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The article reports on research which was conducted to investigate the effect exercise training had on exercise tolerance and left ventricular systolic function and structure in heart failure patients with preserved, mild and moderate to severe reduction of left ventricular ejection fraction. Researchers evaluated 98 heart failure patients who received usual care or exercise training. They found that exercise training can improve the course of heart failure regardless of baseline ventricular dysfunction in the subjects that they evaluated.

BACKGROUND AND PURPOSE 3,4-Methylenedioxymethamphetamine (MDMA or 'Ecstasy') is a worldwide major drug of abuse known to elicit neurotoxic effects. The mechanisms underlying the neurotoxic effects of MDMA are not clear at present, but the metabolism of dopamine and 5-HT by monoamine oxidase (MAO), as well as the hepatic biotransformation of MDMA into pro-oxidant reactive metabolites is thought to contribute to its adverse effects. EXPERIMENTAL APPROACH Using mouse brain synaptosomes, we evaluated the pro-oxidant effects of MDMA and its metabolites, α-methyldopamine (α-MeDA), N-methyl-α-methyldopamine (N-Me-α-MeDA) and 5-(glutathion- S-yl)-α-methyldopamine [5-(GSH)-α-MeDA], as well as those of 5-HT, dopamine, l-DOPA and 3,4-dihydroxyphenylacetic acid (DOPAC). KEY RESULTS 5-HT, dopamine, l-DOPA, DOPAC and MDMA metabolites α-MeDA, N-Me-α-MeDA and 5-(GSH)-α-MeDA, concentration- and time-dependently increased H2O2 production, which was significantly reduced by the antioxidants N-acetyl- l-cysteine (NAC), ascorbic acid and melatonin. From experiments with MAO inhibitors, it was observed that H2O2 generation induced by 5-HT was totally dependent on MAO-related metabolism, while for dopamine, it was a minor pathway. The MDMA metabolites, dopamine, l-DOPA and DOPAC concentration-dependently increased quinoproteins formation and, like 5-HT, altered the synaptosomal glutathione status. Finally, none of the compounds modified the number of polarized mitochondria in the synaptosomal preparations, and the compounds' pro-oxidant effects were unaffected by prior mitochondrial depolarization, excluding a significant role for mitochondrial-dependent mechanisms of toxicity in this experimental model. CONCLUSIONS AND IMPLICATIONS MDMA metabolites along with high levels of monoamine neurotransmitters can be major effectors of neurotoxicity induced by Ecstasy. [ABSTRACT FROM AUTHOR]

The article presents new methodological approaches in the field of sports genetics research, which can be applied in the near future to make an analysis of the genotype profile linked with elite athletic status as of 2011. It talks about studies on genotype-phenotype association making use of gene expression analysis. It is cited that recruitment of large enough samples of elite athletes of various ethnic backgrounds is the main limiting factor for future studies in this field. Also provided are recommendations aimed at reducing research limitations.

The aim of this study was to investigate the influence of lifestyle on the aging alterations in skeletal muscle mitochondrial proteins. Thirty C57BL/6 strain mice (2 months) were randomly divided into three groups (young, Y; old sedentary, S; and old active, A). The S and A mice were individually placed into standard cages and in cages with running wheels for 25 months. Upon killing, mitochondria from the hind limb skeletal muscles were isolated for the evaluation of general proteome alterations, carbonylation, and electron transport chain (ETC) activity. We identified 77 different proteins mostly from the oxidative phosphorylation and mitochondrial metabolism. Sedentary mice presented a significant loss of ETC functionality in opposition to active mice. Although some proteins were found damaged in both A and S mice, damage to ETC proteins was more evident in S. Moreover, it is also possible to conclude that lifestyle is a key modulator for preventing the aging-induced protein expression and functionality in mitochondria. [ABSTRACT FROM PUBLISHER]

A functional C825T polymorphism in the human guanine nucleotide binding protein β polypeptide 3 ( GNB3) gene has been associated with enhanced G protein activation. Since reports regarding the interaction between physical activity and the GNB3 C825T polymorphism are limited and inconsistent, the aim of this study was to determine the frequency of C825T alleles among 155 elite Israeli athletes (endurance athletes and sprinters) and 234 healthy control subjects. Genotyping for GNB3 C825T was performed using polymerase chain reaction on DNA from leucocytes. Results showed that there was a significant difference in GNB3 C825T polymorphism genotype frequencies between endurance athletes and sprinters ( P= 0.045) as well as between endurance athletes and control subjects ( P= 0.046). We also observed a significantly higher proportion of the GNB3 TT genotype in the group of endurance athletes (19%) compared with the sprinters (5%, P= 0.014) and the control subjects (8.5%, P= 0.026). In the group of athletes, the odds ratio of GNB3 TT genotype being an endurance athlete was 4.49 (95% confidence interval 1.4–14.3) and of GNB3 CC genotype was 0.91 (95% confidence interval 0.47–1.77). These results were even more pronounced when we compared between the subgroups of 20 top-level endurance athletes and 24 top-level sprinters. We conclude that in Israeli athletes the GNB3 TT genotype is higher in elite endurance athletes than it is in sprinters, and within the endurance group it is higher in top-level athletes, suggesting a positive association between the TT genotype and the likelihood of being an elite endurance athlete. [ABSTRACT FROM AUTHOR]

Abstract: 3,4-Methylenedioxymethamphetamine (MDMA) is frequently consumed at “rave” parties by polydrug users that usually take this drug in association with ethanol. In addition, many young people are repeatedly exposed to ethanol, which likely leads to tolerance phenomena. Both compounds are metabolized in the liver, with formation of hepatotoxic metabolites, which gives high relevance to the evaluation of their putative toxicological interaction. Therefore, the aim of this study was to evaluate the toxicity induced by 0.8 and 1.6mM MDMA to freshly isolated hepatocytes obtained from ethanol-treated mice whose tap drinking water was replaced by a 5% ethanol solution for 1week and, afterwards, by a 12% ethanol solution for 8weeks (ethanol group) comparatively to non-treated animals (non-ethanol group). The hepatocytes were incubated under normothermic and hyperthermic conditions in order to simulate in vitro the hyperthermic response induced in vivo by MDMA, a condition that has been recognized as a life-threatening effect associated with MDMA exposure and implicated in its hepatotoxicity. Six mice treated under the same protocol as the ethanol group were used for histological analysis, and compared to non-ethanol-treated animals. The pre-treatment of mice with ethanol caused a significant decrease in the hepatocytes yield in the isolation procedure comparatively to the non-ethanol group, which can be explained by an increase in collagen deposition along the hepatic parenchyma as observed in the histological analysis. The initial cell viability of hepatocytes suspensions was similar between ethanol and non-ethanol groups. However, the ethanol group showed a higher GSH oxidation rate, which was enhanced under hyperthermia. Additionally, a concentration-dependent MDMA-induced loss of cell viability and ATP depletion was observed for both groups, at 41°C. In conclusion, the repeated treatment with ethanol seems to increase the vulnerability of freshly isolated mice hepatocytes towards pro-oxidant conditions, as ascertained by the increase in collagen deposition, lower hepatocyte yield and decreased glutathione levels. However, MDMA toxicity to the isolated hepatocytes was independent of ethanol pre-treatment, while significantly dependent on incubation temperature. [Copyright &y& Elsevier]

