Application of machine learning algorithms in thermal images for an automatic classification of lumbar sympathetic blocks.

PURPOSE: There are no previous studies developing machine learning algorithms in the classification of lumbar sympathetic blocks (LSBs) performance using infrared thermography data. The objective was to assess the performance of different machine learning algorithms to classify LSBs carried out in patients diagnosed with lower limbs Complex Regional Pain Syndrome as successful or failed based on the evaluation of thermal predictors. METHODS: 66 LSBs previously performed and classified by the medical team were evaluated in 24 patients. 11 regions of interest on each plantar foot were selected within the thermal images acquired in the clinical setting. From every region of interest, different thermal predictors were extracted and analysed in three different moments (minutes 4, 5, and 6) along with the baseline time (just after the injection of a local anaesthetic around the sympathetic ganglia). Among them, the thermal variation of the ipsilateral foot and the thermal asymmetry variation between feet at each minute assessed and the starting time for each region of interest, were fed into 4 different machine learning classifiers: an Artificial Neuronal Network, K-Nearest Neighbours, Random Forest, and a Support Vector Machine. RESULTS: All classifiers presented an accuracy and specificity higher than 70%, sensitivity higher than 67%, and AUC higher than 0.73, and the Artificial Neuronal Network classifier performed the best with a maximum accuracy of 88%, sensitivity of 100%, specificity of 84% and AUC of 0.92, using 3 predictors. CONCLUSION: These results suggest thermal data retrieved from plantar feet combined with a machine learning-based methodology can be an effective tool to automatically classify LSBs performance.

Chronic and Acute Effects on Skin Temperature from a Sport Consisting of Repetitive Impacts from Hitting a Ball with the Hands.

Valencian handball consists in hitting the ball with the hands and it may contribute to injury development on the hands. This study aimed to analyze skin temperature asymmetries and recovery after a cold stress test (CST) in professional players of Valencian handball before and after a competition. Thirteen professional athletes and a control group of ten physically active participants were measured. For both groups, infrared images were taken at the baseline condition; later they underwent a thermal stress test (pressing for 2 min with the palm of the hand on a metal plate) and then recovery images were taken. In athletes, the images were also taken after their competition. Athletes at baseline condition presented lower temperatures (p < 0.05) in the dominant hand compared with the non-dominant hand. There were asymmetries in all regions after their match (p < 0.05). After CST, a higher recovery rate was found after the game. The regions with the most significant differences in variation, asymmetries and recovery patterns were the index, middle and ring fingers, and the palm of the dominant hand. Taking into account that lower temperatures and the absence of temperature variation may be the consequence of a vascular adaptation, thermography could be used as a method to prevent injuries in athletes from Valencian handball.

Effect of 10 km run on lower limb skin temperature and thermal response after a cold-stress test over the following 24 h.

Skin temperature assessment has received much attention as a possible measurement of physiological response against stress produced by exercise and research studies usually measure skin temperature 24 or 48 h after exercise. Scientific evidence about skin temperature evolution during the 24-h period immediately after exercising is, however, scarce. The aim was to assess the effect of a 10 km run at moderate intensity on baseline skin temperature and thermal response after a cold stress test during that 24 h period. Fourteen participants were measured before, immediately after, and at 2, 5, 9 and 24 h after a 10 km run at a perceived exertion rate of 11 points (max 20 points). Fourteen control participants who undertook no exercise were also measured during that day. The measurements included muscle pain and fatigue perception, reactive oxygen species, heart rate variability, skin temperature of the lower limbs, and skin temperature after cold stress test. Exercise resulted in a skin temperature increase (e.g., 0.5-1.3 °C of posterior leg 9 h after exercise) and this effect continued in some regions (0.4-0.9 °C of posterior leg) over that 24 h period. However, the thermal response to the cold stress test remained the same (p > 0.05). In conclusion, 10 km aerobic running exercise results in a skin temperature increase, peaking at between 5 and 9 h after exercise, but does not alter the thermal response to a cold stress test. This study provides a sound basis for post-exercise skin temperature response that can be used as a setting-off point for comparisons with future studies that analyze greater muscle damage.

Effects of squatting with elastic bands or conventional resistance-training equipment at different effort levels in post-exercise intraocular pressure of healthy men.

