Hyponatremia-related liver steatofibrosis and impaired spermatogenesis: evidence from a mouse model of the syndrome of inappropriate antidiuresis.

PURPOSE: Hyponatremia is the most frequent electrolytic disorder in clinical practice. In addition to neurological symptoms, hyponatremia, even when mild/moderate and chronic, has been related to other manifestations, such as bone demineralization and increased risk of fractures. To better elucidate tissue alterations associated with reduced serum sodium concentration [Na+], we developed an in vivo model of hyponatremia secondary to the Syndrome of Inappropriate Antidiuresis. METHODS AND RESULTS: Hyponatremia was induced in Foxn1nu/nu mice by subcutaneous infusion of the vasopressin analog 1-deamino [8-D-arginine] vasopressin (dDAVP) for 14 days via osmotic mini-pumps. Mice in the control group were infused with isotonic saline solution. Serum [Na+] progressively decreased, with a nadir of 123.4 ± 2.3 mEq/L (mean ± SD, dDAVP 0.3 ng/h) and 111.6 ± 4.7 mEq/L (mean ± SD, dDAVP 0.5 ng/h). Evident signs of liver steatofibrosis were observed at histology in hyponatremic mice. Accordingly, the expression of proteins involved in lipid metabolism (SREBP-1, PPARα and PPARγ) and in myofibroblast formation (αSMA and CTGF) significantly increased. Furthermore, heme oxygenase 1 expression was up-regulated in Kupffer and hepatic stellate cells in the liver of hyponatremic mice. Testis alterations were also observed. In particular, the thickness of the seminiferous epithelium appeared reduced. The expression levels of PCNA and PTMA, which are involved in DNA replication and germ cells maturation, were markedly reduced in the testis of hyponatremic mice. CONCLUSION: Overall, these findings shed new light on the possible consequences of chronic hyponatremia and prompt a more thorough evaluation of hyponatremic patients.

The V2 receptor antagonist tolvaptan counteracts proliferation and invasivity in human cancer cells.

PURPOSE: Hyponatremia, the most frequent electrolyte alteration in clinical practice, has been associated with a worse prognosis in cancer patients. On the other hand, a better outcome has been related to serum sodium normalization. In vitro studies have shown that low extracellular sodium promotes cancer cells proliferation and invasiveness. Tolvaptan, a selective vasopressin receptor type 2 (V2) antagonist, has been effectively used in the last decade for the treatment of hyponatremia secondary to the Syndrome of Inappropriate Antidiuresis. A few in vitro data suggested a direct role of tolvaptan in counteracting cancer progression, so far. The aim of this study was to evaluate the effect and the mechanism of action of tolvaptan in cell lines from different tumours [i.e. colon cancer (HCT-8), hepatocarcinoma (HepG2), neuroblastoma (SK-N-AS)]. METHODS AND RESULTS: First, we showed that these cell lines express the V2 receptor. Tolvaptan significantly reduced cell proliferation with an IC50 in the micromolar range. Accordingly, reduced levels of cAMP, of the catalytic α subunit of PKA, and a reduced pAKT/AKT ratio were observed. Tolvaptan effectively inhibited cell cycle progression, whereas it induced apoptotis. Furthermore, it reduced cell invasiveness. In particular, anchorage-independent growth and the activity of collagenases type IV were blunted in the three cell lines. Accordingly, tolvaptan counteracted the RhoA/ROCK1-2 pathway, which has a pivotal role in regulating cell movement. CONCLUSIONS: Overall, these findings indicate that tolvaptan effectively inhibits tumour progression in vitro. Further studies should clarify whether the V2 receptor might be considered a possible target in anti-cancer strategies in the future.

Validation of questionnaire algorithm based on repeated open application testing with the constituents of fragrance mix II: the EDEN Fragrance Study.

BACKGROUND: In a European study on contact allergy in the general population, it has been hypothesized that the combination of contact allergy to a fragrance together with a history indicating dermatitis at exposure and thereafter subsequent avoidance of scented products implied a diagnosis of allergic contact dermatitis. OBJECTIVES: The primary aim of this study was to validate this hypothesis/algorithm. The secondary aim was to investigate whether there was any association between the outcome of the recent repeated open application test (ROAT) and the patch test reactivity. METHODS: One hundred nine subjects with and without contact allergy to fragrance mix II (FM II) were recruited. Volunteers from six European dermatology clinics participated in the study including a patch test and a ROAT. RESULTS: Twenty-four positive ROAT reactions were noted in total including 20 of those 32 with contact allergy to FM II. None of the volunteers reacted to the vehicle (P < 0.001). More individuals with a positive algorithm had positive ROATs when compared with those with a negative algorithm. However, the difference was not statistically significant (P = 0.12). The lower the patch test concentration eliciting a positive test reaction, the more likely was a positive ROAT and the more likely that the positive ROAT appeared early during the investigative period. CONCLUSIONS: The algorithm used in this study was not validated but it was indicated in this ROAT setup. The stronger the patch test reactivity the more likely was a positive ROAT and the more likely it was that the positive ROAT appeared early during the application period.

Risk-mitigating behaviours in people with inflammatory skin and joint disease during the COVID-19 pandemic differ by treatment type: a cross-sectional patient survey.

