation conditions that allow a recovery of the superconducting properties. A complete suppression of superconductivity happens at ~ 500–550 °C under a pure argon flow. After a complete deoxygenation, we observed that a reoxygenation process at ~ 400–450 °C in pure oxygen flow allows, not only a full recovery, but even an improvement in J c, both at 4 and 77 K. Such an increase of J c is kept or even enhanced, especially at 77 K, in the presence of magnetic fields up to ~ 6 T. A microstructural analysis by transmission electron microscopy did not give evidence of major differences in the densities of Y2O3 nanoparticles and stacking faults between the pristine and reoxygenated samples, suggesting that these defects should not be the cause of the observed enhancement of J c . Therefore, the combined action of other types of defects, which could appear as a consequence of our reoxygenation process, and of a new level of oxygen doping should be responsible of the J c enhancement. The higher J c that can be achieved by using our simple reoxygenation process opens new parameter space for CCs optimization, which means choosing a proper pO2-temperature–time trajectory for optimizing J c.

Abstract To achieve a sustainable human presence on the Moon, it is critical to develop technologies utilising the local resources (a.k.a. in-situ resource utilisation or ISRU) for construction and resource extraction. In this study, we investigate the viability of microwave heating of two lunar soil simulants (JSC-1A and OPRH3N) under vacuum conditions, to simulate a lunar surface environment compared to previous studies performed at atmospheric pressure. All simulants are thermally treated in a bespoke 2.45 GHz microwave apparatus using three input powers: 1000 W, 600 W and 250 W. The microstructures and mechanical properties of the microwaved samples are analysed to identify their potential applications. Our key findings are: (i) higher input powers generate materials in shorter fabrication times with higher mechanical strengths and higher yields despite the same total energy input; (ii) the microstructures of the microwaved samples under vacuum are very different from those under atmospheric conditions due to the widespread vesicles/bubbles; and (iii) different heating rates caused by different input powers can be utilised for specific ISRU purposes: higher input powers for extra-terrestrial construction and lower input powers for resource extraction. Findings from this study have significant implications for developing a microwave-heating payload for lunar ISRU demonstration missions.

PurposeHigh-altitude (HA) affects sensory organ response, but its effects on the inner ear are not fully understood. The present scoping review aimed to collect the available evidence about HA effects on the inner ear with focus on auditory function.MethodsThe scoping review was conducted following the guidelines of the Preferred Reporting Items for Systematic Review and Meta-Analysis extension for scoping reviews. PubMed, Scopus, and Web of Science electronic databases were systematically searched to identify studies conducted in the last 20 years, which quantified in healthy subjects the effects of HA on auditory function.ResultsThe systematic search identified 17 studies on a total population of 888 subjects (88.7% male, age: 27.8 ± 4.1 years; median sample size of 15 subjects). Nine studies were conducted in a simulated environment and eight during real expeditions at HA. To quantify auditory function, six studies performed pure tone audiometry, four studies measured otoacoustic emissions (OAE) and eight studies measured auditory evoked responses (AER). Study protocols presented heterogeneity in the spatio-temporal patterns of HA exposure, with highly varying maximal altitudes and exposure durations.ConclusionMost studies reported a reduction of auditory function with HA in terms of either elevation of auditory thresholds, lengthening of AER latencies, reduction of distortion-product and transient-evoked OAEs. Future studies in larger populations, using standardized protocols and multi-technique auditory function evaluation, are needed to further characterize the spatio-temporal pattern of HA effects along the auditory pathways and clarify the pathophysiological implications and reversibility of the observed changes.

Abstract The D614G mutation in the Spike protein of the SARS-CoV-2 has effectively replaced the early pandemic-causing variant. Using pseudotyped lentivectors, we confirmed that the aspartate replacement by glycine in position 614 is markedly more infectious. Molecular modelling suggests that the G614 mutation facilitates transition towards an open state of the Spike protein. To explain the epidemiological success of D614G, we analysed the evolution of 27,086 high-quality SARS-CoV-2 genome sequences from GISAID. We observed striking coevolution of D614G with the P323L mutation in the viral polymerase. Importantly, the exclusive presence of G614 or L323 did not become epidemiologically relevant. In contrast, the combination of the two mutations gave rise to a viral G/L variant that has all but replaced the initial D/P variant. Our results suggest that the P323L mutation, located in the interface domain of the RNA-dependent RNA polymerase, is a necessary alteration that led to the epidemiological success of the present variant of SARS-CoV-2. However, we did not observe a significant correlation between reported COVID-19 mortality in different countries and the prevalence of the Wuhan versus G/L variant. Nevertheless, when comparing the speed of emergence and the ultimate predominance in individual countries, it is clear that the G/L variant displays major epidemiological supremacy over the original variant.