This study aimed to compare intraocular pressure (IOP), mean ocular perfusion pressure (MOPP) and central corneal thickness (CCT) acute adaptations to squat exercise using elastic bands (EB) or weight plates (WP) together with the weight of the bar and applying maximal or submaximal efforts. Cardiovascular parameters (pulse pressure, mean blood pressure, heart rate), rate of perceived exertion, kilograms, and number of repetitions served to monitor psychophysiological acute variations. Twenty physically active males (25.55 ± 4.75 y.o.) underwent two sessions (one for familiarization and one for the experimental trial). In the experimental session, ocular and cardiovascular pre-exercise measurements were taken. Then, two sets using WP and two using EB attached to the bar with the same load were performed by each subject in random order. Immediately after finishing each set, the subjects rated perceived exertion, and cardiovascular and ocular measurements were taken, in this order. An ANOVA with post-hoc LSD evaluated differences between sets. IOP significantly decreased (p < 0.001, ƞp2 = 0.513), and MOPP (p < 0.001, ƞp2 = 0.413) and cardiovascular variables significantly increased due to the exercise effect; CCT changes were non-significant. No significant effect of the material, level of effort, or their interaction was observed in the IOP and MOPP (p > 0.05). EB permitted more repetitions to be performed and led to non-significantly lower post-exercise IOP values (effect size [d] compared to resting 0.79 and 1.00) in comparison to WP (d = 0.73-0.74). IOP and ocular and systemic hemodynamic responses are similar when using EB instead of WP to load the bar, with EB allowing a larger number of repetitions. Data presented in this paper may help with the prescription of resistance training for people with glaucoma risk factors.

Quantitative Analysis of Real-Time Infrared Thermography for the Assessment of Lumbar Sympathetic Blocks: A Preliminary Study.

Lumbar sympathetic blocks (LSBs) are commonly performed to treat pain ailments in the lower limbs. LSBs involve injecting local anesthetic around the nerves. The injection is guided by fluoroscopy which is sometimes considered to be insufficiently accurate. The main aim was to analyze the plantar foot skin temperature data acquired while performing LSBs in patients with complex regional pain syndrome (CRPS) affecting the lower limbs. Forty-four LSBs for treating lower limb CRPS in 13 patients were assessed. Pain medicine physicians visualized the infrared thermography (IRT) video in real time and classified the performance depending on the observed thermal changes within the first 4 min. Thirty-two percent of the cases did not register temperature variations after lidocaine was injected, requiring the needle to be relocated. Differences between moments are indicated using the 95% confidence intervals of the differences (CI 95%), the Cohen effect size (ES) and the significance (p value). In successful cases, after injecting lidocaine, increases at minute 7 for the mean (CI 95% (1.4, 2.1 °C), p < 0.001 and ES = 0.5), at minute 5 for maximum temperature (CI 95% (2.3, 3.3 °C), p < 0.001 and ES = 0.6) and at minute 6 for SD (CI 95% (0.2, 0.3 °C), p < 0.001 and ES = 0.5) were observed. The results of our preliminary study showed that the measurement of skin temperature in real time by infrared thermography is valuable for assessing the success of lumbar sympathetic blocks.

The Link between Oxidative Stress, Redox Status, Bioenergetics and Mitochondria in the Pathophysiology of ALS.

Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease of the motor system. It is characterized by the degeneration of both upper and lower motor neurons, which leads to muscle weakness and paralysis. ALS is incurable and has a bleak prognosis, with median survival of 3-5 years after the initial symptomatology. In ALS, motor neurons gradually degenerate and die. Many features of mitochondrial dysfunction are manifested in neurodegenerative diseases, including ALS. Mitochondria have shown to be an early target in ALS pathophysiology and contribute to disease progression. Disruption of their axonal transport, excessive generation of reactive oxygen species, disruption of the mitochondrial structure, dynamics, mitophagy, energy production, calcium buffering and apoptotic triggering have all been directly involved in disease pathogenesis and extensively reported in ALS patients and animal model systems. Alterations in energy production by motor neurons, which severely limit their survival capacity, are tightly linked to the redox status and mitochondria. The present review focuses on this link. Placing oxidative stress as a main pathophysiological mechanism, the molecular interactions and metabolic flows involved are analyzed. This leads to discussing potential therapeutic approaches targeting mitochondrial biology to slow disease progression.

Effect of bike-fit in the perception of comfort, fatigue and pain.