• MTX and DOX in clinically relevant doses cause heart mitochondrial injury. • MTX causes more pronounced mitochondrial cardiac proteomic changes than DOX. • Neither MTX- nor DOX-induced proteomic changes resemble cardiac aging. Current cancer therapies are successfully increasing the lifespan of cancer patients. Nevertheless, cardiotoxicity is a serious chemotherapy-induced adverse side effect. Doxorubicin (DOX) and mitoxantrone (MTX) are cardiotoxic anticancer agents, whose toxicological mechanisms are still to be identified. This study focused on DOX and MTX's cardiac mitochondrial damage and their molecular mechanisms. As a hypothesis, we also sought to compare the cardiac modulation caused by 9 mg/kg of DOX or 6 mg/kg of MTX in young adult mice (3 months old) with old control mice (aged control, 18–20 months old) to determine if DOX- and MTX-induced damage had common links with the aging process. Cardiac homogenates and enriched mitochondrial fractions were prepared from treated and control animals and analyzed by immunoblotting and enzymatic assays. Enriched mitochondrial fractions were also characterized by mass spectrometry-based proteomics. Data obtained showed a decrease in mitochondrial density in young adults treated with DOX or MTX and aged control, as assessed by citrate synthase (CS) activity. Furthermore, aged control had increased expression of the peroxisome proliferator-activated receptor γ coactivator 1 α (PGC1α) and manganese superoxide dismutase (MnSOD). Regarding the enriched mitochondrial fractions, DOX and MTX led to downregulation of proteins related to oxidative phosphorylation, fatty acid oxidation, amino acid metabolic process, and tricarboxylic acid cycle. MTX had a greater impact on malate dehydrogenase (MDH2) and pyruvate dehydrogenase E1 component subunit α (PDHA1). No significant proteomic changes were observed in the enriched mitochondrial fractions of aged control when compared to young control. To conclude, DOX and MTX promoted changes in several mitochondrial-related proteins in young adult mice, but none resembling the aged phenotype. [ABSTRACT FROM AUTHOR]

Background: Obesity is considered protective for bone mass, but this view has been progressively challenged. Menopause is characterized by low bone mass and increased adiposity. Our aim was to determine how visceral and bone marrow adiposity change following ovariectomy (OVX), how they correlate with bone quality and if they are influenced by physical activity. Methods: Five-month-old Wistar rats were OVX or sham-operated and maintained in sedentary or physically active conditions for 9 months. Visceral and bone marrow adiposity as well as bone turnover, femur bone quality and biomechanical properties were assessed. Results: OVX resulted in higher weight, visceral and bone marrow adiposity. Visceral adiposity correlated inversely with femur Ct.Th (r = −0.63, p < 0.001), BV/TV (r = −0.67, p < 0.001), Tb.N (r = −0.69, p < 0.001) and positively with Tb.Sp (r = 0.58, p < 0.001). Bone marrow adiposity also correlated with bone resorption (r = 0.47, p < 0.01), bone formation rate (r = −0.63, p < 0.01), BV/TV (r = −0.85, p < 0.001), Ct.Th (r = −0.51, p < 0.0.01), and with higher empty osteocyte lacunae (r = 0.39, p < 0.05), higher percentage of osteocytes with oxidative stress (r = 0.64, p < 0.0.01) and lower femur maximal stress (r = −0.58, p < 0.001). Physical activity correlated inversely with both visceral (r = −0.74, p < 0.01) and bone marrow adiposity (r = −0.92, p < 0.001). Conclusions: OVX increases visceral and bone marrow adiposity which are associated with inferior bone quality and biomechanical properties. Physical activity could contribute to reduce adipose tissue and thereby improve bone quality. [ABSTRACT FROM AUTHOR]

Mitoxantrone (MTX) is a pharmaceutical drug used in the treatment of several cancers and refractory multiple sclerosis (MS). Despite its therapeutic value, adverse effects may be severe, namely the frequently reported cardiotoxicity, whose mechanisms need further research. This work aimed to assess if inflammation or oxidative stress-related pathways participate in the cardiotoxicity of MTX, using the mouse as an animal model, at two different age periods (infant or adult mice) using two therapeutic relevant cumulative doses. Histopathology findings showed that MTX caused higher cardiac toxicity in adults. In MTX-treated adults, at the highest dose, noradrenaline cardiac levels decreased, whereas at the lowest cumulative dose, protein carbonylation increased and the expression of nuclear factor kappa B (NF-κB) p65 subunit and of M1 macrophage marker increased. Moreover, MTX-treated adult mice had enhanced expression of NF-κB p52 and tumour necrosis factor (TNF-α), while decreasing interleukin-6 (IL-6). Moreover, while catalase expression significantly increased in both adult and infant mice treated with the lowest MTX cumulative dose, the expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and glutathione peroxidase only significantly increased in infant animals. Nevertheless, the ratio of GAPDH to ATP synthase subunit beta decreased in adult animals. In conclusion, clinically relevant doses of MTX caused dissimilar responses in adult and infant mice, being that inflammation may be an important trigger to MTX-induced cardiotoxicity. [ABSTRACT FROM AUTHOR]

• FD is more determinant than PI in MS and NAFLD development. • PI potentiate the NAFLD clinical parameters induced by fat diet. • FD and PI showed synergistic effect in NAFLD progress. [ABSTRACT FROM AUTHOR]

