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Background/objectives: Although melasma is highly prevalent, its pathogenesis is not yet fully understood. In the skin, endothelin-1 (ET-1) is primarily produced by keratinocytes in response to UVB exposure, which is mediated by an increase in IL-1α or reactive oxygen species. ET-1 plays a role in melanogenesis by binding to specific receptor B (ERB) or receptor A (ERA). However, the expression of ET-1, ERA, and ERB in melasma has not been systematically investigated. The objective of this study was to evaluate the expression of ET-1, ERA, and ERB in facial melasma compared to the adjacent unaffected skin., Methods: Cross-sectional study, with 40 skin samples (20: facial melasma; 20: adjacent unaffected skin) from women with facial melasma without treatment for 30 days except for sunscreen. A triple staining immunofluorescence technique was performed for anti-vimentin, DAPI, plus one of the following antibodies: (a) anti-ET1, (b) anti-ERA; (c) anti-ERB. Interfollicular areas on the slides of each topography (melasma; unaffected skin) were photographed in triplicate under confocal laser microscopy. The mean staining intensities of the image histograms (0-255 pixels intensity) were estimated for different types of cells (suprabasal keratinocytes, basal layer, and upper dermis) and were blindly compared between topographies., Results: The mean (SD) age of the participants was 44.9 (9.2). The expression of ET-1 was increased in the whole epidermis with melasma when compared to the adjacent skin, being 32.8% (CI95% 14.7%-52.6%) higher in the spinous layer (p=0.013), 30.4% (CI95% 13.7%-47.9%) higher in the basal layer (p=0.014), and 29.7% (CI95% 11.4%-49.7%) higher in the melanocytes (p=0.006). There was no noticeable expression of ET-1 within the cells on the upper dermis. Neither ERA nor ERB resulted in differential epidermal expression between melasma and unaffected skin (p≥0.1)., Conclusion: ET-1 is expressed more intensely on the epidermis from the skin with facial melasma compared to the unaffected adjacent skin., Competing Interests: The authors report no conflicts of interest in this work., (© 2023 da Silva et al.)

Resistance training has been proposed as a valid practice to counteract the aging effect on body mass and its components, which can be easily evaluated though the bioelectrical impedance analysis. This study aimed to achieve a systematic review with meta-analysis on the impact of resistance training on bioelectrical proprieties in older adults.A literature review was done in four electronic databases up to 1 January 2022. The inclusion criteria were: (i) participants aged ≥ 60 years; (ii) resistance training lasted ≥ 8 weeks; (iii) measurement of raw bioelectrical parameters in randomized controlled study designs.The outcomes of the trial had to be bioelectrical phase angle (PhA), resistance (R), and reactance (Xc). The methodological quality was assessed using the Rosendal scale.Overall, seven studies with a total of 344 participants were eligible for the analysis. The quality assessment yielded a score of 71.3%. Bioelectrical PhA (0.52 degree [95%CI 0.32, 0.71], p < 0.001) and Xc (3.58 ohms [95%CI 1.97, 5.19], p < 0.001) increased, whereas R decreased (-28.50 ohms [95%CI -41.39, -15.60], p < 0.001) after the resistance training programs.In this meta-analysis, resistance training promoted increases of PhA, which result from an increase in Xc concomitant with a reduction in R. According to the bioimpedance vector analysis, resistance-trained people experienced a beneficial leftward vector displacement, whilst inactivity induced a rightward vector displacement within the R-Xc graph. In future, more sophisticated and rigorous studies that address specific criteria, methods and targeted designs are required to identify which equipment and protocols allow for an optimization of the resistance training effects.Registration code in PROSPERO: CRD42020168057., (© 2022. The Author(s).)