Abstract Folliculotropic Mycosis Fungoides (FMF) is a rare variant of Mycosis Fungoides involving the scalp leading to alopecia. The clinical and trichoscopic features in 18 patients were analyzed and compared with the reports in the literature. Gender, age, disease stage, site of onset were taken into consideration. Clinical and trichoscopic analyses were performed on each patient. From a clinical point of view, Folliculotropic Mycosis Fungoides lesions involving the scalp presented as generalized alopecia (27.8%) or patchy-plaque alopecia (72.2%). Trichoscopic analysis revealed six most frequent features: single hair (83.3%), dotted dilated vessels (77.8%), broken-dystrophic hairs (66.7%), vellus hairs (61.1%), spermatozoa-like pattern vessels (55.6%), and yellow dots (55.6%). Additional identified trichoscopic patterns were dilation of follicular openings, scales-crusts, purpuric dots, short hair with split-end, pigtail hairs, perifollicular hyperkeratosis, milky-white globules, black dots, white dots/lines and absence of follicular dots. These trichoscopic features were further correlated to clinical presentations and stage of the disease. The rarity of the disease is a limitation. The relatively high number of patients allowed to identify several clinical and trichoscopic patterns that could be featured as specific or highly suspicious for FMF in order to consider trichoscopy as a complementary diagnostic approach and improve the differential diagnoses between FMF and other scalp disorders.

Abstract For a sustainable human presence on the Moon, it is critical to develop technologies that could utilise the locally available resources (a.k.a. in situ resource utilisation or ISRU) for habitat construction. As the surface soil is one of the most widely available resources at the Moon, we have investigated the viability of microwave heating of a lunar soil simulant (JSC-1A). JSC-1A was thermally treated in a bespoke microwave apparatus using 2.45 GHz frequency, using five different microwave powers in the range of 250 W to 1000 W. The structural properties of the resulting products were analysed to determine whether their microstructures and mechanical strengths differ under different input powers; and whether input power plays a crucial role in triggering thermal runaway, for identifying the optimum power for developing a microwave-heating. Our key findings are: (i) the higher input powers (800 W and 1000 W) generate the highest yields and microstructures with the greatest mechanical strengths, at the shortest fabrication times, and (ii) thermal runaway improves the microwave heating efficiency despite the rapid increase in temperature, once it is triggered. Our findings are of key importance for developing a microwave-heating payload for future lunar ISRU demonstration missions, contributing towards 3D printing-based extra-terrestrial construction processes.

Among perinatal stem cells of the umbilical cord, human Wharton’s jelly mesenchymal stem cells (hWJ-MSCs) are of great interest for cell-based therapy approaches in regenerative medicine, showing some advantages over other MSCs. In fact, hWJ-MSCs, placed between embryonic and adult MSCs, are not tumorigenic and are harvested with few ethical concerns. Furthermore, these cells can be easily cultured in vitro, maintaining both stem properties and a high proliferative rate for several passages, as well as trilineage capacity of differentiation. Recently, it has been demonstrated that cytoskeletal organization influences stem cell biology. Among molecules able to modulate its dynamics, Cytochalasin B (CB), a cyto-permeable mycotoxin, influences actin microfilament polymerization, thus affecting several cell properties, such as the ability of MSCs to differentiate towards a specific commitment. Here, we investigated for the first time the effects of a 24 h-treatment with CB at different concentrations (0.1–3 μM) on hWJ-MSCs. CB influenced the cytoskeletal organization in a dose-dependent manner, inducing changes in cell number, proliferation, shape, and nanomechanical properties, thus promoting the osteogenic commitment of hWJ-MSCs, as confirmed by the expression analysis of osteogenic/autophagy markers.