Background/aim: This study aimed to investigate the influence of Western diet on mammary cancer in Wistar female rats, focusing on systemic responses and tumor development., Materials and Methods: Twenty-eight Wistar female rats were acclimatized and divided into four experimental groups (n=7 each): Western diet (WD), Western diet with N-methyl-N-nitrosourea (MNU) administration (WD+MNU), standard diet (CTR), and standard diet with MNU administration (CTR+MNU). MNU was administered intraperitoneally at 50 mg/kg at seven weeks of age to induce mammary cancer. The 20-week experiment involved monitoring animal weight, food and water intake. At the end of the study, rats were euthanized, and blood samples and organs were collected for hematological and plasma biochemical analysis, oxidative stress, and histo-pathological and immunobiological evaluations of the tumors., Results: No significant differences were found in body weight, composition, or organ weights, but the WD group showed reduced food and water intake and lower cholesterol levels. Leptin and adiponectin levels were higher in the WD+MNU group, suggestive of changes in appetite regulation. Histopathological analysis showed malignant tumors in both MNU-induced groups. However, WD groups had fewer tumors compared to the CTR+MNU group., Conclusion: WD led to higher feed efficiency and increased visceral adipose tissue but decreased systemic cholesterol and triglyceride levels. While this diet resulted in lower tumor incidence, the volume and weight of the tumors were higher. Additionally, the WD decreased ERα and progesterone receptor immunoexpression, while Ki-67 immunoexpression was elevated., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Echocardiography is a reliable and non-invasive method for assessing cardiac structure and function in both clinical and experimental settings, offering valuable insights into disease progression and treatment efficacy. The successful application of echocardiography in murine models of disease has enabled the evaluation of disease severity, drug testing, and continuous monitoring of cardiac function in these animals. However, there is insufficient standardization of echocardiographic measurements for smaller animals. This article aims to address this gap by providing a guide and practical tips for the appropriate acquisition and analysis of echocardiographic parameters in adult rats, which may also be applicable in other small rodents used for scientific purposes, like mice. With advancements in technology, such as ultrahigh-frequency ultrasonic transducers, echocardiography has become a highly sophisticated imaging modality, offering high temporal and spatial resolution imaging, thereby allowing for real-time monitoring of cardiac function throughout the lifespan of small animals. Moreover, it allows the assessment of cardiac complications associated with aging, cancer, diabetes, and obesity, as well as the monitoring of cardiotoxicity induced by therapeutic interventions in preclinical models, providing important information for translational research. Finally, this paper discusses the future directions of cardiac preclinical ultrasound, highlighting the need for continued standardization to advance research and improve clinical outcomes to facilitate early disease detection and the translation of findings into clinical practice.

Breast cancer (BC) stands out as the most commonly type of cancer diagnosed in women worldwide, and chemotherapy, a key component of treatment, exacerbates cancer-induced skeletal muscle wasting, contributing to adverse health outcomes. Notably, the impact of chemotherapy on skeletal muscle seems to surpass that of the cancer itself, with inflammation identified as a common trigger for muscle wasting in both contexts. In skeletal muscle, pro-inflammatory cytokines modulate pathways crucial for the delicate balance between protein synthesis and breakdown, as well as satellite cell activation and myonuclear accretion. Physical exercise consistently emerges as a crucial therapeutic strategy to counteract cancer and chemotherapy-induced muscle wasting, ultimately enhancing patients' quality of life. However, a "one size fits all" approach does not apply to the prescription of exercise for BC patients, with factors such as age, menopause and comorbidities influencing the response to exercise. Hence, tailored exercise regimens, considering factors such as duration, frequency, intensity, and type, are essential to maximize efficacy in mitigating muscle wasting and improving disease outcomes. Despite the well-established anti-inflammatory role of aerobic exercise, resistance exercise proves equally or more beneficial in terms of mass and strength gain, as well as enhancing quality of life. This review comprehensively explores the molecular pathways affected by distinct exercise regimens in the skeletal muscle of cancer patients during chemotherapy, providing critical insights for precise exercise implementation to prevent skeletal muscle wasting.

Competing Interests: Financial/Nonfinancial Disclosures None declared.

Doxorubicin (DOX) is a topoisomerase II inhibitor used in cancer therapy. Despite its efficacy, DOX causes serious adverse effects, such as short- and long-term cardiotoxicity. This work aimed to assess the short- and long-term cardiotoxicity of DOX and the role of inflammation and antioxidant defenses on that cardiotoxicity in a mice model. Adult CD-1 male mice received a cumulative dose of 9.0 mg/kg of DOX (2 biweekly intraperitoneal injections (ip), for 3 weeks). One week (1W) or 5 months (5M) after the last DOX administration, the heart was collected. One week after DOX, a significant increase in p62, tumor necrosis factor receptor (TNFR) 2, glutathione peroxidase 1, catalase, inducible nitric oxide synthase (iNOS) cardiac expression, and a trend towards an increase in interleukin (IL)-6, TNFR1, and B-cell lymphoma 2 associated X (Bax) expression was observed. Moreover, DOX induced a decrease on nuclear factor erythroid-2 related factor 2 (Nrf2) cardiac expression. In both 1W and 5M, DOX led to a high density of infiltrating M1 macrophages, but only the 1W-DOX group had a significantly higher number of nuclear factor κB (NF-κB) p65 immunopositive cells. As late effects (5M), an increase in Nrf2, myeloperoxidase, IL-33, tumor necrosis factor-α (TNF-α), superoxide dismutase 2 (SOD2) expression, and a trend towards increased catalase expression were observed. Moreover, B-cell lymphoma 2 (Bcl-2), cyclooxygenase-2 (COX-2), and carbonylated proteins expression decreased, and a trend towards decreased p38 mitogen-activated protein kinase (MAPK) expression were seen. Our study demonstrated that DOX induces adverse outcome pathways related to inflammation and oxidative stress, although activating different time-dependent response mechanisms., (© 2023. The Author(s).)

This work aimed to understand how lifelong exercise training promotes the remodelling of the immune system and prostate signalome in a rat model of PCa. Fifty-five male Wistar rats were divided into four groups: control sedentary, control exercised, induced PCa sedentary and induced PCa exercised. Exercised animals were trained in a treadmill for 53 weeks. Pca induction consisted on the sequential administration of flutamide, N-methyl-N-nitrosourea and testosterone propionate implants. Serum concentrations of C-reactive protein (CRP) and tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) were not different among groups. Peripheral levels of γδ T cells were higher in Pca exercised group than in the PCa sedentary group (p < 0.05). Exercise training also induced Oestrogen Receptor (ESR1) upregulation and Mitogen-activated Protein Kinase 13 (MAPK13) downregulation, changed the content of the phosphorylated (at Ser-104) form of this receptor (coded by the gene ESR1) and seemed to increase Erα phosphorylation and activity in exercised PCa rats when compared with sedentary PCa rats. Our data highlight the exercise-induced remodelling of peripheral lymphocyte subpopulations and lymphocyte infiltration in prostate tissue. Moreover, exercise training promotes the remodelling prostate signalome in this rat model of prostate carcinogenesis., (© 2023. The Author(s).)