Regulation of proteolytic activity in the skin plays a pivotal role in epidermal homeostasis. This is best exemplified in Netherton syndrome, a severe genetic skin condition caused by loss-of-function mutations in the gene serine protease inhibitor Kazal-type 5 encoding lympho-epithelial Kazal-type-related inhibitor, a serine protease inhibitor that regulates kallikrein (KLK)-related peptidase 5, 7, and 14 activities. KLK5 plays a central role in stratum corneum shedding and inflammatory cell signaling, activates KLK7 and KLK14, and is therefore an optimal therapeutic target. We aimed to identify a potent and selective small-molecule inhibitor of KLK5 amenable to epidermal delivery. GSK951 was identified using a structure-based design strategy and showed a half maximal inhibitory concentration of 250 pM for KLK5 and greater than 100-fold selectivity over KLK7 and KLK14. Cocrystal structure analysis identified the critical catalytic site interactions to a surrogate for KLK5. Topical application of GSK951-containing cream inhibited KLK5 activity in TgKLK5 mouse skin, reduced transepidermal water loss, and decreased proinflammatory cytokine expression. GSK951 achieved high concentrations in healthy human epidermis following topical application in a cream formulation. Finally, KLK5 protease activity was increased in stratum corneum of patients with Netherton syndrome and significantly inhibited by GSK951. These findings unveil a KLK5-specific small-molecule inhibitor with a high therapeutic potential for patients with Netherton syndrome., (Copyright © 2021 GlaxoSmithKline. Published by Elsevier Inc. All rights reserved.)

Muscular strength and hypertrophy following resistance training may be obtained in different degrees depending on the approach performed. This study was designed to compare the responses of the biceps brachii to two preacher curl exercises, one performed on a cable-pulley system (CAB; in which a greater torque was applied during the exercise when elbows were flexed and biceps shortened) and one performed with a barbell (BAR; in which greater torque was applied when the elbows were extended and biceps stretched). Thirty-five young adults (CAB: 13 men, 5 women; BAR: 12 men, 5 women; age = 24 ± 5 years) performed a resistance training program three times per week for 10 weeks, with preacher curl exercises performed in three sets of 8-12 repetitions. Outcomes measured included elbow flexion peak isokinetic torque at angles of 20°, 60°, and 100° (considering 0° as elbow extended), and biceps brachii thickness (B-mode ultrasound). Following the training period, there were significant increases for both groups in elbow flexion peak torque at the 20° (CAB: 30%; BAR = 39%; p = 0.046), 60° (CAB: 27%; BAR = 32%; p = 0.874), and 100° (CAB: 17%; BAR = 19%; p = 0.728), and biceps brachii thickness (CAB: 7%; BAR = 8%; p = 0.346). In conclusion, gains in muscular strength were greater for BAR only at longer muscle length, whereas hypertrophy was similar regardless of whether torque emphasis was carried out in the final (CAB) or initial (BAR) degrees of the range of motion of the preacher curl in young adults.

Objective: The purpose of the present study was to analyze whether improvements in fast walking speed induced by resistance training (RT) are associated with changes in body composition, muscle quality, and muscular strength in older women., Methods: Twenty-three healthy older women (69.6 ± 6.4 years, 64.95 ± 12.9 kg, 1.55 ± 0.07 m, 27.06 ± 4.6 kg/m²) performed a RT program for 8 weeks consisting of 8 exercises for the whole body, 3 sets of 10-15 repetitions maximum, 3 times a week. Anthropometric, body composition (fat-free mass [FFM], skeletal muscle mass [SMM], legs lean soft tissue [LLST], fat mass), knee extension muscular strength (KE1RM), muscle quality index (MQI [KE1RM/LLST]), and 10-meter walking test (10-MWT) were performed before and after the intervention., Results: Significant (P < .05) changes were observed from pre- to post-training for FFM (+1.6%), MQI (+7.2%), SMM (+2.4%), LLST (+1.8%), KE1RM (+8.6%), fat mass (-1.4%), and time to perform 10-MWT (-3.7%). The percentage change in 10-MWT was significantly associated with percentage change in MQI (r = -0.46, P = .04) and KE1RM (r = -0.45, P = .04), however not associated percentage of changes in SMM (r = 0.01, P = .97), LLST (r = -0.22, P = .33), and body fat (r = 0.10, P = .66)., Conclusion: We conclude that the improvement in the 10-MWT after an 8-week RT program is associated with increases in lower limb muscular strength and muscle quality, but not with muscle mass or body fat changes in older women.

