Estudio piloto para determinar la asociación entre la microbiota intestinal y la fractura de cadera por fragilidad / Pilot study to determine the association between gut microbiota and fragility hip fracture

Introducción: Las fracturas de cadera son la causa más frecuente de ingreso hospitalario en los servicios de ortopedia de Europa y suponen un importante problema sanitario. Por ello, es de gran interés identificar factores de riesgo adicionales que nos ayuden a comprender mejor la fisiopatología de estas fracturas y a mejorar nuestra capacidad preventiva. Existen datos suficientes para apoyar la teoría de la modulación de la masa ósea por la microbiota intestinal (osteomicrobiología); sin embargo, faltan estudios clínicos en humanos que relacionen directamente la microbiota con el riesgo de fractura de cadera. Material y métodos: Estudio observacional, analítico, de casos y controles. La muestra consta de 50 pacientes y se distribuye de la siguiente manera: 25 pacientes ancianos con fractura de cadera por fragilidad y 25 controles sanos sin fractura. Se analizó la microbiota intestinal mediante extracción de ADN de muestras de heces y secuenciación del ADN ribosómico 16S tras la generación de bibliotecas de genes. Resultados: La diversidad alfa reveló una elevación de los estimadores para el nivel taxonómico de clase en el grupo de fracturas de cadera. Los órdenes Bacteroidales, Oscillospirales, Lachnospirales, Peptostreptococcales-Tissierellales y Enterobacterales fueron los órdenes dominantes en ambos grupos. En los pacientes con fractura, se observó un aumento porcentual significativo del orden de Bacteroidales (p<0,001) y Peptostreptococcales-Tissierellales (p<0,005), así como una disminución de las del orden Lachnospirales (p<0,001) respecto a los controles. Conclusiones:Este estudio ha encontrado una asociación entre una microbiota específica en pacientes ancianos con fractura de cadera por fragilidad. Estos hallazgos abren la puerta a nuevas estrategias para prevenir las fracturas de cadera. Es posible que la modificación de la microbiota mediante probióticos se revele como un método eficaz para reducir el riesgo de fractura de cadera.(AU)

Introduction: Hip fractures are the most common cause of hospital admission to orthopaedic departments in Europe and they generate a major health problem. Therefore, it is of great interest to identify additional risk factors that will help us to better understand the pathophysiology of these fractures and improve our preventive capacity. There is sufficient data to support the theory of modulation of bone mass by gut microbiota (osteomicrobiology); however, there is a lack of human clinical studies directly linking microbiota to hip fracture risk. Material and methods: Observational, analytical, case–control study. The sample consisted of 50 patients and it was distributed as follows: 25 elderly patients with fragility hip fracture and 25 subjects without fracture. The intestinal microbiota was determined by DNA extraction from stool samples and 16S ribosomal DNA sequencing after generation of gene libraries. Results: Alpha diversity revealed an elevation of the estimators for the taxonomic class level in the hip fracture group. The orders Bacteroidales, Oscillospirales, Lachnospirales, Peptostreptococcales-Tissierellales and Enterobacterales were the dominant orders in both groups. In patients with fracture, a significant percentage increase in the orders Bacteroidales (p<.001) and Peptostreptococcales-Tissierellales (p<.005) was observed, as well as a decrease in the orders Lachnospirales (p<.001) compared to controls. Conclusions: This study has found an association between a specific microbiota in elderly patients with fragility hip fracture. These findings open the door to new strategies to prevent hip fractures. Modification of the microbiota through probiotics may prove to be an effective method to reduce the risk of hip fracture.(AU)

[Translated article] Pilot study to determine the association between gut microbiota and fragility hip fracture / Estudio piloto para determinar la asociación entre la microbiota intestinal y la fractura de cadera por fragilidad

Introducción: Las fracturas de cadera son la causa más frecuente de ingreso hospitalario en los servicios de ortopedia de Europa y suponen un importante problema sanitario. Por ello, es de gran interés identificar factores de riesgo adicionales que nos ayuden a comprender mejor la fisiopatología de estas fracturas y a mejorar nuestra capacidad preventiva. Existen datos suficientes para apoyar la teoría de la modulación de la masa ósea por la microbiota intestinal (osteomicrobiología); sin embargo, faltan estudios clínicos en humanos que relacionen directamente la microbiota con el riesgo de fractura de cadera. Material y métodos: Estudio observacional, analítico, de casos y controles. La muestra consta de 50 pacientes y se distribuye de la siguiente manera: 25 pacientes ancianos con fractura de cadera por fragilidad y 25 controles sanos sin fractura. Se analizó la microbiota intestinal mediante extracción de ADN de muestras de heces y secuenciación del ADN ribosómico 16S tras la generación de bibliotecas de genes. Resultados: La diversidad alfa reveló una elevación de los estimadores para el nivel taxonómico de clase en el grupo de fracturas de cadera. Los órdenes Bacteroidales, Oscillospirales, Lachnospirales, Peptostreptococcales-Tissierellales y Enterobacterales fueron los órdenes dominantes en ambos grupos. En los pacientes con fractura, se observó un aumento porcentual significativo del orden de Bacteroidales (p<0,001) y Peptostreptococcales-Tissierellales (p<0,005), así como una disminución de las del orden Lachnospirales (p<0,001) respecto a los controles. Conclusiones:Este estudio ha encontrado una asociación entre una microbiota específica en pacientes ancianos con fractura de cadera por fragilidad. Estos hallazgos abren la puerta a nuevas estrategias para prevenir las fracturas de cadera. Es posible que la modificación de la microbiota mediante probióticos se revele como un método eficaz para reducir el riesgo de fractura de cadera.(AU)