Introducción: apuntando a la prevención y disminución de la siniestralidad vial, se promulgó la Ley 19360 “de alcohol cero” que modifica la tolerancia de alcohol en sangre para conductores, bajándola de 0,3 g/l a 0,0 g/l, con probados resultados de disminución de siniestros fatales en el corto plazo. Objetivo: analizar el impacto de dicha norma en la venta declarada de alcohol y sobre los usuarios de vías siniestrados por tipo de vehículo y región. Metodología: estudio inferencial, de impacto de intervención. Se analizaron series de tiempo de distintas fuentes, para medir si hubo cambios significativos en éstas mediante la modelización ARIMA, comparando antes y después de la sanción de la Ley 19360. Resultados: el consumo de alcohol declarado no sufrió modificaciones importantes a pesar de la ley cero, mientras que la cantidad de motociclistas fallecidos y heridos de gravedad caen de manera significativa a partir de la sanción de la Ley 19360. Conclusiones: los motociclistas son los más beneficiados con esta legislación, con numerosas vidas salvadas. Los datos sugieren un posible cambio de comportamiento de los conductores de vehículos respecto al consumo de alcohol antes y durante el manejo. La mejora continua de la información disponible para la ciudadanía es clave para comprender mejor estos fenómenos.

Scalp sarcoidosis is generally uncommon and it may present itself with varying morphologies; therefore, it is important to differentiate this disease from other forms of cicatricial and non-cicatricial causes of alopecia. Trichoscopy and histopathology are essential to rule out other skin diseases and to confirm diagnosis. Treatment options include topical, oral, and intralesional corticosteroids; immunosuppressive agents; and hydroxychloroquine, in order to arrest the progression of alopecia. Here, the authors present a case of scalp sarcoidosis with systemic involvement, in which dermoscopy gives important clues for its diagnosis. The authors have also reviewed the literature and identified 46 cases of sarcoidosis that induced alopecia.

In swine and nonhuman primates, kidney allografts can induce tolerance of heart allografts, leading to their long-term, immunosuppression-free survival. We refer to this phenomenon as kidney-induced cardiac allograft tolerance (KICAT). In this study, we have developed a murine model for KICAT to determine the underlining cellular/molecular mechanisms. Here, we show that spontaneously accepted DBA/2J kidneys in C57BL/6 recipients induce systemic tolerance that results in the long-term acceptance of DBA/2J heart allografts but not third-party cardiac allografts. The state of systemic tolerance of hearts was established 2 weeks after transplantation of the kidney, after which time, the kidney allograft is no longer required. Depletion of Foxp3+ T cells from these mice precipitated rejection of the heart allografts, indicating that KICAT is dependent on Treg function. Acceptance of kidney allografts and cotransplanted heart allografts did not require the thymus. In conclusion, these data show that kidney allografts induce systemic, donor-specific tolerance of cardiac allografts via Foxp3 cells, and that tolerance is independent of the thymus and continued presence of the kidney allograft. This experimental system should promote increased understanding of the tolerogenic mechanisms of the kidney.

Cystic fibrosis (CF), one of the most commonly observed and diagnosed fatal monogenic disorders globally, was initially thought to affect individuals of Caucasian/European descent almost exclusively. It is increasingly appreciated, however, that non-Caucasian populations are also affected by this condition. Although this has been known in South Africa (SA) for over two decades, a large disparity still exists in data pertaining to the different population groups in the country. This article seeks to highlight existing published data on CF in SA populations and reflects on the means through which these have been generated over the years. Additionally, the article briefly discusses the consequences of incomplete data and how this could potentially be addressed in the future through innovative and collaborative approaches.

A paediatric nail consultation is often required to reduce parents’ concerns regarding their child’s abnormal nail appearance. Nail pigmentation in children is a dermatological challenge because guidelines are not standardised, causing many doubts for dermatologists. In general, the majority of cases of melanonychia are benign in children and nail melanoma cases are very rare. However, alarming clinical and dermoscopic features can be observed, requiring nail surgery to confirm a diagnosis. Here, we present a case of longitudinal melanonychia in a teenager with atypical signs and a good prognosis.

The mobile nature of fishing activity entails dynamic spatial relations and dependencies between coastal communities and fishing grounds drawn by the movement of fishing vessels. Analysing these spatial relations is essential to allocate the socio-economic impact of the fishing activity into the relevant coastal communities. In addition, such spatial information gives the possibility, on the one hand, to assess the impacts from fisheries on the marine environment and, on the other, to manage competing uses of the sea space between different activities. In this paper, we use AIS data, which is individual vessels' positioning data, to examine the activity of the EU large-scale fishing fleets, their home ports, high intensity fishing areas (i.e., main fishing grounds), main ports and coastal communities involved.