Objective: To evaluate factors associated with poor survival in patients with non-active treatment of hepatocellular carcinoma (HCC)., Material and Methods: Between May 2003 and June 2005, 50 patients with HCC were deemed unsuitable for active treatment, following the Barcelona Clinic Liver Cancer staging system. Symptomatic treatment was provided. Kaplan-Meier curves were constructed and compared by the log-rank test to identify factors associated with poor survival. Independent factors predictive of survival were evaluated by multivariate Cox regression analysis., Results: The mean age was 65.6 +/- 11.9 years and 84% of the patients were men. Forty-eight percent of the patients had hepatitis C infection and 58% were Child-Pugh grade A. HCC was multinodular in 54% and the total tumor size was more than 5 cm in 90% of patients. Thirty-four percent of the patients had malignant portal thrombosis and four patients had metastases. Thirty-eight percent of the patients had received previous treatment. The median follow-up was 9.2 months and 1- and 2-year survival was 46% and 17.5%, respectively. Poor survival was associated with male sex, alpha-fetoprotein values of > 400 ng/ml, albumin levels of < 3 g/dl, and metastases. Independent predictors identified by multivariate Cox regression analysis were male sex, albumin levels of < 3 g/dl, and alpha-fetoprotein values of > 400 ng/ml. The median survival in patients with two or more independent factors was significantly lower than that in patients with none or only one factor (14.2 vs. 4.1 months)., Conclusion: Survival in patients with non-active treatment of hepatocellular carcinoma can be estimated and the factors involved allow separate groups of patients with different short- to medium-term prognoses to be identified.

A series of novel N-1, N-2 and S-5 saccharide substituted tetrazole derivatives linked at anomeric and nonanomeric positions were obtained from commercial tetrazoles under microwave irradiation. Yields are compared with conventional methodologies.

Purpose: The aim was to compare the clinical and hemodynamic outcome between polytetrafluoroethylene (PTFE)-coated stent-grafts and bare stents in patients who required both elective and emergency transjugular intrahepatic portosystemic shunt (TIPS) placement due to portal hypertension related complications., Materials and Methods: Retrospective analysis of all seventy patients with portal hypertension related complications who required TIPS placement in a referral hospital from September 1998 to May 2002 was done. Follow-up was extended until May 2003. PTFE-covered stent-grafts were used in the latter 20. Demographic variables, cirrhosis etiology and Child-Pugh class, indication of TIPS placement and clinical outcome were recorded. The following TIPS-related outcomes were registered: recurrent variceal bleeding and/or ascites, hepatic encephalopathy and mortality., Results: Baseline characteristics, portacaval gradient (PCG) after TIPS placement and at 1 month angiographic revision were similar in both groups. At 6 month follow-up, PCG was significantly lower in patients with stent-grafts (14.2 mmHg (5.6 mmHg) versus 7 mmHg (1 mmHg), p<0.001). Overall, there were no cases of clinically relevant TIPS dysfunction in the coated stent group while 22% of patients in the bare stent group had recurrence of portal hypertension related complications (p=0.085). Actuarial probability of TIPS dysfunction in bare stents was 82% at 12 months compared to no episode in covered stent-grafts (p=0.03). Mean increase in total serum bilirubin was higher in the PTFE-coated stent group (6.7 mg/dl (14.4 mg/dl) versus 0.5 mg/dl (2.4 mg/dl), p=0.01) without differences in encephalopathy nor mortality rate., Conclusion: One year shunt patency rate is improved with placement of ePTFE-covered stent-grafts without a higher rate of encephalopathy. Further prospective trials are required.

A trend toward a higher incidence of hepatocelullar carcinoma (HCC) in patients with cirrhosis treated with bare-stent transjugular intrahepatic portosystemic shunt (TIPS) has been observed in previous studies. To assess the influence of TIPS as a risk factor for developing HCC, we have compared the incidence of HCC in two retrospective cohorts of patients. The TIPS cohort (n = 138) included patients with cirrhosis who underwent TIPS placement for the treatment of portal hypertension-related complications; the non-TIPS cohort was composed of patients admitted at the hospital at the same time of TIPS insertion who were individually matched 1:1 according to age, sex, Child-Turcotte-Pugh class, and cause of cirrhosis. A stratified Cox model was used to assess risk of HCC development. The median time of follow-up was similar in TIPS and non-TIPS cohorts (30.3 [range, 7.8-119.5] and 31.4 [range, 7.8-110.8] months, respectively). The cumulative probability of developing HCC at 1, 3, and 5 years was 3%, 24%, and 34% for the TIPS cohort and 1%, 6%, and 25%, for the non-TIPS cohort, respectively (Breslow test = 5.23, P = .022). The adjusted hazard ratio was 1.52 (95% confidence interval, 1.06-2.19; P = .02). Hepatitis C virus infection and age were independent predictors of HCC development in patients without TIPS. In conclusion, patients with cirrhosis who are treated with TIPS may have a higher incidence of HCC. This observation suggests the need for a strict HCC surveillance program for these patients, especially if they are not expected to undergo a short- or medium-term liver transplantation.