Introduction: Hip fractures are the most common cause of hospital admission to orthopaedic departments in Europe and they generate a major health problem. Therefore, it is of great interest to identify additional risk factors that will help us to better understand the pathophysiology of these fractures and improve our preventive capacity. There is sufficient data to support the theory of modulation of bone mass by gut microbiota (osteomicrobiology); however, there is a lack of human clinical studies directly linking microbiota to hip fracture risk. Material and methods: Observational, analytical, case–control study. The sample consisted of 50 patients and it was distributed as follows: 25 elderly patients with fragility hip fracture and 25 subjects without fracture. The intestinal microbiota was determined by DNA extraction from stool samples and 16S ribosomal DNA sequencing after generation of gene libraries. Results: Alpha diversity revealed an elevation of the estimators for the taxonomic class level in the hip fracture group. The orders Bacteroidales, Oscillospirales, Lachnospirales, Peptostreptococcales-Tissierellales and Enterobacterales were the dominant orders in both groups. In patients with fracture, a significant percentage increase in the orders Bacteroidales (p<.001) and Peptostreptococcales-Tissierellales (p<.005) was observed, as well as a decrease in the orders Lachnospirales (p<.001) compared to controls. Conclusions: This study has found an association between a specific microbiota in elderly patients with fragility hip fracture. These findings open the door to new strategies to prevent hip fractures. Modification of the microbiota through probiotics may prove to be an effective method to reduce the risk of hip fracture.(AU)

[Translated article] Pilot study to determine the association between gut microbiota and fragility hip fracture.

INTRODUCTION: Hip fractures are the most common cause of hospital admission to orthopaedic departments in Europe and they generate a major health problem. Therefore, it is of great interest to identify additional risk factors that will help us to better understand the pathophysiology of these fractures and improve our preventive capacity. There is sufficient data to support the theory of modulation of bone mass by gut microbiota (osteomicrobiology); however, there is a lack of human clinical studies directly linking microbiota to hip fracture risk. MATERIAL AND METHODS: Observational, analytical, case-control study. The sample consisted of 50 patients and it was distributed as follows: 25 elderly patients with fragility hip fracture and 25 subjects without fracture. The intestinal microbiota was determined by DNA extraction from stool samples and 16S ribosomal DNA sequencing after generation of gene libraries. RESULTS: Alpha diversity revealed an elevation of the estimators for the taxonomic class level in the hip fracture group. The orders Bacteroidales, Oscillospirales, Lachnospirales, Peptostreptococcales-Tissierellales and Enterobacterales were the dominant orders in both groups. In patients with fracture, a significant percentage increase in the orders Bacteroidales (p<.001) and Peptostreptococcales-Tissierellales (p<.005) was observed, as well as a decrease in the orders Lachnospirales (p<.001) compared to controls. CONCLUSIONS: This study has found an association between a specific microbiota in elderly patients with fragility hip fracture. These findings open the door to new strategies to prevent hip fractures. Modification of the microbiota through probiotics may prove to be an effective method to reduce the risk of hip fracture.

Pilot study to determine the association between gut microbiota and fragility hip fracture. / Estudio piloto para determinar la asociación entre la microbiota intestinal y la fractura de cadera por fragilidad.

INTRODUCTION: Hip fractures are the most common cause of hospital admission to orthopaedic departments in Europe and they generate a major health problem. Therefore, it is of great interest to identify additional risk factors that will help us to better understand the pathophysiology of these fractures and improve our preventive capacity. There is sufficient data to support the theory of modulation of bone mass by gut microbiota (osteomicrobiology); however, there is a lack of human clinical studies directly linking microbiota to hip fracture risk. MATERIAL AND METHODS: Observational, analytical, case-control study. The sample consisted of 50 patients and it was distributed as follows: 25 elderly patients with fragility hip fracture and 25 subjects without fracture. The intestinal microbiota was determined by DNA extraction from stool samples and 16S ribosomal DNA sequencing after generation of gene libraries. RESULTS: Alpha diversity revealed an elevation of the estimators for the taxonomic class level in the hip fracture group. The orders Bacteroidales, Oscillospirales, Lachnospirales, Peptostreptococcales-Tissierellales and Enterobacterales were the dominant orders in both groups. In patients with fracture, a significant percentage increase in the orders Bacteroidales (p<.001) and Peptostreptococcales-Tissierellales (p<.005) was observed, as well as a decrease in the orders Lachnospirales (p<.001) compared to controls. CONCLUSIONS: This study has found an association between a specific microbiota in elderly patients with fragility hip fracture. These findings open the door to new strategies to prevent hip fractures. Modification of the microbiota through probiotics may prove to be an effective method to reduce the risk of hip fracture.

