Activation of the NLRP3 Inflammasome Is Associated with Valosin-Containing Protein Myopathy

Aberrant activation of the NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome, triggers a pathogenic inflammatory response in many inherited neurodegenerative disorders. Inflammation has recently been associated with valosin-containing protein (VCP)-associated diseases, caused by missense mutations in the VCP gene. This prompted us to investigate whether NLRP3 inflammasome plays a role in VCP-associated diseases, which classically affects the muscles, bones, and brain. In this report, we demonstrate (i) an elevated activation of the NLRP3 inflammasome in VCP myoblasts, derived from induced pluripotent stem cells (iPSCs) of VCP patients, which was significantly decreased following in vitro treatment with the MCC950, a potent and specific inhibitor of NLRP3 inflammasome; (ii) a significant increase in the expression of NLRP3, caspase 1, IL-1β, and IL-18 in the quadriceps muscles of VCP^R155H/+ heterozygote mice, an experimental mouse model that has many clinical features of human VCP-associated myopathy; (iii) a significant increase of number of IL-1β⁽⁺⁾F4/80⁽⁺⁾Ly6C⁽⁺⁾ inflammatory macrophages that infiltrate the muscles of VCP^R155H/+ mice; (iv) NLRP3 inflammasome activation and accumulation IL-1β⁽⁺⁾F4/80⁽⁺⁾Ly6C⁽⁺⁾ macrophages positively correlated with high expression of TDP-43 and p62/SQSTM1 markers of VCP pathology in damaged muscle; and (v) treatment of VCP^R155H/+ mice with MCC950 inhibitor suppressed activation of NLRP3 inflammasome, reduced the F4/80⁽⁺⁾Ly6C⁽⁺⁾IL-1β⁽⁺⁾ macrophage infiltrates in the muscle, and significantly ameliorated muscle strength. Together, these results suggest that (i) NLRP3 inflammasome and local IL-1β⁽⁺⁾F4/80⁽⁺⁾Ly6C⁽⁺⁾ inflammatory macrophages contribute to pathogenesis of VCP-associated myopathy and (ii) identified MCC950 specific inhibitor of the NLRP3 inflammasome with promising therapeutic potential for the treatment of VCP-associated myopathy.     

Prevalence and risk factors of actinic keratosis in patients attending Italian dermatology clinics

Background

Actinic keratosis (AK) is a common keratinocyte intraepidermal neoplasia.

Objective

To assess AK prevalence and potential risk factors in patients attending Italian general dermatology clinics.

Materials & methods

This retrospective study was conducted on clinical data from consecutive white outpatients aged ≥30 years, attending 24 general dermatology clinics between December 2014 and February 2015. AK prevalence (entire population) and multivariate risk factor analysis (patients with current/previous AK and complete data) are presented.

Results

AK prevalence in 7,284 patients was 27.4% (95% CI: 26.4-28.4%); 34.3% in men and 20.0% in women (p<0.001). Independent AK risk factors in 4,604 patients were: age (OR: 4.8 [95% CI: 3.5-6.5] for 46-60 years, increasing with older age to OR: 41.5 [95% CI: 29.5-58.2] for >70 years), history of other non-melanoma skin cancers (OR: 2.7 [2.2-3.3]), residence in southern Italy/Sardinia (OR: 2.6 [2.1-3.0]), working outdoors >6 hours/day (OR: 1.9 [1.4-2.4]), male gender (OR: 1.7 [1.4-2.0]), facial solar lentigos (OR: 1.6 [1.4-1.9]), light hair colour (OR: 1.5 [1.2-1.8]), prolonged outdoor recreational activities (OR: 1.4 [1.2-1.7]), light eye colour (OR: 1.3 [1.1-1.6]), skin type I/II (OR: 1.3 [1.1-1.6]), and alcohol consumption (OR: 1.2 [1.0-3.3]). BMI ≥25.0 (OR: 0.6 [0.5-0.7]), regular sunscreen use (OR: 0.7 [0.6-0.8]), and a lower level of education (OR: 0.8 [0.7-1.0]) were independent protective factors.

Conclusions

AK prevalence was high in Italian dermatology outpatients. We confirm several well-known AK risk factors and reveal possible novel risk and protective factors. Our results may inform on the design and implementation of AK screening and educational programmes.

