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Deficiencies in mice and in humans have brought to the fore the importance of the caveolar network in key aspects of adipocyte biology. The conserved N-terminal caveolin-binding motif (CBM) of the ubiquitous Na/K-ATPase (NKA) α1 isoform, which allows NKA/caveolin-1 (Cav1) interaction, influences NKA signaling and caveolar distribution. It has been shown to be critical for animal development and ontogenesis, as well as lineage-specific differentiation of human induced pluripotent stem cells (hiPSCs). However, its role in postnatal adipogenesis has not been fully examined. Using a genetic approach to alter CBM in hiPSC-derived adipocytes (iAdi-mCBM) and in mice (mCBM), we investigated the regulatory function of NKA CBM signaling in adipogenesis. Seahorse XF cell metabolism analyses revealed impaired glycolysis and decreased ATP synthesis-coupled respiration in iAdi-mCBM. These metabolic dysfunctions were accompanied by evidence of extensive remodeling of the extracellular matrix (ECM), including increased collagen staining, overexpression of ECM marker genes, and heightened TGF-β signaling uncovered by RNAseq analysis. Rescue of mCBM by lentiviral delivery of WT NKA α1 or treatment of mCBM hiPSCs with the TGF-β inhibitor SB431542 normalized ECM, suggesting that NKA CBM signaling integrity is required for adequate control of TGF-β signaling and ECM stiffness during adipogenesis. The physiological impact was revealed in mCBM male mice with reduced fat mass accompanied by histological and transcriptional evidence of elevated adipose fibrosis and decreased adipocyte size. Based on these findings, we propose that the genetic alteration of the NKA/Cav1 regulatory path uncovered in human iAdi leads to lipodystrophy in mice. NEW & NOTEWORTHY A Na/K-ATPase α1 caveolin-binding motif regulates adipogenesis. Mutation of this binding motif in the mouse leads to reduced fat with increased extracellular matrix production and inflammation. RNA-seq analysis and pharmacological interventions in human iPSC-derived adipocytes revealed that TGF-β signal, rather than Na/K-ATPase-mediated ion transport, is a key mediator of NKA regulation of adipogenesis.

Na/K-ATPase (NKA)-mediated regulation of Src kinase, which involves defined amino acid sequences of the NKA α1 polypeptide, has emerged as a novel regulatory mechanism of mitochondrial function in metazoans. Mitochondrial metabolism ensures adequate myocardial performance and adaptation to physiological demand. It is also a critical cellular determinant of cardiac repair and remodeling. To assess the impact of the proposed NKA/Src regulatory axis on cardiac mitochondrial metabolic function, we used a gene targeting approach in human cardiac myocytes. Human induced pluripotent stem cells (hiPSC) expressing an Src-signaling null mutant (A420P) form of the NKA α1 polypeptide were generated using CRISPR/Cas9-mediated genome editing. Total cellular Na/K-ATPase activity remained unchanged in A420P compared to the wild type (WT) hiPSC, but baseline phosphorylation levels of Src and ERK1/2 were drastically reduced. Both WT and A420P mutant hiPSC readily differentiated into cardiac myocytes (iCM), as evidenced by marker gene expression, spontaneous cell contraction, and subcellular striations. Total NKA α1-3 protein expression was comparable in WT and A420P iCM. However, live cell metabolism assessed functionally by Seahorse extracellular flux analysis revealed significant reductions in both basal and maximal rates of mitochondrial respiration, spare respiratory capacity, ATP production, and coupling efficiency. A significant reduction in ROS production was detected by fluorescence imaging in live cells, and confirmed by decreased cellular protein carbonylation levels in A420P iCM. Taken together, these data provide genetic evidence for a role of NKA α1/Src in the tonic stimulation of basal mitochondrial metabolism and ROS production in human cardiac myocytes. This signaling axis in cardiac myocytes may provide a new approach to counteract mitochondrial dysfunction in cardiometabolic diseases.