The aim of this study was to assess the influence of different bike positions on the perception of fatigue, pain and comfort. Twenty cyclists underwent three tests that involved cycling for 45 min at their individual 50% peak aerobic power output while adopting different positions on the bike. Participants performed the cycling tests adopting three positions defined by two parameters (knee flexion angle [20°, 30°, 40°] and trunk flexion angle [35°, 45°, 55°]) in random order. Angles were measured using a 2D motion analysis system during cycling and applying Fonda's correction factor. Perceptions of comfort, fatigue and pain were reported before the end of each test. The combination of 40° knee flexion and 35° trunk flexion was perceived as the most uncomfortable position. Moreover, greater knee flexion had a negative effect on trunk comfort, accompanied by greater levels of fatigue and pain perception in the anterior part of the thigh and knee. In conclusion, cyclists perceived the most comfortable position to be when the saddle height was within the recommended knee angle (30° calculated from the offset position or 40 ± 4.0° of absolute value). Upright trunk was found to be the most comfortable position for recreational cyclists, where aerodynamics is not so important. Cyclists' bike perceptions should be taken into account when it comes to choosing the most beneficial position, since this can play a role in injury prevention and enhance cycling performance.

Infrared thermography is useful for ruling out fractures in paediatric emergencies.

UNLABELLED: Musculoskeletal injuries are a leading cause of paediatric injuries and emergency department visits in Western countries. Diagnosis usually involves radiography, but this exposes children without fractures to unnecessary ionising radiation. We explored whether infrared thermography could provide a viable alternative in trauma cases. We compared radiography and thermal images of 133 children who had been diagnosed with a trauma injury in the emergency unit of a Spanish hospital. As well as the thermal variables in the literature, we introduced a new quantifier variable, the size of the lesion. Decision tree models were built to assess the technique's accuracy in diagnosing whether a bone had been fractured or not. Infrared thermography had a sensitivity of 0.91, a specificity of 0.88 and a negative predictive value of 0.95. The new lesion size variable introduced appeared to be of main importance to the discriminatory power of the method. CONCLUSION: The high negative predictive value of infrared thermography suggests that it is a promising method for ruling out fractures.

Relationship between skin temperature and muscle activation during incremental cycle exercise.

While different studies showed that better fitness level adds to the efficiency of the thermoregulatory system, the relationship between muscular effort and skin temperature is still unknown. Therefore, the present study assessed the relationship between neuromuscular activation and skin temperature during cycle exercise. Ten physically active participants performed an incremental workload cycling test to exhaustion while neuromuscular activations were recorded (via surface electromyography - EMG) from rectus femoris, vastus lateralis, biceps femoris and gastrocnemius medialis. Thermographic images were recorded before, immediately after and 10 min after finishing the cycling test, at four body regions of interest corresponding to the muscles where neuromuscular activations were monitored. Frequency band analysis was conducted to assess spectral properties of EMG signals in order to infer on priority in recruitment of motor units. Significant inverse relationship between changes in skin temperature and changes in overall neuromuscular activation for vastus lateralis was observed (r<-0.5 and p<0.04). Significant positive relationship was observed between skin temperature and low frequency components of neuromuscular activation from vastus lateralis (r>0.7 and p<0.01). Participants with larger overall activation and reduced low frequency component for vastus lateralis activation presented a better adaptive response of their thermoregulatory system by showing fewer changes in skin temperature after incremental cycling test.

Nicotinamide riboside, pterostilbene and ibudilast protect motor neurons and extend survival in ALS mice.

Oxidative stress and neuroinflammation are major contributors to the pathophysiology of ALS. Nicotinamide riboside (a NAD+ precursor) and pterostilbene (a natural antioxidant) were efficacious in a human pilot study of ALS patients and in ALS SOD1G93A transgenic mice. Ibudilast targets different phosphodiesterases and the macrophage migration inhibitory factor, reduces neuroinflammation, and in early-phase studies improved survival and slowed progression in ALS patients. Using two ALS murine models (SOD1G93A, FUSR521C) the effects of nicotinamide riboside, pterostilbene, and ibudilast on disease onset, progression and survival were studied. In both models ibudilast enhanced the effects of nicotinamide riboside and pterostilbene on survival and neuromotor functions. The triple combination reduced microgliosis and astrogliosis, and the levels of different proinflammatory cytokines in the CSF. TNFα, IFNγ and IL1ß increased H2O2 and NO generation by motor neurons, astrocytes, microglia and endothelial cells isolated from ALS mice. Nicotinamide riboside and pterostilbene decreased H2O2 and NO generation in all these cells. Ibudilast specifically decreased TNFα levels and H2O2 generation by microglia and endothelial cells. Unexpectedly, pathophysiological concentrations of H2O2 or NO caused minimal motor neuron cytotoxicity. H2O2-induced cytotoxicity was increased by NO via a trace metal-dependent formation of potent oxidants (i.e. OH and -OONO radicals). In conclusion, our results show that the combination of nicotinamide riboside, pterostilbene and ibudilast improve neuromotor functions and survival in ALS murine models. Studies on the underlying mechanisms show that motor neuron protection involves the decrease of oxidative and nitrosative stress, the combination of which is highly damaging to motor neurons.