The salivary glands play a central role in the secretion of saliva, whose composition and volume affect oral and overall health. A lesser-explored dimension encompasses the possible changes in salivary gland proteomes in response to fluctuations in sex hormone levels. This study aimed to examine the effects of chronic exposure to testosterone on salivary gland remodeling, particularly focusing on proteomic adaptations. Therefore, male Wistar rats were implanted with subcutaneous testosterone-releasing devices at 14 weeks of age. Their submandibular glands were histologically and molecularly analyzed 47 weeks later. The results underscored a significant increase in gland mass after testosterone exposure, further supported by histologic evidence of granular duct enlargement. Despite increased circulating sex hormones, there was no detectable shift in the tissue levels of estrogen alpha and androgen receptors. GeLC-MS/MS and subsequent bioinformatics identified 308 proteins in the submandibular glands, 12 of which were modulated by testosterone. Of note was the pronounced upregulation of Klk3 and the downregulation of Klk6 and Klk7 after testosterone exposure. Protein-protein interaction analysis with the androgen receptor suggests that Klk3 is a potential target of androgenic signaling, paralleling previous findings in the prostate. This exploratory analysis sheds light on the response of salivary glands to testosterone exposure, providing proteome-level insights into the associated weight and histological changes.

Doxorubicin (DOX) is a potent chemotherapeutic agent used against several cancer types. However, due to its cardiotoxic adverse effects, the use of this drug may be also life-threatening. Although most cancer patients are elderly, they are poorly represented and evaluated in pre-clinical and clinical studies. Considering this, the present work aims to evaluate inflammation and oxidative stress as the main mechanisms of DOX-induced cardiotoxicity, in an innovative approach using an experimental model constituted of elderly animals treated with a clinically relevant human cumulative dose of DOX. Elderly (18-20 months) CD-1 male mice received biweekly DOX administrations, for 3 weeks, to reach a cumulative dose of 9.0 mg/kg. One week (1W) or two months (2 M) after the last DOX administration, the heart was collected to determine both drug's short and longer cardiac adverse effects. The obtained results showed that DOX causes cardiac histological damage and fibrosis at both time points. In the 1W-DOX group, the number of nuclear factor kappa B (NF-κB) p65 immunopositive cells increased and a trend toward increased NF-κB p65 expression was seen. An increase of inducible nitric oxide synthase (iNOS) and interleukin (IL)-33 and a trend toward increased IL-6 and B-cell lymphoma-2-associated X (Bax) expression were seen after DOX. In the same group, a decrease in IL-1β, p62, and microtubule-associated protein 1A/1B-light chain 3 (LC3)-I, p38 mitogen-activated protein kinase (MAPK) expression was observed. Contrariwise, the animals sacrificed 2 M after DOX showed a significant increase in glutathione peroxidase 1 and Bax expression with persistent cardiac damage and fibrosis, while carbonylated proteins, erythroid-2-related factor 2 (Nrf2), NF-κB p65, myeloperoxidase, LC3-I, and LC3-II expression decreased. In conclusion, our study demonstrated that in an elderly mouse population, DOX induces cardiac inflammation, autophagy, and apoptosis in the heart in the short term. When kept for a longer period, oxidative-stress-linked pathways remained altered, as well as autophagy markers and tissue damage after DOX treatment, emphasizing the need for continuous post-treatment cardiac monitoring., (© 2023. The Author(s).)

Background: Muscle wasting is a common phenomenon in oncology and seems to be attenuated by exercise training. The aim of this study is to determine the degree of aggressiveness of cancer-induced muscle wasting in two different phenotypic muscles. It will also determine whether exercise training can attenuate this muscle dysfunction., Methods: Fifty Sprague Dawley rats were randomly assigned to four experimental groups: two breast cancer model groups (sedentary and exercise) and two control groups (sedentary and exercise). Breast cancer was induced by 1-methyl-1-nitrosoureia (MNU). After 35 weeks of endurance training, animals were sacrificed, and gastrocnemius and soleus muscles harvested for morphometric analysis., Results: In sedentary tumor-bearing animals, a significant reduction in cross-sectional area was found in both muscles ( p < 0.05). Interstitial fibrosis was significantly higher in the gastrocnemius muscle of the sedentary tumor-bearing animals ( p < 0.05), but not in the soleus muscle. In the gastrocnemius of sedentary tumor-bearing animals, a shift from large to small fibers was observed. This cancer-related muscle dysfunction was prevented by long-term exercise training., Conclusions: In sedentary animals with tumors, the gastrocnemius muscle showed a very pronounced reduction in cross-sectional area and a marked degree of interstitial fibrosis. There was no difference in collagen deposition between tumor groups, and the soleus muscle showed a less pronounced but significant reduction in cross-sectional area. These contrasting results confirm that cancer-induced muscle wasting can affect specific types of fibers and specific muscles, namely fast glycolytic muscles, and that exercise training can be used to improve it.

Cancer is one of the most important public health problems worldwide. Despite the great contribution of in-vitro studies for biomedical research, animals are essential to study diseases' biopathology and diagnosis, and searching for new preventive and therapeutic strategies. Breast cancer is currently the most common cancer globally, accounting for 12.5% of all new annual cancer cases worldwide. Although the rat model of mammary cancer chemically-induced is widely used to study this disease, there is a lack of standardization in procedures for cancer induction, sample collection, and analysis. Therefore, it is important to provide a practical guide for researchers aiming to work with this model to make the analysis of results more uniform. Thus, in this review, we provide the researchers with a detailed step-by-step guide to implement a rat model of mammary cancer, based on our wide experience in this field, to obtain the best results, maximum throughput of each experiment, and easy comparison among researches., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Silva, et al.)