Aim: Highly prevalent diseases such as insulin resistance and heart failure are characterized by reduced metabolic flexibility and reserve. We tested whether Na/K-ATPase (NKA)-mediated regulation of Src kinase, which requires two NKA sequences specific to the α1 isoform, is a regulator of metabolic capacity that can be targeted pharmacologically., Methods: Metabolic capacity was challenged functionally by Seahorse metabolic flux analyses and glucose deprivation in LLC-PK1-derived cells expressing Src binding rat NKA α1, non-Src-binding rat NKA α2 (the most abundant NKA isoform in the skeletal muscle), and Src binding gain-of-function mutant rat NKA α2. Mice with skeletal muscle-specific ablation of NKA α1 (skα1-/-) were generated using a MyoD:Cre-Lox approach and were subjected to treadmill testing and Western diet. C57/Bl6 mice were subjected to Western diet with or without pharmacological inhibition of NKA α1/Src modulation by treatment with pNaKtide, a cell-permeable peptide designed by mapping one of the sites of NKA α1/Src interaction., Results: Metabolic studies in mutant cell lines revealed that the Src binding regions of NKA α1 are required to maintain metabolic reserve and flexibility. Skα1-/- mice had decreased exercise endurance and mitochondrial Complex I dysfunction. However, skα1-/- mice were resistant to Western diet-induced insulin resistance and glucose intolerance, a protection phenocopied by pharmacological inhibition of NKA α1-mediated Src regulation with pNaKtide., Conclusions: These results suggest that NKA α1/Src regulatory function may be targeted in metabolic diseases. Because Src regulatory capability by NKA α1 is exclusive to endotherms, it may link the aerobic scope hypothesis of endothermy evolution to metabolic dysfunction., (© 2021 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

The Na/K-ATPase is the specific receptor for cardiotonic steroids (CTS) such as ouabain and digoxin. At pharmacological concentrations used in the treatment of cardiac conditions, CTS inhibit the ion-pumping function of Na/K-ATPase. At much lower concentrations, in the range of those reported for endogenous CTS in the blood, they stimulate hypertrophic growth of cultured cardiac myocytes through initiation of a Na/K-ATPase-mediated and reactive oxygen species (ROS)-dependent signaling. To examine a possible effect of endogenous concentrations of CTS on cardiac structure and function in vivo, we compared mice expressing the naturally resistant Na/K-ATPase α1 and age-matched mice genetically engineered to express a mutated Na/K-ATPase α1 with high affinity for CTS. In this model, total cardiac Na/K-ATPase activity, α1, α2, and β1 protein content remained unchanged, and the cardiac Na/K-ATPase dose-response curve to ouabain shifted to the left as expected. In males aged 3-6 months, increased α1 sensitivity to CTS resulted in a significant increase in cardiac carbonylated protein content, suggesting that ROS production was elevated. A moderate but significant increase of about 15% of the heart-weight-to-tibia-length ratio accompanied by an increase in the myocyte cross-sectional area was detected. Echocardiographic analyses did not reveal any change in cardiac function, and there was no fibrosis or re-expression of the fetal gene program. RNA sequencing analysis indicated that pathways related to energy metabolism were upregulated, while those related to extracellular matrix organization were downregulated. Consistent with a functional role of the latter, an angiotensin-II challenge that triggered fibrosis in the α1 r/r α2 s/s mouse failed to do so in the α1 s/s α2 s/s . Taken together, these results are indicative of a link between circulating CTS, Na/K-ATPase α1, ROS, and physiological cardiac hypertrophy in mice under baseline laboratory conditions.