IntroductionCoronavirus disease 2019 (COVID-19) can lead to respiratory failure due to severe immune response. Treatment targeting this immune response might be beneficial but there is limited evidence on its efficacy. The aim of this study was to determine if early treatment of patients with COVID-19 pneumonia with tocilizumab and/or steroids was associated with better outcome.MethodsThis observational single-center study included patients with COVID-19 pneumonia who were not intubated and received either standard of care (SOC, controls) or SOC plus early (within 3 days from hospital admission) anti-inflammatory treatment. SOC consisted of hydroxychloroquine 400mg bid plus, in those admitted before March 24th, also darunavir/ritonavir. Anti-inflammatory treatment consisted of either tocilizumab (8mg/kg intravenously or 162mg subcutaneously) or methylprednisolone 1 mg/kg for 5 days or both. Failure was defined as intubation or death, and the endpoints were failure-free survival (primary endpoint) and overall survival (secondary) at day 30. Difference between the groups was estimated as Hazard Ratio by a propensity score weighted Cox regression analysis (HROW).ResultsOverall, 196 adults were included in the analyses. They were mainly male (67.4%), with comorbidities (78.1%) and severe COVID-19 pneumonia (83.7%). Median age was 67.9 years (range, 30-100) and median PaO2/FiO2 200 mmHg (IQR 133-289). Among them, 130 received early anti-inflammatory treatment with: tocilizumab (n = 29, 22.3%), methylprednisolone (n = 45, 34.6%), or both (n = 56, 43.1%). The adjusted failure-free survival among tocilizumab/methylprednisolone/SOC treated patients vs. SOC was 80.8% (95%CI, 72.8-86.7) vs. 64.1% (95%CI, 51.3-74.0), HROW 0.48, 95%CI, 0.23-0.99; p = 0.049. The overall survival among tocilizumab/methylprednisolone/SOC patients vs. SOC was 85.9% (95%CI, 80.7-92.6) vs. 71.9% (95%CI, 46-73), HROW 0.41, 95%CI: 0.19-0.89, p = 0.025.ConclusionEarly adjunctive treatment with tocilizumab, methylprednisolone or both may improve outcomes in non-intubated patients with COVID-19 pneumonia.

IntroductionAlthough vaccination against influenza is recommended for pregnant women in France because it exposes them to a risk of death and severe respiratory complications, their vaccination coverage in 2016 was estimated at 7%. This study's principal objective was to assess the association between the availability of influenza vaccination at prenatal care visits and vaccination coverage.Material and methodsThis multicenter survey took place in 3 Paris-area public hospital (AP-HP) maternity wards (A, B, and C). Only maternity ward A offered the vaccine and vaccination without charge at prenatal visits. Data were collected from parturients during 10 days in January 2017 by a self-administered anonymous questionnaire.ResultsData from 248 women showed overall vaccination coverage of 19.4% (48/248): 35.4% (46/130) in maternity unit A, 2.7% (2/75) in B, and 0% (0/43) in C (PConclusionOur results show that availability of influenza vaccination, free of charge, at prenatal consultations at the maternity ward increases vaccination coverage significantly.

Dandruff is a common condition, generally due to seborrheic dermatitis (SD) and occasionally to scalp psoriasis (SP), which is characterized by accumulation of scales, oily, red and flaky scalp, often accompanied by itch. The aim of our study was to evaluate the cleansing efficacy and tolerability of a new shampoo (Psorisdin Shampoo®) containing urea, glycolic acid, salicylic acid, ichthyol pale and laureth 9 compared to a nonspecific shampoo. A total of 10 subjects (4 males and 6 females, 18–60 years) with mild–moderate scalp inflammation with redness, itching and flaking, due to SP and/or SD, were included in this open clinical study. The treatment efficacy was assessed by comparison of global photography and trichoscopy pictures, evaluating the presence of scales and erythema on the scalp, the number and morphology of capillaries and verifying disease evolution, severity of symptoms and presence of scalp irritation/itch. The use of this medicated shampoo resulted in an important improvement of patient’s scalp and hair clinical appearance and was well tolerated, with disappearance of scalp irritation and itching in almost all patients, showing higher cleansing and soothing property than a nonspecific shampoo. The effect of the tested shampoo was maintained over time, even after 5 days since the last wash.