The present review was conducted to determine the efficacy of high-voltage monophasic pulsed current (HVMPC) in treating diabetic ulcers, assess its effect on skin lesions with each of the pathophysiologic factors potentially contributing to diabetic ulcers, evaluate its safety, and identify treatment parameters. Electronic search of PubMed, Scopus, PEDro and Google Scholar databases was conducted. The revised tool for assessing risk of bias in randomised trials (RoB 2), the risk of bias in non-randomised studies-of interventions (ROBINS-I) and the Joanna Briggs Institute (JBI) critical appraisal tool were used to assess risk of bias and methodological quality. Overall quality of evidence was determined using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) principles. Thirty-two studies matched the eligibility criteria, and included 1061 patients with 1103 skin lesions of selected aetiologies; 12 randomised controlled trials were included in quantitative synthesis. HVMPC plus standard wound care (SWC) likely increased the probability of complete wound healing of pressure ulcers (PrUs) compared with sham/no stimulation plus SWC; relative risk (RR) 2.08; 95% CI: [1.42, 3.04], p = 0.0002; I 2  = 0%, p = 0.61; eight studies, 358 ulcers. Although conclusive evidence regarding the effect of HVMPC on diabetic ulcers was not found, collateral evidence might suggest a potential benefit. Direct evidence, with moderate certainty, may support its efficacy in treating PrUs, albeit few adverse reactions were reported. Other observations, moreover, might indicate that this efficacy may not be limited to PrUs. Nonetheless, several aspects remain to be clarified for safe and effective application of electrical stimulation for wound healing., (© 2022 The Wound Healing Society.)

Most studies on the effects of physical exercise have focused on its influence on muscle tissue, forgetting its interference in liver function. Ageing leads to the progressive impairment of hepatic functions. Several biochemical and bioenergetics parameters were determined to test the impact of a lifelong aerobic training program in the hepatic age-related and the development of an adaptative response. Liver samples were collected from 28 male Wistar rats (4-week-old, 159.4 ± 11.9 g at the beginning of the protocol), randomly distributed into two groups: non-exercised or exercised and submitted to a treadmill exercise program (60 min/day, 5 days/week, at 70% of maximal running speed), for 24 (n = 9) or 54 weeks (n = 10). A maximal running speed test was performed to determine the training speed. Antioxidant enzyme activity, cellular redox status, oxidative stress, mitochondrial respiratory chain enzymes and respiratory activity were performed in liver samples. Lifelong exercise decreased the age-associated decline in mitochondrial dysfunction, increasing the respiratory rate in state 2 (mitochondrial respiration stimulated by the substrate in the absence of added ADP) (p = 0.03) and citrate synthase enzymatic activity (p = 0.007). Complex II (p < 0.0001) and IV (p < 0.001) showed a decrease in enzymatic activity. Ageing-related oxidative stress was also attenuated by physical exercise, as showed by the increase in first-line defense antioxidant enzymes (superoxide dismutase (p = 0.07) and catalase (p = 0.03)), decreased lipid peroxidation levels (p = 0.864 for total fraction, p = 0,27 for mitochondrial fraction) and higher glutathione reduced/oxidized ratio (p = 0.02). According to our results, the regular practice of exercise can prevent the liver’s mitochondrial dysfunction and loss of antioxidant system efficacy that may arise from ageing, highlighting the benefit of lifelong aerobic exercise in preventing age-related hepatic impairment and associated diseases.

Background and Purpose : Nonspecific chronic lower back pain (CLBP) is a difficult to manage clinical condition that is more prevalent in adulthood but also affects adolescents, compromising their well-being and activities of daily living. This case report aimed to describe the clinical evolution of a female adolescent with nonspecific and severe CLBP treated successfully through a combination of high-intensity exercise and motor imagery training. Case Description : A 13-year-old girl with CLBP with radicular pain to the lower limbs, spasms, and movement limitations, for whom pharmacological treatment (i.e. analgesic and muscle relaxant agents) and hydrotherapy, hot wet therapy, and muscle relaxation were unsuccessful. After a careful physiotherapy evaluation, the patient underwent a 36-session intervention, performed 3 times/week for 12 weeks, which was composed of high-intensity therapeutic exercise, adjusted for the patient condition, along with motor imagery training. The patient was reevaluated after the intervention and again 3 years later by the same physiotherapist. Outcomes : The intervention led to a favorable clinical outcome, with pain relief, improved posture, and decreased disability. The patient's clinical condition remained stable at the time of the last follow-up evaluation. Conclusion : These results show that the adjusted combined program led to favorable clinical improvement in the condition, with sustained long-term effects after the intervention.

Prostate cancer (PCa) is one of the most lethal diseases in men, which justifies the search for new diagnostic tools. The aim of the present study was to gain new insights into the progression of prostate carcinogenesis by analyzing the urine proteome. To this end, urine from healthy animals and animals with prostate adenocarcinoma was analyzed at two time points: 27 and 54 weeks. After 54 weeks, the incidence of pre-neoplastic and neoplastic lesions in the PCa animals was 100%. GeLC-MS/MS and subsequent bioinformatics analyses revealed several proteins involved in prostate carcinogenesis. Increased levels of retinol-binding protein 4 and decreased levels of cadherin-2 appear to be characteristic of early stages of the disease, whereas increased levels of enolase-1 and T-kininogen 2 and decreased levels of isocitrate dehydrogenase 2 describe more advanced stages. With increasing age, urinary levels of clusterin and corticosteroid-binding globulin increased and neprilysin levels decreased, all of which appear to play a role in prostate hyperplasia or carcinogenesis. The present exploratory analysis can be considered as a starting point for studies targeting specific human urine proteins for early detection of age-related maladaptive changes in the prostate that may lead to cancer.

Purpose: Although the role of signal transducers and activators of transcription (STAT3) in cachexia due to the association of circulating IL-6 and muscle wasting has been extensively demonstrated, the effect of resistance training on STAT3 in mediating muscle atrophy in tumor-bearing mice is unknown. The aim of this study is to investigate the effects of resistance exercise training on inflammatory cytokines and oxidative-mediated STAT3 activation and muscle loss prevention in tumor-bearing mice., Methods: Male Swiss mice were inoculated with Ehrlich tumor cells and exposed or not exposed to resistance exercise protocol of ladder climbing. Skeletal muscle STAT3 protein content was measured, compared between groups, and tested for possible association with plasma interleukins and local oxidative stress markers. Components of the ubiquitin-proteasome and autophagy pathways were assessed by real-time PCR or immunoblotting., Results: Resistance training prevented STAT3 excessive activation in skeletal muscle mediated by the overabundance of plasma IL-6 and muscle oxidative stress. These mechanisms contributed to preventing the increased key genes and proteins of ubiquitin-proteasome and autophagy pathways in tumor-bearing mice, such as Atrogin-1, LC3B-II, and Beclin-1. Beyond preventing muscle atrophy, RT also prevented strength loss and impaired locomotor capacity, hallmarks of sarcopenia., Conclusion: Our results suggest that STAT3 inhibition is central in resistance exercise protective effects against cancer-induced muscle atrophy and strength loss., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Testa, Cella, Marinello, Frajacomo, Padilha, Perandini, Moura, Duarte, Cecchini, Guarnier and Deminice.)