Background: Major thoracic surgery is characterized by release of inflammatory markers.The objective of this study was to assess the preoperative and postoperative systemic inflammatory markers of patients undergoing lung cancer resection., Methods: This is a prospective follow up study conducted with 48 patients submitted to lung cancer resection.All patients were assessed before and 1 month after surgery through measurement of fibrinogen and C-reative protein(CRP), pulmonary function tests, 6- minute Walk Test (6 MWT), maximal inspiratory pressure (PImax) and maximal expiratory pressure (PEmax), anxiety and depression scale and karnofsky performance status scale., Results: Both fibrinogen and CRP were higher 1 month after surgery, although only the change in CRP was statistically significant (p= 0.03). The following functional parameters: 6 MWT, PImax, PEmax, FEV1(%) and FVC(%) decreased after surgery with p ≤ 0.001 for all the parameters. Anxiety and depression improved and Karnofsky decrease after surgery (p= 0.03, p= 0.01 and p= 0.02; respectively). Change in CRP score following lung resection correlated significantly with changes in fibrinogen (r= 0.40; p= 0.003), change in Karnofsky scale (r= -0.50; p< 0.001) and a borderline significant trend with the 6 MWT (r= -0.28; p= 0.05). With the exception of video-assisted thoracoscopic surgery (VATS), who had a significantly lower fibrinogen level 1 month after surgery compared with thoracotomy (p= 0.01), no significant differences in fibrinogen or CRP were noted in other subgroups of patients considered at increased risk for higher levels of inflammation compared with lower risk counterparts., Conclusion: Lung cancer resection surgery was associated with increased level of CRP, 1 month after surgery, and correlated directly with change in fibrinogen and inversely with measurement of performance status. VATS provided lower level of fibrinogen after surgery.

Background: Comorbidities are common in COPD and have been associated with reduced health status, increased health care utilization, all-cause hospitalization, and mortality. There is a scarcity of data on the relationship between comorbidities and functional capacity., Objective: to evaluate the impact of comorbidities on functional capacity of COPD patients., Methods: a cross-sectional study was conducted at two teaching hospitals in Fortaleza, Brazil. The functional capacity was assessed by spirometry and the 6-min walking test (6MWT). The health status was assessed by the St. George's respiratory questionnaire (SGRQ) and the COPD assessment test (CAT). The sample was stratified as having "none", "one" and "two or three" comorbidities groups. One-way ANOVA was used to compare means of the three groups and a multiple linear regression was run to predict the impact of comorbidities on 6MWT., Results: Comorbidities (hypertension, coronary disease and diabetes) were found in 54% of the studied patients. The mean age of the 79 patients was 67±8 years and 55% were male. CAT scores increased from "no comorbidity" (17.9±7.7) to "one comorbidity" (22.8±6.8) and "two or three comorbidities" groups (24.2±10.2). A post hoc test showed a significant difference in the "no comorbidity" compared to the "two or three comorbidities" groups (p=0.01). The distance walked by the patients decreased from "no comorbidity" (386.1±83.2m) to "one comorbidity" (350±98m) and "two or three comorbidities" groups (312.6±91m). A post hoc test showed significant difference in the "no comorbidity" compared to "two or three comorbidities" groups (p=0.007). Numbers of comorbidities were independently associated with the 6MWT adjusting for age, severity of COPD and CAT scores., Conclusion: in the studied sample, the presence of comorbidities contributed to impair exercise capacity in patients with COPD., (Copyright © 2014 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. All rights reserved.)