Background Oxytetracycline (OTC), which is largely employed in zootechnical and veterinary practices to ensure wellness of farmed animals, is partially absorbed within the gastrointestinal tract depositing in several tissues. Therefore, the potential OTC toxicity is relevant when considering the putative risk derived by the entry and accumulation of such drug in human and pet food chain supply. Despite scientific literature highlights several OTC-dependent toxic effects on human and animal health, the molecular mechanisms of such toxicity are still poorly understood. Methods Here, we evaluated DNA damages and epigenetic alterations by quantitative reverse transcription polymerase chain reaction, quantitative polymerase chain reaction, chromatin immuno-precipitation and Western blot analysis. Results We observed that human peripheral blood mononuclear cells (PBMCs) expressed DNA damage features (activation of ATM and p53, phosphorylation of H2AX and modifications of histone H3 methylation of lysine K4 in the chromatin) after the in vitro exposure to OTC. These changes are linked to a robust inflammatory response indicated by an increased expression of Interferon (IFN)-γ and type 1 superoxide dismutase (SOD1). Discussion Our data reveal an unexpected biological in vitro activity of OTC able to modify DNA and chromatin in cultured human PBMC. In this regard, OTC presence in foods of animal origin could represent a potential risk for both the human and animal health.

Systemic sclerosis (scleroderma) is a disease of unknown cause, the hallmark of which is induration of the skin. This bad condition of the skin influences negatively the quality of life of patients with scleroderma. The aim of the study was to verify the efficacy of two formulations, specifically designed to wash, moisturize and soothe the scleroderma skin. An independent, randomized, double blind, controlled trial was conducted in the Department of Rheumatology of “A. Galateo” Hospital in San Cesario di Lecce. Forty-six women affected by scleroderma, and treated with Iloprost every month, were divided into two groups: group 1 followed a specific treatment with cleansing formulation only, group 2 followed a combined treatment with the cleansing solution and the moisturizing solution. In addition, a third group was evaluated: 14 women, who did not undergo intravenous Iloprost therapy, were treated simultaneously with the cleansing formulation and the moisturizing formulation. The three treatments lasted for 4 weeks. Reduction in trans epidermal water loss (TEWL), increase in moisturization of the stratum corneum, reduction in Skin Score and improvement in quality of life were assessed. Very significant improvement in quality of life occurred in each group. Group 2 obtained very significant improvement in hydration and reduction in skin score and TEWL. The study showed that the daily use of both formulations proved to be effective in washing, hydrating and soothing the skin of patients with scleroderma, especially in association with Iloprost therapy.

Allergen-specific immunotherapy (AIT) is the only curative treatment for type-1 allergies, but sometimes shows limited therapeutic response as well as local and systemic side effects. Limited control of local inflammation and patient symptoms hampers its widespread use in severe allergic asthma.Our aim was to evaluate whether AIT is more effective in suppression of local inflammation if performed under the umbrella of short-term non-specific immunomodulation using a small molecule inhibitor of JAK pathways.In C57BL/6J mice, a model of ovalbumin (OVA)-induced allergic airway inflammation and allergen-specific immunotherapy was combined with the administration of Tofacitinib (TOFA, a FDA-approved JAK inhibitor) from 48 hours prior to 48 hours after therapeutic OVA-injection. The effect of TOFA on human FOXP3+CD4+ T cells was studied in vitro.AIT combined with short-term TOFA administration was significantly more effective in suppressing total cell and eosinophil infiltration into the lung, local cytokine production including IL-1β and CXCL1 and showed a trend for the reduction of IL-4, IL-13, TNF-α and IL-6 compared to AIT alone. Furthermore, TOFA co-administration significantly reduced systemic IL-6, IL-1β and OVA-specific IgE levels and induced IgG1 to the same extent as AIT alone. Additionally, TOFA enhanced the induction of human FOXP3+CD4+ T cells.This proof of concept study shows that JAK inhibition did not inhibit tolerance induction, but improved experimental AIT at the level of local inflammation. The improved control of local inflammation might extend the use of AIT in more severe conditions such as polyallergy, asthma and high-risk patients suffering from mastocytosis or anaphylaxis.