Sex-related differences in profiles of muscle oxygen saturation of different muscles in trained cyclists during graded cycling exercise.

Although in recent years near-infrared spectroscopy has been used in many sports to monitor muscle oxygen saturation (SmO2), there is a lack of knowledge about the sex differences in SmO2 during exercise in different muscles. Our study aimed to examine SmO2 differences in muscles between female and male cyclists, during a graded cycling test and at the first and second lactate thresholds. Twenty-five trained cyclists and triathletes (15 males: 23 ± 7 yr, 1.78 ± 0.05 m, 70.2 ± 5.3 kg, and 10 females: 22 ± 5 yr, 1.64 ± 0.06 m, 58 ± 8 kg) performed a graded cycling test on the cycle ergometer. Power output and SmO2 in five muscles (dominant vastus lateralis, tibialis anterior, gastrocnemius medial, biceps femoris, and triceps brachii) were measured. Our mixed regression models showed that the interaction between power output and sex was significant for all the muscles analyzed (P < 0.001), indicating a greater decrease in SmO2 for males as power output increased. Moreover, the statistical parametric mapping analyses showed for females higher SmO2 in the middle of the test in biceps femoris (P = 0.03), gastrocnemius medial (P = 0.02), and tibialis anterior (P = 0.04). Finally, the males presented a lower SmO2 in all muscles where the second lactate threshold occurred, with greater evidence than in the first lactate threshold. In conclusion, females have higher SmO2 in all muscles, and these differences are more noticeable during the graded cycling test, such that males seem to have a greater reliance on oxygen extraction than females for a given relative intensity of exercise.NEW & NOTEWORTHY This study investigated the profiles of muscle oxygen saturation (SmO2) during incremental exercise in females and males. Females presented higher overall SmO2 than males during moderate and heavy intensity domain exercise in all muscles including muscles that are not mainly involved in pedaling (triceps brachii), from those that are stabilizers (medial gastrocnemius, tibialis anterior, and biceps femoris), to those that are related to power output production (vastus lateralis).

A comparative analysis of mathematical methods for detecting lactate thresholds using muscle oxygenation data during a graded cycling test.

Objective. Threshold determination for improving training and sports performance is important for researchers and trainers, who currently use different methods for determining lactate, ventilatory or muscle oxygenation (SmO2) thresholds. Our study aimed to compare the identification of the intensity at the first and second thresholds using lactate and SmO2data by different mathematical methods in different muscles during a graded cycling test.Approach. Twenty-six cyclists (15 males and 11 females; 23 ±6 years, 1.71 ± 0.09 m, 64.3 ± 8.8 Kg and 12 ± 3 training hours per week) performed a graded test on the cycle ergometer. Power output and saturation of muscle oxygen in four muscles (vastus lateralis, biceps femoris, gastrocnemius and tibialis anterior) were measured, along with systemic lactate concentration.Main Results. Our results showed that any method was reliable for determining the first muscle oxygenation threshold (MOT1) when comparing the lactate threshold in any muscle. However, the best method for determining the second muscle oxygenation threshold (MOT2) was the Exp-Dmax (p< 0.01; ICC = 0.79-0.91) in all muscles. In particular, the vastus lateralis muscle showed the highest intraclass correlation coefficient (ICC = 0.91, CI95% [0.81, 0.96]). However, results varied per sex across all muscles analyzed.Significance. Although the first muscle oxygenation threshold could not be determined using mathematical methods in all the muscles analyzed, the Exp-Dmax method presented excellent results in detecting the second systemic threshold in the vastus lateralis.

Combination of natural polyphenols with a precursor of NAD+ and a TLR2/6 ligand lipopeptide protects mice against lethal γ radiation.