Cardiotonic steroids are used to treat heart failure and arrhythmia and have promising anticancer effects. The prototypic cardiotonic steroid ouabain may also be a hormone that modulates epithelial cell adhesion. Cardiotonic steroids consist of a steroid nucleus and a lactone ring, and their biological effects depend on the binding to their receptor, Na,K-ATPase, through which, they inhibit Na+ and K+ ion transport and activate of several intracellular signaling pathways. In this study, we added a styrene group to the lactone ring of the cardiotonic steroid digoxin, to obtain 21-benzylidene digoxin (21-BD), and investigated the effects of this synthetic cardiotonic steroid in different cell models. Molecular modeling indicates that 21-BD binds to its target Na,K-ATPase with low affinity, adopting a different pharmacophoric conformation when bound to its receptor than digoxin. Accordingly, 21-DB, at relatively high µM amounts inhibits the activity of Na,K-ATPase α1, but not α2 and α3 isoforms. In addition, 21-BD targets other proteins outside the Na,K-ATPase, inhibiting the multidrug exporter Pdr5p. When used on whole cells at low µM concentrations, 21-BD produces several effects, including: 1) up-regulation of Na,K-ATPase expression and activity in HeLa and RKO cancer cells, which is not found for digoxin, 2) cell specific changes in cell viability, reducing it in HeLa and RKO cancer cells, but increasing it in normal epithelial MDCK cells, which is different from the response to digoxin, and 3) changes in cell-cell interaction, altering the molecular composition of tight junctions and elevating transepithelial electrical resistance of MDCK monolayers, an effect previously found for ouabain. These results indicate that modification of the lactone ring of digoxin provides new properties to the compound, and shows that the structural change introduced could be used for the design of cardiotonic steroid with novel functions.

Background: Systemic inflammation plays an important role in the initiation, promotion, and progression of lung carcinogenesis. In patients with non-small cell lung cancer (NSCLC), fibrinogen levels correlate with neoplasia. Here we compared the effects of pulmonary rehabilitation (PR) with chest physical therapy (CPT) on fibrinogen and albumin levels in patients with LC and previous inflammatory lung disease awaiting lung resection., Methods: We conducted a randomized clinical trial with 24 patients who were randomly assigned to Pulmonary Rehabilitation (PR) and Chest Physical Therapy (CPT) groups. Each group underwent training 5 days weekly for 4 weeks. All patients were assessed before and after four weeks of training through clinical assessment, measurement of fibrinogen and albumin levels, spirometry, 6-minute Walk Test (6MWT), quality of life survey, and anxiety and depression scale. PR involved strength and endurance training, and CPT involved lung expansion techniques. Both groups attended educational classes., Results: A mixed between-within subjects analysis of variance (ANOVA) revealed a significant interaction between time (before and after intervention) and group (PR vs. CPT) on fibrinogen levels (F(1, 22)=0.57, p<0.0001) and a significant main effect of time (F(1, 22)=0.68, p=0.004). Changes in albumin levels were not statistically significant relative to the interaction effect between time and group (F(1, 22)=0.96, p=0.37) nor the main effects of time (F(1, 22)=1.00, p=1.00) and group (F(1, 22 )=0.59, p=0.45). A mixed between-within subjects ANOVA revealed significant interaction effects between time and group for the peak work rate of the unsupported upper limb exercise (F(1, 22)=0.77, p=0.02), endurance time (F(1, 22)=0.60, p=0.001), levels of anxiety (F(1, 22)=0.60, p=0.002) and depression (F(1, 22)=0.74, p=0.02), and the SF-36 physical component summary (F(1, 22)=0.83, p=0.07)., Conclusion: PR reduced serum fibrinogen levels, improved functional parameters, and quality of life of patients with LC and inflammatory lung disease awaiting lung resection., Trial Registration: Current Controlled Trials RBR-3nm5bv.

The first International Classification of Diseases (ICD) was approved in 1893 and since then it has been periodically reviewed. The last, 10th revision (ICD-10), was approved in 1989. Since 1989, it was possible to update from ICD revisions, which did not happen before. The next revision (ICD-11) would probably be published in 2015. In 1989, mechanisms were established to update ICD-10, through the creation of the Morbidity Reference Group (MbRG) in 1997 and the Update and Revision Committee (URC) in 2000. The Morbidity Reference Group (MbRG) was created in 2007 to discuss in more detail the issues to update morbidity. A specific code in ICD was not included in the revision of ICD-10 in 1989 for the post-polio syndrome (PPS). However, the ICD new code G14 for PPS was included in ICD-10 since 2010.