Background: Intensive Care Unit (ICU) patients are known to lose muscle mass and function during ICU stay. Ultrasonography (US) application for the assessment of the skeletal muscle is a promising tool and might help detecting muscle changes and thus several dysfunctions during early stages of ICU stay. MUSiShock is a research project aiming to investigate structure and function of diaphragm and peripheral muscles using ultrasound techniques in septic shock patients, and to assess their relevance in several clinical outcomes such as the weaning process., Methods and Design: This is a research protocol from an observational prospective cohort study. We plan to assess eighty-four septic shock patients during their ICU stay at the following time-points: at 24 hours of ICU admission, then daily until day 5, then weekly, at extubation time and at ICU discharge. At each time-point, we will measure the quadriceps rectus femoris and diaphragm muscles, using innovative US muscle markers such as Shear-Wave Elastography (SWE). In parallel, the Medical Research Council (MRC) sum score for muscle testing and the Airway occlusion pressure (P0.1) will also be collected. We will describe the association between SWE assessment and other US markers for each muscle. The association between the changes in both diaphragm and rectus femoris US markers over time will be explored as well; finally, the analysis of a combined model of one diaphragm US marker and one limb muscle US marker to predict weaning success/failure will be tested., Discussion: By using muscle ultrasound at both diaphragm and limb levels, MUSiShock aims to improve knowledge in the early detection of muscle dysfunction and weakness, and their relationship with muscle strength and MV weaning, in critically ill patients. A better anticipation of these short-term muscle structure and function outcomes may allow clinicians to rapidly implement measures to counteract it., Trial Registration: ClinicalTrials.gov, NCT04550143. Registered on 16 September 2020., Competing Interests: The authors have declared that no competing interests exist.

The authors would like to thank Dr. Seet-Lee and colleagues for their comments on our recently-published manuscript in the International Journal of Sports Medicine 1. Dr. Seet-Lee and colleagues highlighted some inadequacies, specifically when using mean difference or raw mean difference as effect measure. However, when evaluating blood vessel density by different reliable and validated histological procedures, would it be wrong to assume, as we did, that all the obtained measurements from different staining always vary equally, directly and linearly, with the actual parameter under study? Are Dr. Seet-Lee and colleagues assuming that the results of histological observations of blood vessels, marked with different techniques and stains, are neither compatible nor governed by the same measurement scales? We regret, but we are firmly convinced that we proceeded properly. Moreover, we should not assume that standardized effect sizes will make comparisons meaningful 2. Particularly, as the standardized mean difference indicates the difference before and after the intervention in terms of standard deviations instead of actual scores, it assumes that different outcome scales are linear transformation of each other and the standard deviation (SD) is equal across all studies 3., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Thieme. All rights reserved.)

Orthodontic treatment acts through the application of forces and/or by stimulating and redirecting the functional forces within the craniofacial complex. Considering the interrelationship between craniomandibular and craniocervical systems, this intervention may alter craniocervical posture. Thus, our aim is to (a) compare craniocervical posture, hyoid bone position, and craniofacial morphology before, after, and also in the contention phase at least one year after the orthodontic treatment, in patients with temporomandibular disorders and (b) to verify whether the presence of condylar displacement, the skeletal class, or the facial biotype interferes with the abovementioned outcomes. To do so an observational, analytical, longitudinal, and retrospective design study was carried out. A non-probabilistic convenience sampling method was applied. The sample consisted of clinical records of patients diagnosed with temporomandibular disorders in order to compare pre-orthodontic treatment with post-orthodontic treatment ( n = 42) and contention phase data ( n = 26). A cephalometric analysis of several variables was performed. The p -value was set as 0.05. When the pre- and post-orthodontic treatment data were analyzed, there were statistically significant changes in variables concerning craniocervical posture (CV angle, C0-C1, and AA-PNS) and also concerning hyoid bone position (C3-Rgn). When pre- and post-orthodontic treatment and contention phase data were analyzed the variables concerning craniocervical posture (C0-C1, CVT/Ver, NSL/OPT, NSL/CVT, NSL/Ver; OPT/CVT, OPT/Ver) and facial biotype had statistically significant changes. This allowed us to conclude that in the sample studied, there were significant differences regarding hyoid bone position (pre- versus post-orthodontic treatment) and craniocervical posture (pre- versus post-orthodontic versus contention), with the craniocervical posture being prone to return to basal values. The presence of condylar displacement was found to significantly increase the H-H1 distance in the three moments of evaluation. Facial biotype was found to significantly increase the NSL/Ver angle on hypodivergent compared to hyperdivergent in the contention phase.