INTRODUCTION: Effective agents that could confer long-term protection against ionizing radiation in vivo would have applications in medicine, biotechnology, and in air and space travel. However, at present, drugs that can effectively protect against lethal ionizing radiations are still an unmet need. OBJECTIVE: To investigate if combinations of natural polyphenols, known for their antioxidant potential, could protect against ionizing radiations. METHODS: Plant-derived polyphenols were screened for their potential ability to confer radioprotection to mice given a lethal whole-body γ radiation (137Cs) dose expected to kill 50% of the animals in 30 days. Telomere and centromere staining, Q-FISH and comet assays were used to investigate chromosomal aberration, micronuclei formation and DNA breaks. Molecular oxidations were investigated by enzyme immunoassays and UPLC-MS/MS. RT-PCR, western blotting and siRNA-induced gene silencing were used to study signaling mechanisms and molecular interactions. RESULTS: The combination of pterostilbene (PT) and silibinin (SIL) was the most effective against γ-irradiation, resulting in 100% of the mice surviving at 30 days and 20% survival at one year. Treatment post γ-irradiation with two potential radiomitigators nicotinamide riboside (NR, a vitamin B3 derivative), and/or fibroblast-stimulating lipoprotein 1 (FSL1, a toll-like receptor 2/6 agonist), did not extend survival. However, the combination of PT, SIL, NR and FSL1 achieved a 90% survival one year post γ-irradiation. The mechanism involves induction of the Nrf2-dependent cellular antioxidant defense, reduction of NF-kB signaling, upregulation of the PGC-1α/sirtuins 1 and 3 axis, PARP1-dependent DNA repair, and stimulation of hematopoietic cell recovery. The pathway linking Nrf2, sirtuin 3 and SOD2 is key to radioprotection. Importantly, this combination did not interfere with X-ray mediated killing of different tumor cells in vivo. CONCLUSION: The combination of the radioprotectors PT and SIL with the radiomitigators NR and FSL1 confer effective, long-term protection against γ radiation in vivo. This strategy is potentially capable of protecting mammals against ionizing radiations.

Survival Mechanisms of Metastatic Melanoma Cells: The Link between Glucocorticoids and the Nrf2-Dependent Antioxidant Defense System.

Circulating glucocorticoids increase during stress. Chronic stress, characterized by a sustained increase in serum levels of cortisol, has been associated in different cases with an increased risk of cancer and a worse prognosis. Glucocorticoids can promote gluconeogenesis, mobilization of amino acids, fat breakdown, and impair the body's immune response. Therefore, conditions that may favor cancer growth and the acquisition of radio- and chemo-resistance. We found that glucocorticoid receptor knockdown diminishes the antioxidant protection of murine B16-F10 (highly metastatic) melanoma cells, thus leading to a drastic decrease in their survival during interaction with the vascular endothelium. The BRAFV600E mutation is the most commonly observed in melanoma patients. Recent studies revealed that VMF/PLX40-32 (vemurafenib, a selective inhibitor of mutant BRAFV600E) increases mitochondrial respiration and reactive oxygen species (ROS) production in BRAFV600E human melanoma cell lines. Early-stage cancer cells lacking Nrf2 generate high ROS levels and exhibit a senescence-like growth arrest. Thus, it is likely that a glucocorticoid receptor antagonist (RU486) could increase the efficacy of BRAF-related therapy in BRAFV600E-mutated melanoma. In fact, during early progression of skin melanoma metastases, RU486 and VMF induced metastases regression. However, treatment at an advanced stage of growth found resistance to RU486 and VMF. This resistance was mechanistically linked to overexpression of proteins of the Bcl-2 family (Bcl-xL and Mcl-1 in different human models). Moreover, melanoma resistance was decreased if AKT and NF-κB signaling pathways were blocked. These findings highlight mechanisms by which metastatic melanoma cells adapt to survive and could help in the development of most effective therapeutic strategies.

Reliability of threshold determination using portable muscle oxygenation monitors during exercise testing: a systematic review and meta-analysis.

Over the last few years, portable Near-Infrared Spectroscopy (NIRS) technology has been suggested for determining metabolic/ventilator thresholds. This systematic review and meta-analysis aimed to assess the reliability of a portable muscle oxygenation monitor for determining thresholds during exercise testing. The proposed PICO question was: Is the exercise intensity of muscle oxygenation thresholds, using portable NIRS, reliable compared with lactate and ventilatory thresholds for exercise intensity determined in athletes? A search of Pubmed, Scopus and Web of Science was undertaken and the review was conducted following PRISMA guidelines. Fifteen articles were included. The domains which presented the highest biases were confounders (93% with moderate or high risk) and participant selection (100% with moderate or high risk). The intra-class correlation coefficient between exercise intensity of the first ventilatory or lactate threshold and the first muscle oxygenation threshold was 0.53 (obtained with data from only 3 studies), whereas the second threshold was 0.80. The present work shows that although a portable muscle oxygenation monitor has moderate to good reliability for determining the second ventilatory and lactate thresholds, further research is necessary to investigate the mathematical methods of detection, the capacity to detect the first threshold, the detection in multiple regions, and the effect of sex, performance level and adipose tissue in determining thresholds.