The aim of this study was to give an in-depth consideration of the chronic obstructive pulmonary disease (COPD) patients' subjective view of the impact of pulmonary rehabilitation (PR) on their lives. A systematic review in PubMed, Embase, CINAHL and PsychInfo databases yielded 3306 articles, of which 387 were duplicates, 263 remained after screening abstract and title; of them, 4 were excluded (editorial or due to lacking of full text) remaining a total of 259 for full text reading. Among these, eight studies met the inclusion criteria and were finally included. The meta-ethnography approach synthesized an understanding of the studies, which focused on constructing interpretations and developed a 'line-of-argument' synthesis. The psychosocial support of PR contributes to the patients' strength and desire for participation and the health education leads to illness-perception learning. Both psychosocial support and health education develop patients' empowerment, while PR promotes opportunities to health transitions. The empowerment experienced by the patients in taking advantage of these opportunities leads to positive impacts over time. If they do not exploit these occasions, negative impacts arise in their life, which make the treatment assistance or follow-up more difficult. The COPD patients' feedback revealed that PR promotes a better 'way of life', well-being and important behavioural changes towards health promotion.

Objective: To validate a Portuguese-language version of the COPD assessment test (CAT) for use in Brazil and to assess the reproducibility of this version., Methods: This was multicenter study involving patients with stable COPD at two teaching hospitals in the city of Fortaleza, Brazil. Two independent observers (twice in one day) administered the Portuguese-language version of the CAT to 50 patients with COPD. One of those observers again administered the scale to the same patients one week later. At baseline, the patients were submitted to pulmonary function testing and the six-minute walk test (6MWT), as well as completing the previously validated Portuguese-language versions of the Saint George's Respiratory Questionnaire (SGRQ), modified Medical Research Council (MMRC) dyspnea scale, and hospital anxiety and depression scale (HADS)., Results: Inter-rater and intra-rater reliability was excellent (intraclass correlation coefficient [ICC] = 0.96; 95% CI: 0.93-0.97; p < 0.001; and ICC = 0.98; 95% CI: 0.96-0.98; p < 0.001, respectively). Bland Altman plots showed good test-retest reliability. The CAT total score correlated significantly with spirometry results, 6MWT distance, SGRQ scores, MMRC dyspnea scale scores, and HADS-depression scores., Conclusions: The Portuguese-language version of the CAT is a valid, reproducible, and reliable instrument for evaluating patients with COPD in Brazil.

Objective: To determine the frequency and clinical manifestations of patients with post-poliomyelitis syndrome (PPS) in a Brazilian division of neuromuscular disorders., Methods: A total of 167 patients with prior history of paralytic poliomyelitis was investigated for PPS, based on international diagnostic criteria. Other variables analyzed were: gender, race, age at poliomyelitis infection, age at PPS onset, and PPS symptoms., Results: One hundred and twenty-nine patients presented PPS, corresponding to 77.2% of the studied population. 62.8% were women and 37.2% were men. Mean age of patients with PPS at onset of PPS symptoms was 39.9±9.69 years. Their main clinical manifestations were: new weakness in the previously affected limbs (69%) and in the apparently not affected limbs (31%); joint pain (79.8%); fatigue (77.5%); muscle pain (76%); and cold intolerance (69.8%)., Conclusions: Most patients of our sample presented PPS. In Brazil, PPS frequency and clinical features are quite similar to those of other countries.

This study sought to analyze characteristics of the social support network of the elderly with chronic pneumopathies, establishing links with health maintenance/rehabilitation. The assumptions of Social Network Analysis (SNA) methodology were used, addressing the social support concept. A questionnaire and semi-structured interviews, both applied to 16 elderly people attended by a public hospital in Fortaleza-CE, were used for data collection. Quantitative data were processed using the UCINET 6.123, NetDraw 2.38 and Microsoft Excel software programs. In the qualitative analysis, the body of material was subjected to interpretations based on relevant and current theoretical references. Each informant brought an average of 10.37 individuals into the network. Among the 3 types of social support, there was a predominance of informational support given by health professionals. The importance of reciprocity in providing/receiving social support was also noted, as well as the participation of health professionals and the family functioning as social support. The conclusion reached was that the network of the elderly with pneumopathies is not cohesive, being restricted to the personal network of each individual, and that even so, the informants recognize and are satisfied with the social support it provides.