Objectives: Physical inactivity (PIn) and a fatty diet (FD) are closely linked to development of metabolic syndrome (MetS), overloading the endocrine pancreas seeking energy homeostasis. However, the relative contribution of FD and PIn to the pancreatic overload is unknown. The aim of this study was to verify the isolated and conjugated influence of FD and PIn in the islets of Langer hans (islets) structure and function related to overload in Wistar rats., Methods: Male Wistar rats were divided into four groups (n = 10/group): active groups, fed with fat (AFD) or standard (ASD) diet; and physically inactive groups, fed with fat (SFD) or standard (SSD) diet for 21 wk. Glucose tolerance (GT) and insulin sensitivity (IS) were assessed before sacrifice. Retroperitoneal adipose tissue and pancreas were weighted (PW), and pancreas samples processed for histologic analyses., Results: Only the FD-fed animals presented MS. Compared with standard diet, FD impaired GT and IS, decreased PW, and enlarged islets dimensions, with islets cellular death, inflammatory response, and enhanced collagen content, which were attenuated in AFD. Independent of the diet, PIn groups presented higher amounts of islets connective tissue, but without influence on inflammatory reaction and cellular death. The GT impairment was higher in the FD-fed groups, whereas the decreased IS was more pronounced in the PIn groups., Conclusion: FD induced MS with detrimental effects on pancreas overload, inducing islets morphologic and functional maladaptation, which were attenuated in active animals. Physical activity was not able to prevent FD-induced MS. FD showed a negative influence on GT, whereas PIn mainly affected IS., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To summarize evidence in the last decade regarding the efficacy of physical therapy interventions to treat tendinopathy, as a single disease entity, as determined in systematic reviews (SRs) and/or meta-analyses (MAs)., Methods: Electronic search of PubMed, PEDro, and Scopus database was performed from year 2010 to January 2020. The methodological quality of the identified studies was assessed using the AMSTAR 2 tool. Studies scoring 9 points or higher were further analyzed using GRADE principles., Results: 40 SRs and/or MAs were included in qualitative synthesis, whereas only 5 MAs were included in quantitative synthesis. Low-level laser therapy (LLLT) intervention showed a pooled improvement in pain reduction of 1.53 cm; 95% CI, [1.14, 1.91] (I 2  = 1.9%, p = 0.361) on visual analogue scale, and grip strength of 9.59 kg; 95% CI, [5.90, 13.27]., Conclusions: Moderate-quality evidence may support these following interventions: LLLT revealed a statistically and potentially clinically significant improvement in pain and function on the short-term. Extracorporeal shockwave therapy showed a statistically significant enhancement in pain and function at all follow-up durations; however, its clinical significance was undetermined. Eccentric exercise was supported by qualitative evidence only. Caution is advised when interpreting results due to possible pathological differences in tendinopathy at each region., Competing Interests: Declaration of competing interest None declared., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Despite pulmonary arterial hypertension (PAH) directly affects the right ventricle (RV), important structural, functional, and molecular changes also occur in left ventricle (LV). The objective of our study was to analyze the hypothetical cardioprotective effects of exercise preconditioning on LV in rats with monocrotaline (MCT)-induced PAH., Methods: Forty male Wistar rats were randomly separated in sedentary (SED) and trained group (EX; running sessions of 60 min/day, 5 days/wk, at 25 m/min, for 4 weeks). After 4 weeks, animals were injected with MCT (60 mg/kg; SED + MCT; EX + MCT) or vehicle (SED + V). Following an additional period of 4 weeks where all animals remained sedentary, we completed LV hemodynamic evaluation in baseline and isovolumic conditions and collected LV samples for histological and molecular analysis., Results: Preconditioning with exercise was capable to restore LV systolic and diastolic dysfunction in both baseline and isovolumic conditions ( P  < .05). This improved was paralleled with prevention of LV cardiomyocytes atrophy, fibrosis, and endothelin 1 mRNA levels ( P  < .05)., Conclusions: Our findings suggest that exercise preconditioning can prevent LV dysfunction secondary to MCT-induced PAH, which is of particular interest for the familial form of the disease that is manifested by greater severity or earlier onset., Competing Interests: Sponsorships or competing interests that may be relevant to content are disclosed at the end of this articleNone., (Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of PBJ-Associação Porto Biomedical/Porto Biomedical Society. All rights reserved.)

Iron oxide nanoparticles (ION) are gaining importance as diagnostic and therapeutic tool of central nervous system diseases. Although oleic acid-coated ION (O-ION) have been described as stable and biocompatible, their potential neurotoxicity was scarcely evaluated in human nervous cells so far. The primary aim of this work was to assess the molecular and cellular effects of O-ION on human astrocytes (A172 cells) under different experimental conditions. An extensive set of cyto- and genotoxicity tests was carried out, including lactate dehydrogenase release assay, cell cycle alterations, and cell death production, as well as comet assay, γH2AX assay, and micronucleus (MN) test, considering also iron ion release capacity and alterations in DNA repair ability. Results showed a moderate cytotoxicity related to cell cycle arrest and cell death promotion, regardless of serum presence. O-ION induced genotoxic effects, namely primary DNA damage, as detected by the comet assay and H2AX phosphorylation, but A172 cells were able to repair this particular damage because no chromosome alterations were found (confirmed by MN test results). Accordingly, no effects on the DNA repair ability were observed. The presence of serum proteins did not influence O-ION toxicity. Iron ions released from the O-ION surface seemed not to be responsible for the cytotoxic and genotoxic effects observed. Environ. Mol. Mutagen. 2019. © 2019 Wiley Periodicals, Inc., (© 2019 Wiley Periodicals, Inc.)

Context: Deep friction massage (DFM) is often used in the treatment of tendinopathies; however, the pressure applied may vary and interfere with the obtained results., Objective: To assess whether the immediate effects of DFM on pain (pain intensity and time to onset of analgesia) and muscle strength are dependent on the pressure applied during the DFM application in athletes with patellar tendinopathy., Design: Randomized, controlled, cross-over trial., Setting: University research laboratory (institutional)., Participants: Ten athletes with diagnosis of unilateral patellar tendinopathy (age 27.90 [5.24] y)., Interventions: All participants attended 4 sessions, 3 treatment sessions with DFM applied with different pressures (the mean pressure-previously determined for each participant-and the mean pressure ± 25%) and a control session, each of which was separated by 48 hours., Main Outcome Measures: Pain (intensity upon palpation and time to onset of analgesia), and muscle strength of knee extensors were assessed before and immediately after each session., Results: Pain intensity changed significantly over time (F1,9 = 52.364; P < .001; ηp2=.853) and among sessions (F3,27 = 82.588; P < .001; ηp2=.902), with a significant interaction for group × time (F3,27 = 19.841; P < .001; ηp2=.688). The knee extensors strength did not change significantly over time (F1,9 = 2.240; P = .17; ηp2=.199), nor a significant interaction for session × time was observed (F3,27 = 3.276; P = .07; ηp2=.267). Regardless of the pressure applied, the time to onset of analgesia was not significantly different (F2,18 = 1.026; P > .05; ηp2=.102)., Conclusion: It was shown that DFM induces an immediate reduction in pain intensity upon palpation, regardless of the pressure performed. Notwithstanding, the reader should take into account the small sample size and the caution needed in the results' interpretation.

Objective: The aim of the present systematic review and meta-analysis is to know, based on the available randomized controlled trials, if the non-surgical and non-pharmacological interventions commonly used for knee osteoarthritis (OA) patients are effective and which are the most effective ones., Material and Methods: RCTs were identified through electronic databases respecting the following terms to guide the search strategy: PICO (Patients - Humans with knee OA; Intervention - Non-surgical and non-pharmacological interventions; Comparison - Pharmacological, surgical, placebo, no intervention, or other non-pharmacological/non-surgical interventions; Outcomes - Pain, physical function and patient global assessment). The methodological quality of the selected publications was evaluated using the PEDro and GRADE scales. Additionally, a meta-analysis was performed using the RevMan. Only studies with similar control group, population characteristics, outcomes, instruments and follow-up, were compared in each analysis., Results: Initially, 52 RCTs emerge however, after methodological analysis, only 39 had sufficient quality to be included. From those, only 5 studies meet the meta-analysis criteria. Exercise (especially resistance training) had the best positive effects on knee OA patients. Pulsed Electromagnetic Fields and Moxibustion showed to be the most promising interventions from the others. Balance Training, Diet, Diathermy, Hydrotherapy, High Level Laser Therapy, Interferential Current, Mudpack, Neuromuscular Electrical Stimulation, Musculoskeletal Manipulations, Shock Wave Therapy, Focal Muscle Vibration, stood out, however more studies are needed to fully recommend their use. Other interventions did not show to be effective or the results obtained were heterogeneous., Conclusions: Exercise is the best intervention for knee OA patients. Pulsed Electromagnetic Fields and Moxibustion showed to be the most promising interventions from the others options available.