Externally Applied Electromagnetic Fields and Hyperthermia Irreversibly Damage Cancer Cells.

At present, the applications and efficacy of non-ionizing radiations (NIR) in oncotherapy are limited. In terms of potential combinations, the use of biocompatible magnetic nanoparticles as heat mediators has been extensively investigated. Nevertheless, developing more efficient heat nanomediators that may exhibit high specific absorption rates is still an unsolved problem. Our aim was to investigate if externally applied magnetic fields and a heat-inducing NIR affect tumor cell viability. To this end, under in vitro conditions, different human cancer cells (A2058 melanoma, AsPC1 pancreas carcinoma, MDA-MB-231 breast carcinoma) were treated with the combination of electromagnetic fields (EMFs, using solenoids) and hyperthermia (HT, using a thermostated bath). The effect of NIR was also studied in combination with standard chemotherapy and targeted therapy. An experimental device combining EMFs and high-intensity focused ultrasounds (HIFU)-induced HT was tested in vivo. EMFs (25 µT, 4 h) or HT (52 °C, 40 min) showed a limited effect on cancer cell viability in vitro. However, their combination decreased viability to approximately 16%, 50%, and 21% of control values in A2058, AsPC1, and MDA-MB-231 cells, respectively. Increased lysosomal permeability, release of cathepsins into the cytosol, and mitochondria-dependent activation of cell death are the underlying mechanisms. Cancer cells could be completely eliminated by combining EMFs, HT, and standard chemotherapy or EMFs, HT, and anti-Hsp70-targeted therapy. As a proof of concept, in vivo experiments performed in AsPC1 xenografts showed that a combination of EMFs, HIFU-induced HT, standard chemotherapy, and a lysosomal permeabilizer induces a complete cancer regression.

Association between malocclusion and articulation of phonemes in early childhood.

OBJECTIVES: To evaluate the relationship between dental malocclusion and speech to understand the etiology of speech sound disorders (SSD) in schoolchildren and to make a correct diagnosis and treatment plan. MATERIALS AND METHODS: Articulation and dental occlusion, oromyofunctional evaluation with orofacial praxis and musculature, resting tongue position, and swallowing pattern were analyzed in 290 schoolchildren between the ages of 4 and 7 years. Statistical tests were considered significant for P < .05. RESULTS: A significant association between dental malocclusions (Angle Class II and III, anterior open bite, edge-to-edge bite, overjet and anterior crossbite) and phonetic alterations (P = .008) was observed. Sigmatisms and rhotacisms were the most frequent disorders. Malocclusions also showed a significant association with oral habits and with orofacial praxis and muscle activity. CONCLUSIONS: The presence of malocclusion can cause imbalances in the functions involved in the stomatognathic system. Awareness of this relationship in young children would help professionals to implement preventive measures for the optimum development of children's oral health.

N-Acetylcysteine Promotes Metastatic Spread of Melanoma in Mice.

N-acetylcysteine (NAC) is a direct Cys donor and a promoter of glutathione (GSH) synthesis. GSH regulates melanoma growth and NAC has been suggested to increase melanoma metastases in mice. We found that high therapeutic doses of NAC do not increase the growth of melanoma xenografts, but can cause metastatic spread and distant metastases. Nevertheless, this is not due to an antioxidant effect since NAC, in fact, increases the generation of reactive oxygen species in the growing metastatic melanoma. Trolox, an antioxidant vitamin E derivative, administered in vivo, decreased metastatic growth. Metastatic cells isolated from NAC-treated mice showed an increase in the nuclear translocation of Nrf2, as compared to controls. Nrf2, a master regulator of the antioxidant response, controls the expression of different antioxidant enzymes and of the γ-glutamylcysteine ligase (the rate-limiting step in GSH synthesis). Cystine uptake through the xCT cystine-glutamate antiporter (generating intracellular Cys) and the γ-glutamylcysteine ligase activity are key to control metastatic growth. This is associated to an increase in the utilization of L-Gln by the metastatic cells, another metastases promoter. Our results demonstrate the potential of NAC as an inducer of melanoma metastases spread, and suggest that caution should be taken when administering GSH promoters to cancer patients.