Peroxidases can be used in the decolorization process. There is a growing interest for new sources of this enzyme and for obtaining economically viable processes. In this work, a low-cost vegetable peroxidase extraction process is proposed; the resulting enzyme is characterized to determine its optimum pH, temperature, and stability conditions, and it is then applied in the decolorization of reactive dye Remazol Turquoise G 133%. The turnip peroxidase (TP) was utilized as an enzymatic source. This enzyme exhibited maximum activity at pH 7.0, and it was active in the temperature range of 30 to 50 °C, which favors its use in industrial processes. Acetone was the most efficient solvent to induce precipitation. The removal of Remazol Turquoise G 133% was 56.0% complete after 50 min, while 41.0% of the same dye was removed with the commercial horseradish peroxidase enzyme in 50 min. TP presents potential as a viable alternative in the decolorization of textile wastewaters.

Objective: To describe the mortality rates of amyotrophic lateral sclerosis (ALS) in the city of São Paulo as a function of demographics, year, and region., Method: This was a retrospective descriptive study. Information was obtained from death certificates registered at the Program for the Improvement of Mortality Information, Municipal Health Department (PRO-AIM/SMS), coded as G12.2 according to International Classification of Diseases (ICD-10), from 2002 to 2006., Results: Over the studied time, were found 326 deaths (51.6% women, overall mean age of 64.1 years). Highest deaths percentages happened in those from 60 to 69 and 70 to 79 years and in white individuals. ALS mortality rates ranged 0.44/100,000 in 2002 and 0.76/100,000 in 2006. No significant changes overtime in administrative districts were found., Conclusion: ALS mortality rates in São Paulo were lower in comparison to other countries, however any risk factor in our environment, lifestyle or genetic characteristics were found.

Ethanol/water organosolv pulping was used to obtain sugarcane bagasse pulp that was bleached with sodium chlorite. This bleached pulp was used to obtain cellulosic films that were further evaluated by Fourier transform infrared (FTIR) spectroscopy, thermogravimetric analysis (TGA), and scanning electron microscopy (SEM). A good film formation was observed when temperature of 74 degrees C and baths of distilled water were used, which after FTIR, TGA, and SEM analysis indicated no significant difference between the reaction times. The results showed this to be an interesting and promising process, combining the prerequisites for a more efficient utilization of agro-industrial residues.

Sugar cane bagasse pulps were obtained by ethanol/water organosolv process under acid and alkaline conditions. The best condition of acid pulping for the sugarcane bagasse was 0.02 mol/L sulfuric acid at 160 degrees C, for 1 h, whereas the best condition for alkaline pulping was 5% sodium hydroxide (base pulp) at 160 degrees C, for 3 h. For the residual lignin removal, the acid and alkaline pulps were submitted to a chemical bleaching using sodium chlorite. Pulps under acid and alkaline conditions bleached with sodium chlorite presented viscosities of 3.6 and 7.8 mPa x s, respectively, and mu-kappa numbers of 1.1 and 2.4, respectively. The pulp under acid condition, bleached with sodium chlorite was used to obtain carboxymethylcellulose (CMC). CMC yield was 35% (pulp based), showing mass gain after the carboxymethylation reaction corresponding to 23.6% of substitution or 0.70 groups -CH(2) COONa per unit of glucose residue. The infrared spectra showed the CMC characteristic bands and by the infrared technique it was possible to obtain a substitution degree (0.63), similar to the substitution degree calculated by mass gain (0.70).