This review was conducted to determine and quantify the efficacy of high-voltage monophasic pulsed current (HVMPC) in the treatment of stage II-IV pressure ulcers (PrUs), identify the details of HVMPC intervention parameters and the superior protocol, and ascertain other potential benefits and the safety of HVMPC intervention. Eleven studies, nine randomized controlled trials (RCTs) and two case series studies, matched the criteria and were included in the systematic review, whereas, only level 1 evidence RCTs were included in the meta-analysis. The percentage of wound surface area reduction per week was 12.39%; 95% CI, [10.43-14.37] for HVMPC plus standard wound care (SWC) and 6.96%; 95% CI, [5.56-8.38] for SWC alone or SWC plus sham HVMPC. The net effect of HVMPC was 5.4% per week (an increase of 78% greater than SWC alone or SWC plus sham HVMPC). Level 1, 2 and 4 evidence studies have consistently indicated that HVMPC plus SWC were more effective than SWC alone or SWC plus sham HVMPC in treating stage II-IV PrUs. Level 1 evidence studies showed that HVMPC intervention improved the healing of PrUs (reduced wound surface area), and combined with SWC, increased the probability of complete healing and almost eliminated the probability of worsening of healing. HVMPC intervention was shown to be relatively safe, with rare adverse reactions., (Copyright © 2018 Tissue Viability Society. Published by Elsevier Ltd. All rights reserved.)

Knowing the therapeutic effects of regular physical exercise on kidney toxicity induced by a single dose of doxorubicin (DOX) in animal models, the aim of this study is to verify the effectiveness of regular voluntary running on kidney histology after a prolonged DOX administration, mimicking a chemotherapy protocol. Thirty-four male Wistar rats were randomly divided into two clusters: DOX (n = 17) and SSS (sterile saline solution, n = 17), receiving a weekly intraperitoneal injection of DOX (2 mg/kg) or vehicle for 7 weeks, respectively. Two weeks after the last injection, five animals from each cluster (SSSG, n = 5; DOXG, n = 5) were euthanized, while the remaining ones were divided into sedentary (DOXsed, n = 6; SSSsed, n = 6) and active subgroups (DOXact, n = 6; SSSact, n = 6). Active animals were placed individually in cages with a running wheel for regular voluntary activity. After 2 months, the animals were euthanized and kidneys were histologically examined. Compared to SSSG, kidneys from DOXG revealed higher levels of damage, more collagen content and thickening of Bowman's capsule (p < .05). The levels of damage and thickness of Bowman's capsule increased in DOXsed as compared to DOXG (p < .05). Compared to DOXsed, the DOXact presented an overall improvement in kidney structure (p < .05), with a decrease in collagen content and of the thickness of Bowman's capsule. The results allow concluding that regular voluntary running attenuate the long-term harmful effects on kidney structure induced by a prolonged DOX treatment. These results, supporting the potential benefit of physical activity in patients under DOX treatment, need to be tested in humans.

Objective - Update the last known umbrella review and summarize the available high-quality evidence from systematic reviews on the effectiveness of non-pharmacological and non-surgical interventions for patients with knee OA. Methods - The systematic reviews were identified thought electronic databases such as, MEDLINE, Embase, Physiotherapy Evidence Database (PEDro), The Cochrane Library, SciELo, Science Direct, Google Scholar, Research Gate and B-ON. The studies selection respected the following terms to guide the search strategy using the P (humans with knee osteoarthritis) I (non-pharmacological and non-surgical treatments) C (pharmacological, surgical, placebo, no intervention, or other non-pharmacological/ non-surgical conservative treatments) O (pain, functional status, stiffness, inflammation, quality of life and patient global assessment) model. Results - Following the PRISMA statement, 41 systematic reviews were found on the electronic databases that could be included in the umbrella review. After methodical analysis (R-AMSTAR), only 35 had sufficient quality to be included. There is gold evidence that Standard Exercise programs can reduce pain and improve physical function in patients with knee OA. Additionally, there is silver evidence for Acupuncture, Aquatic Exercise, Electroacupuncture, Interferential Current, Kinesio Taping, Manual Therapy, Moxibustion, Pulsed Electromagnetic Fields, Tai Chi, Ultrasound, Yoga, and Whole-Body Vibration. For other interventions, the quality of evidence is low or did not show sufficient efficacy from the systematic reviews to support their use. Conclusion - Comparing to last known umbrella review, similar results were achieved on Acupuncture and Exercise interventions to improve the patients' pain, stiffness, function and quality of life, but it was found different results regarding the utilization of Transcutaneous Electrical Nerve Stimulation and Low-Level Laser Therapy as they do not improved the patients' pain and physical function.

Methylphenidate (MPH) is a first-line stimulant drug to treat attention deficit hyperactivity disorder (ADHD). Overdiagnosis of ADHD and MPH abuse lead to serious concerns about the possible long-term adverse consequences of MPH in healthy children and adolescents. We aimed to evaluate MPH effects in adolescent male Wistar rats (postnatal day 40) using an oral dose scheme (2 daily MPH doses 5 mg/kg in a 5% sucrose solution, 5 h apart, for 7 days) that mimics the therapeutic doses given to human adolescents. Twenty-four hours after the last MPH administration, rats were sacrificed and brain areas [cerebellum, prefrontal cortex (PFC), hippocampus, and striatum], peripheral organs (liver, heart, and kidneys), and blood were collected for biochemical and histological analysis. MPH treatment did not alter rats' body temperature or weight, neither food or water intake throughout the experiment. The ratio of reduced glutathione/oxidized glutathione (GSH/GSSG) significantly increased in the PFC and hippocampus of MPH-treated rats, meanwhile protein carbonylation remained unchanged in the brain. In the heart, the GSH/GSSG ratio and GSH levels were significantly increased, with decreased GSSG, while histology revealed significant damage, namely interstitial edema, vascular congestion, and presence of a fibrin-like material in the interstitial space. In the kidneys, MPH treatment resulted in extensive necrotic areas with cellular disorganization and cell infiltration, and immunohistochemistry analysis revealed a marked activation of nuclear factor-ĸB. This study showed that clinically relevant oral MPH doses improve the GSH redox status in the brain and heart, but evoke heart and kidney tissue damage to adolescent rats., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)