     

O Papel dos Níveis Séricos de ANP na Perda de Peso,Risco Cardiometabólico e Composição Corporal de Adolescentes com Obesidade Submetidos a Terapia Interdisciplinar

BackgroundThe action of atrial natriuretic peptide (ANP) on natriuresis, diuresis and vasodilatation, insulin resistance, liver, kidney, and adipose tissue may contribute to the healthy metabolic and cardiovascular development. Even though the circulating level of ANP is reduced in patients with obesity, its response to weight loss remains poorly explored in pediatric populations.ObjectiveTo evaluate the effects of ANP variations in response to interdisciplinary weight loss intervention on metabolic syndrome (MetS) and cardiometabolic risks in adolescents with obesity.Methods73 adolescents with obesity attended a 20-week clinical interdisciplinary weight loss therapy including clinical, nutritional, psychological and exercise training approach. Body composition, biochemical analyses and blood pressure were evaluated. MetS was classified according to the International Diabetes Federation (IDF) (2007). After the treatment, volunteers were divided according to Increasing (n=31) or Decreasing (n=19) ANP plasma levels.ResultsBoth groups present significant reduction of body weight, Body Mass Index (BMI), waist, neck and hip circumferences (WC, NC and HC, respectively) and increasing fat-free mass (FFM). Interestingly, a significant reduction in body fat, TG/HDL-c ratio and MetS prevalence (from 23% to 6%) was observed in the Increased ANP group only.ConclusionThis study suggests that an increase in ANP serum levels after weight loss therapy could be associated with improvements in cardiometabolic risks and the reduced prevalence of MetS in adolescents with obesity.     

Developing and validating a new nomogram for diagnosing bladder outlet obstruction in women

Objective

To develop and validate a nomogram for assessing bladder outlet obstruction (BOO) in women derived from concurrent P_det.Qmax and Q_max based on radiographic evidence of increased urethral resistance.

Patients and Methods

Retrospective analysis of prospectively acquired video‐urodynamics and clinical data of 185 women (development cohort) was performed. The P_det.Qmax were plotted against Q_max and cluster analysis was performed to determine an axis that best divided the definitively obstructed and unobstructed. Using data from a further 350 women (validation cohort), the sensitivity and specificity of the derived criterion was calculated. Finally, the data from both groups was pooled together and using binary logistic regression analysis, a nomogram was produced.

Results

Of the 535 patients in the two cohorts, (122 [22.8%]) demonstrated radiographic evidence of BOO. Cluster analysis identified the axis that best separates the radiographically obstructed and unobstructed as P_det.Qmax = 2*Q_max. Using the data from the validation cohort, the sensitivity and specificity for this was calculated as 0.94 and 0.93, respectively. A nomogram, representing the probability of BOO for concurrent P_det.Qmax and Q_max measurements was derived by pooling data from both cohorts. Alternatively, a female BOO index (BOOIf) may be calculated mathematically using the formula BOOIf = P_det.Qmax ? 2.2*Q_{max, that is,} BOOIf < 0, <10% probability of obstruction, BOOIf > 5 likely obstructed (50%) and If BOOIf > 18, obstruction almost certain (>90%).

Conclusion

A female BOO nomogram (the SG nomogram) with high sensitivity and specificity is proposed. The nomogram can be used to stratify the degree of BOO or assess response to treatment.     

Distribution of exogenous [125I]-3-iodothyronamine in mouse in vivo: relationship with trace amine-associated receptors

3-Iodothyronamine (T1AM) is a novel chemical messenger, structurally related to thyroid hormone, able to interact with G protein-coupled receptors known as trace amine-associated receptors (TAARs). Little is known about the physiological role of T1AM. In this prospective, we synthesized [125I]-T1AM and explored its distribution in mouse after injecting in the tail vein at a physiological concentration (0.3?nM). The expression of the nine TAAR subtypes was evaluated by quantitative real-time PCR. [125I]-T1AM was taken up by each organ. A significant increase in tissue vs blood concentration occurred in gallbladder, stomach, intestine, liver, and kidney. Tissue radioactivity decreased exponentially over time, consistent with biliary and urinary excretion, and after 24?h, 75% of the residual radioactivity was detected in liver, muscle, and adipose tissue. TAARs were expressed only at trace amounts in most of the tissues, the exceptions being TAAR1 in stomach and testis and TAAR8 in intestine, spleen, and testis. Thus, while T1AM has a systemic distribution, TAARs are only expressed in certain tissues suggesting that other high-affinity molecular targets besides TAARs exist.