A number of reports indicated that Aurora-A or Aurora-B overexpression represented a negative prognostic factor in several human malignancies. In thyroid cancer tissues a deregulated expression of Aurora kinases has been also demonstrated, but no information regarding its possible prognostic role in differentiated thyroid cancer is available. Here, we evaluated Aurora-A and Aurora-B mRNA expression and its prognostic relevance in a series of 87 papillary thyroid cancers (PTC), with a median follow-up of 63 months. The analysis of Aurora-A and Aurora-B mRNA levels in PTC tissues, compared to normal matched tissues, revealed that their expression was either up- or down-regulated in the majority of cancer tissues. In particular, Aurora-A and Aurora-B mRNA levels were altered, respectively, in 55 (63.2%) and 79 (90.8%) out of the 87 PTC analyzed.A significant positive correlation between Aurora-A and Aurora-B mRNAs was observed (p=0.001). The expression of both Aurora genes was not affected by the BRAFV600E mutation. Univariate, multivariate and Kaplan-Mayer analyses documented the lack of association between Aurora-A or Aurora-B expression and clinicopathological parameters such as gender, age, tumor size, histology, TNM stage, lymph node metastasis and BRAF status as well as disease recurrences or disease-free interval. Only Aurora-B mRNA was significantly higher in T(3-4) tissues, with respect to T(1-2) PTC tissues. The data reported here demonstrate that the expression of Aurora kinases is deregulated in the majority of PTC tissues, likely contributing to PTC progression. However, differently from other human solid cancers, detection of Aurora-A or Aurora-B mRNAs is not a prognostic biomarker in PTC patients.

Several research initiatives have been undertaken to map fishing effort at high spatial resolution using the Vessel Monitoring System (VMS). An alternative to the VMS is represented by the Automatic Identification System (AIS), which in the EU became compulsory in May 2014 for all fishing vessels of length above 15 meters. The aim of this paper is to assess the uptake of the AIS in the EU fishing fleet and the feasibility of producing a map of fishing effort with high spatial and temporal resolution at European scale. After analysing a large AIS dataset for the period January-August 2014 and covering most of the EU waters, we show that AIS was adopted by around 75% of EU fishing vessels above 15 meters of length. Using the Swedish fleet as a case study, we developed a method to identify fishing activity based on the analysis of individual vessels' speed profiles and produce a high resolution map of fishing effort based on AIS data. The method was validated using detailed logbook data and proved to be sufficiently accurate and computationally efficient to identify fishing grounds and effort in the case of trawlers, which represent the largest portion of the EU fishing fleet above 15 meters of length. Issues still to be addressed before extending the exercise to the entire EU fleet are the assessment of coverage levels of the AIS data for all EU waters and the identification of fishing activity in the case of vessels other than trawlers.

Functional brain activation studies described the presence of separate cortical areas responsible for central processing of peripheral vestibular information and reported their activation and interactions with other sensory modalities and the changes of this network associated to strategic peripheral or central vestibular lesions. It is already known that cortical changes induced by acute unilateral vestibular failure (UVF) are various and undergo variations over time, revealing different cortical involved areas at the onset and recovery from symptoms. The present study aimed at reporting the earliest change in cortical metabolic activity during a paradigmatic form of UVF such as vestibular neuritis (VN), that is, a purely peripheral lesion of the vestibular system, that offers the opportunity to study the cortical response to altered vestibular processing. This research reports [(18)F]fluorodeoxyglucose positron emission tomography brain scan data concerning the early cortical metabolic activity associated to symptoms onset in a group of eight patients suffering from VN. VN patients' cortical metabolic activity during the first two days from symptoms onset was compared to that recorded one month later and to a control healthy group. Beside the known cortical response in the sensorimotor network associated to vestibular deafferentation, we show for the first time the involvement of Entorhinal (BAs 28, 34) and Temporal (BA 38) cortices in early phases of symptomatology onset. We interpret these findings as the cortical counterparts of the attempt to reorient oneself in space counteracting the vertigo symptom (Bas 28, 34) and of the emotional response to the new pathologic condition (BA 38) respectively. These interpretations were further supported by changes in patients' subjective ratings in balance, anxiety, and depersonalization/derealization scores when tested at illness onset and one month later. The present findings contribute in expanding knowledge about early, fast-changing, and complex cortical responses to pathological vestibular unbalanced processing.