BACKGROUND: Registry data suggest that people with immune-mediated inflammatory diseases (IMIDs) receiving targeted systemic therapies have fewer adverse coronavirus disease 2019 (COVID-19) outcomes compared with patients receiving no systemic treatments. OBJECTIVES: We used international patient survey data to explore the hypothesis that greater risk-mitigating behaviour in those receiving targeted therapies may account, at least in part, for this observation. METHODS: Online surveys were completed by individuals with psoriasis (globally) or rheumatic and musculoskeletal diseases (RMDs) (UK only) between 4 May and 7 September 2020. We used multiple logistic regression to assess the association between treatment type and risk-mitigating behaviour, adjusting for clinical and demographic characteristics. We characterized international variation in a mixed-effects model. RESULTS: Of 3720 participants (2869 psoriasis, 851 RMDs) from 74 countries, 2262 (60·8%) reported the most stringent risk-mitigating behaviour (classified here under the umbrella term 'shielding'). A greater proportion of those receiving targeted therapies (biologics and Janus Kinase inhibitors) reported shielding compared with those receiving no systemic therapy [adjusted odds ratio (OR) 1·63, 95% confidence interval (CI) 1·35-1·97]. The association between targeted therapy and shielding was preserved when standard systemic therapy was used as the reference group (OR 1·39, 95% CI 1·23-1·56). Shielding was associated with established risk factors for severe COVID-19 [male sex (OR 1·14, 95% CI 1·05-1·24), obesity (OR 1·37, 95% CI 1·23-1·54), comorbidity burden (OR 1·43, 95% CI 1·15-1·78)], a primary indication of RMDs (OR 1·37, 95% CI 1·27-1·48) and a positive anxiety or depression screen (OR 1·57, 95% CI 1·36-1·80). Modest differences in the proportion shielding were observed across nations. CONCLUSIONS: Greater risk-mitigating behaviour among people with IMIDs receiving targeted therapies may contribute to the reported lower risk of adverse COVID-19 outcomes. The behaviour variation across treatment groups, IMIDs and nations reinforces the need for clear evidence-based patient communication on risk-mitigation strategies and may help inform updated public health guidelines as the pandemic continues.

Cutaneous manifestations of SARS-CoV-2 infection: a clinical update.

On 11 March 2020, the World Health Organization (WHO) has declared the novel coronavirus disease (COVID-19) a global pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 virus). A consistent number of case reports and clinical series have been already published describing a complex spectrum of skin manifestations associated with the SARS-CoV-2 infection. We carried out a review of the English-language literature up to 20 May 2020, reporting original cases or case series of the cutaneous manifestations of SARS-CoV-2 virus infection. The following databases were consulted: PubMed, Embase, Google Scholar and ResearchGate. The search of papers was conducted by using the key term 'COVID-19' or 'SARS-CoV-2' or 'coronavirus' combined with each of the following: 'skin', 'cutaneous', 'dermatologic' or 'dermatology', 'manifestation', 'lesions', or 'rash'. The patterns of dermatological manifestations associated with SARS-CoV-2 infection could be classified into four categories: exanthema (varicella-like, papulo-vesicular and morbilliform rash), vascular (chilblain-like, purpuric/petechial and livedoid lesions), urticarial and acro-papular eruption. Lastly, other skin manifestations to be considered are the cutaneous adverse reactions to the drugs prescribed for the treatment of COVID-19. Whether SARS-CoV-2 infection can directly cause a worsening of chronic inflammatory diseases such as psoriasis or atopic dermatitis remains to be determined. Dermatology's outlook in the COVID-19 pandemic is multidimensional.

Dermatologists and SARS-CoV-2: the impact of the pandemic on daily practice.

Since the first case of 'pneumonia of unknown aetiology' was diagnosed at the Wuhan Jinyintan Hospital in China on 30 December 2019, what was recognized thereafter as 'severe acute respiratory syndrome coronavirus 2' (SARS-CoV-2) has spread over the four continents, causing the respiratory manifestations of coronavirus disease-19 (COVID-19) and satisfying the epidemiological criteria for a label of 'pandemic'. The ongoing SARS-CoV-2 pandemic is having a huge impact on dermatological practice including the marked reduction of face-to-face consultations in favour of teledermatology, the uncertainties concerning the outcome of COVID-19 infection in patients with common inflammatory disorders such as psoriasis or atopic dermatitis receiving immunosuppressive/immunomodulating systemic therapies; the direct involvement of dermatologists in COVID-19 care for patient assistance and new research needs to be addressed. It is not known yet if skin lesions and derangement of the skin barrier could make it easier for SARS-CoV-2 to transmit via indirect contact; it remains to be defined if specific mucosal or skin lesions are associated with SARS-CoV-2 infection, although some unpublished observations indicate the occurrence of a transient varicelliform exanthema during the early phase of the infection. SARS-CoV-2 is a new pathogen for humans that is highly contagious, can spread quickly, and is capable of causing enormous health, economic and societal impacts in any setting. The consequences may continue long after the pandemic resolves, and new management modalities for dermatology may originate from the COVID-19 disaster. Learning from experience may help to cope with future major societal changes.