BACKGROUND: Androgens are critical in male external genital development. Alterations in the androgen sensitivity pathway have been identified in severely undermasculinized boys, and mutations of the androgen receptor gene (AR) are usually found in partial or complete androgen insensitivity syndrome (AIS). OBJECTIVE: The aim of this study was to determine whether even the most minor forms of isolated hypospadias are associated with AR mutations and thus whether all types of hypospadias warrant molecular analysis of the AR. MATERIALS AND METHODS: Two hundred and ninety-two Caucasian children presenting with isolated hypospadias without micropenis or cryptorchidism and 345 controls were included prospectively. Mutational analysis of the AR through direct sequencing (exons 1-8) was performed. In silico and luciferase functional assays were performed for unreported variants. RESULTS: Five missense mutations of the AR were identified in 9 patients with glandular or penile anterior (n = 5), penile midshaft (n = 2) and penile posterior (n = 2) hypospadias, i.e., 3%: p.Q58L (c.173A>T), 4 cases of p.P392S (c.1174C>T), 2 cases of p.A475V (c.1424C>T), p.D551H (c.1651G>C) and p.Q799E (c.2395C>G). None of these mutations was present in the control group. One mutation has never been reported to date (p.D551H). It was predicted to be damaging based on 6 in silico models, and in vitro functional studies confirmed the lowered transactivation function of the mutated protein. Three mutations have never been reported in patients with genital malformation but only in isolated infertility: p.Q58L, p.P392S, and p.A475V. It is notable that micropenis, a cardinal sign of AIS, was not present in any patient. CONCLUSION: AR mutations may play a role in the cause of isolated hypospadias, even in the most minor forms. Identification of this underlying genetic alteration may be important for proper diagnosis and longer follow-up is necessary to find out if the mutations cause differences in sexual function and fertility later in life.

A major challenge for the treatment of many central nervous system (CNS) disorders is the lack of convenient and effective methods for delivering biological agents to the brain. Mucopolysaccharidosis II (Hunter syndrome) is a rare inherited lysosomal storage disorder resulting from a deficiency of iduronate-2-sulfatase (I2S). I2S is a large, highly glycosylated enzyme. Intravenous administration is not likely to be an effective therapy for disease-related neurological outcomes that require enzyme access to the brain cells, in particular neurons and oligodendrocytes. We demonstrate that intracerebroventricular and lumbar intrathecal administration of recombinant I2S in dogs and nonhuman primates resulted in widespread enzyme distribution in the brain parenchyma, including remarkable deposition in the lysosomes of both neurons and oligodendrocytes. Lumbar intrathecal administration also resulted in enzyme delivery to the spinal cord, whereas little enzyme was detected there after intraventricular administration. Mucopolysaccharidosis II model is available in mice. Lumbar administration of recombinant I2S to enzyme deficient animals reduced the storage of glycosaminoglycans in both superficial and deep brain tissues, with concurrent morphological improvements. The observed patterns of enzyme transport from cerebrospinal fluid to the CNS tissues and the resultant biological activity (a) warrant further investigation of intrathecal delivery of I2S via lumbar catheter as an experimental treatment for the neurological symptoms of Hunter syndrome and (b) may have broader implications for CNS treatment with biopharmaceuticals.

The management of chronic hand eczema is usually difficult. The aim of this open-label study is to assess the effectiveness and ‘steroid-sparing’ activity of a barrier cream containing polyvinylpyrrolidone in patients with chronic hand eczema. Rescue treatment with topical corticosteroids (TCs) was permitted in the event of eczema worsening, whereas preventive measures were maintained unchanged with respect to those adopted by patients in the past. Among the 207 participants, the main diagnosis was irritant contact dermatitis, followed by allergic contact dermatitis and atopic dermatitis. Nearly half of the patients (49%) applied the barrier cream once or twice a day, while the remaining patients used it three or more times per day. Regardless of rescue therapy with TCs, regular use of the barrier cream caused a progressive significant improvement of eczema severity, as indicated by dermatologists' and patients' assessments. A significant reduction in the amount of the TC applied in the last 3 months and in the number of TC treatment days during the previous 4 weeks was found at the end of 12-week treatment with the barrier cream as compared with baseline. The product was also well-tolerated and accepted by the majority of patients. The results of this study suggest that a barrier cream containing polyvinylpyrrolidone can represent a useful tool in the management of chronic hand eczema and may show steroid-sparing effects.

Results of topical treatments can be influenced by several factors, including accurate dosing based on the affected skin area. The aim of this open-labelled multicenter study is to evaluate if correct dosing of calcitriol ointment has an impact on the clinical response of plaque psoriasis. For this purpose, patients with plaque psoriasis eligible to be treated with calcitriol ointment were randomized to treatment with a ‘standardized dose’ method, using a dosing device (N. 100), or treatment without the device (N. 101), for 12 weeks. Regardless of the use of the dosing device, calcitriol ointment caused a significant reduction of both the severity of signs and symptoms and the extent of body surface area affected after both 4 weeks and 12 weeks. Clinical response was not significantly different between the two groups. Local adverse events occurred in 12 subjects (of whom five treated with the device) and were mild and transient in most cases.

The promise stem cell therapy holds for curing diseases for which no therapy currently exists is often translated as fact. Unfortunately, enforced misconceptions between fact and promise often also translate into exploitation and harming of patients. This article aims to clear up misconceptions about the biological promise and legal consequences of insisting on promises not based on scientific facts.Â

Combined treatment with oral lymecycline and topical adapalene has been shown to induce greater and faster improvement of acne than monotherapy with lymecycline. We wanted to evaluate the effects of combined therapy with topical adapalene (cream or gel) plus oral lymecycline used at different dosages (group A: 300mg/day for 2 weeks and then 150mg/day for 14 weeks; group B: 300mg/day for 16 weeks) in 242 patients with inflammatory acne. Both dosage regimens were well tolerated in the majority of patients and significantly improved both the acne lesion count and seborrhoea. There was a trend towards a greater reduction of seborrhoea and nodules in patients of group B. After the initial 16-week phase, patients entered an 8-week follow-up phase, consisting of the use of adapalene monotherapy. The results obtained after this phase confirm the therapeutic value and the favourable tolerability of adapalene as maintenance treatment after successful treatment of inflammatory acne. At the same time, a significantly reduced count of comedones was observed in patients of group B as compared with group A, suggesting that prolonged use of high-dose lymecycline may have a more pronounced influence on comedogenesis.

Oral antibiotics, especially tetracyclines, are commonly used to treat moderate to moderately severe acne vulgaris. There are hints suggesting that a combination treatment with oral tetracyclines and topical retinoids can cause a greater and prompter improvement of acne than monotherapy with tetracyclines. We evaluated the clinical activity of a 12-week combined therapy with oral lymecycline (300mg/day for 2 weeks and then 150mg/day) and topical adapalene (gel or cream) in 419 patients with inflammatory acne. A significant reduction in the number of acne lesions was noted at 4 and 12 weeks (P

Treatment of cheilitis is usually difficult and often disappointing. We evaluated the effects of a topical preparation containing vitamin E acetate (VEA® lipogel) in 254 patients (mean age, 29.5) with cheilitis of various nature and etiology, involving the vermilion region and/or the perioral skin. The most frequent form of cheilitis was that induced by oral isotretinoin; other forms were irritant contact dermatitis, atopic cheilitis, and contact allergy. Patients were instructed to apply VEA® lipogel daily; the number of daily applications was modulated on the basis of the severity of symptoms (two or three times a day in the majority of cases). After 4 weeks of treatment, clinical examination showed that the severity of symptoms and signs significantly improved (P

Topical corticosteroids are commonly used for the short-term management of seborrhoeic dermatitis (SD) of the scalp. The aim of this study was to evaluate the effectiveness, tolerance and cosmetic acceptability of desonide 0.05% solution, whose alcohol-free formulation is innovative with respect to traditional corticosteroid lotions, in the treatment of SD of the scalp. For this purpose, 155 adult subjects applied on scalp lesions desonide once daily for 1 week, on alternate days for 3 weeks, and two times a week for 4 weeks. A significant reduction of the severity of erythema, scaling and pruritus was observed (P

A major challenge for the treatment of many central nervous system (CNS) disorders is the lack of convenient and effective methods for delivering biological agents to the brain. Mucopolysaccharidosis II (Hunter syndrome) is a rare inherited lysosomal storage disorder resulting from a deficiency of iduronate-2-sulfatase (I2S). I2S is a large, highly glycosylated enzyme. Intravenous administration is not likely to be an effective therapy for disease-related neurological outcomes that require enzyme access to the brain cells, in particular neurons and oligodendrocytes. We demonstrate that intracerebroventricular and lumbar intrathecal administration of recombinant I2S in dogs and nonhuman primates resulted in widespread enzyme distribution in the brain parenchyma, including remarkable deposition in the lysosomes of both neurons and oligodendrocytes. Lumbar intrathecal administration also resulted in enzyme delivery to the spinal cord, whereas little enzyme was detected there after intraventricular administration. Mucopolysaccharidosis II model is available in mice. Lumbar administration of recombinant I2S to enzyme deficient animals reduced the storage of glycosaminoglycans in both superficial and deep brain tissues, with concurrent morphological improvements. The observed patterns of enzyme transport from cerebrospinal fluid to the CNS tissues and the resultant biological activity (a) warrant further investigation of intrathecal delivery of I2S via lumbar catheter as an experimental treatment for the neurological symptoms of Hunter syndrome and (b) may have broader implications for CNS treatment with biopharmaceuticals.