Redox modulation of muscle mass and function.

Muscle mass and strength are very important for exercise performance. Training-induced musculoskeletal injuries usually require periods of complete immobilization to prevent any muscle contraction of the affected muscle groups. Disuse muscle wasting will likely affect every sport practitioner in his or her lifetime. Even short periods of disuse results in significant declines in muscle size, fiber cross sectional area, and strength. To understand the molecular signaling pathways involved in disuse muscle atrophy is of the utmost importance to develop more effective countermeasures in sport science research. We have divided our review in four different sections. In the first one we discuss the molecular mechanisms involved in muscle atrophy including the main protein synthesis and protein breakdown signaling pathways. In the second section of the review we deal with the main cellular, animal, and human atrophy models. The sources of reactive oxygen species in disuse muscle atrophy and the mechanism through which they regulate protein synthesis and proteolysis are reviewed in the third section of this review. The last section is devoted to the potential interventions to prevent muscle disuse atrophy with especial consideration to studies on which the levels of endogenous antioxidants enzymes or dietary antioxidants have been tested.

Reversal of age-associated frailty by controlled physical exercise: The pre-clinical and clinical evidences.

Demographic aging is one of the most serious challenges facing our society. Although we live longer, we do not live better because it is considered that approximately 16-20% of our life is spent in late-life morbidity. Older people have the greatest risk of developing frailty increasing the risk of presenting various adverse health events such as low quality of life, disability, hospitalization and even death. Frail men and women over 65 years old have lower muscle quality and muscle mass and higher percentage of body fat than non-frail people of the same age. In this review we will address the main physiological changes in the muscular and nervous system associated to aging. More specifically we will review the changes in muscle mass, quality, and strength relating them with the decrease in capillarization and muscular oxidative capacity as well as with the alterations in protein synthesis in the muscle with aging. The last section of the manuscript will be devoted to the animal models of frailty and the indexes developed to measure frailty in these models. We will finally address the importance of exercise training as an intervention to delay or even reverse frailty.

Sarcopenia, frailty and their prevention by exercise.

Sarcopenia is a major component of the frailty syndrome, both being considered as strong predictors of morbidity, disability, and death in older people. In this review, we explore the definitions of sarcopenia and frailty and summarize the current knowledge on their relationship with oxidative stress and the possible therapeutic interventions to prevent or treat them, including exercise-based interventions and multimodal strategies. We highlight the relevance of the impairment of the nervous system and of the anabolic response (protein synthesis) in muscle aging leading to frailty and sarcopenia. We also discuss the importance of malnutrition and physical inactivity in these geriatric syndromes. Finally, we propose multimodal interventions, including exercise programs and nutritional supplementation, as the strategies to prevent and treat both sarcopenia and frailty.

Active paraplegics are protected against exercise-induced oxidative damage through the induction of antioxidant enzymes.

STUDY DESIGN: Experimental study. OBJECTIVES: Exercise improves functional capacity in spinal cord injury (SCI). However, exhaustive exercise, especially when sporadic, is linked to the production of reactive oxygen species that may have a detrimental effect on SCI. We aimed to study the effect of a single bout of exhaustive exercise on systemic oxidative stress parameters and on the expression of antioxidant enzymes in individuals with paraplegia. SETTING: The study was conducted in the Physical Therapy department and the Physical Education and Sports department of the University of Valencia. METHODS: Sixteen paraplegic subjects were submitted to a graded exercise test (GET) until volitional exhaustion. They were divided into active or non-active groups. Blood samples were drawn immediately, 1 and 2 h after the GET. We determined plasma malondialdehyde (MDA) and protein carbonylation as markers of oxidative damage. Antioxidant gene expression (catalase and glutathione peroxidase-GPx) was determined in peripheral blood mononuclear cells. RESULTS: We found a significant increase in plasma MDA and protein carbonyls immediately after the GET (P<0.05). This increment correlated significantly with the lactate levels. Active paraplegics showed lower levels of exercise-induced oxidative damage (P<0.05) and higher exercise-induced catalase (P<0.01) and GPx (P<0.05) gene expression after the GET. CONCLUSIONS: These results suggest that exercise training may be useful in SCI patients to develop systemic antioxidant defenses that may protect them against exercise-induced oxidative damage.

Properties of Resveratrol: In Vitro and In Vivo Studies about Metabolism, Bioavailability, and Biological Effects in Animal Models and Humans.

Plants containing resveratrol have been used effectively in traditional medicine for over 2000 years. It can be found in some plants, fruits, and derivatives, such as red wine. Therefore, it can be administered by either consuming these natural products or intaking nutraceutical pills. Resveratrol exhibits a wide range of beneficial properties, and this may be due to its molecular structure, which endow resveratrol with the ability to bind to many biomolecules. Among these properties its activity as an anticancer agent, a platelet antiaggregation agent, and an antioxidant, as well as its antiaging, antifrailty, anti-inflammatory, antiallergenic, and so forth activities, is worth highlighting. These beneficial biological properties have been extensively studied in humans and animal models, both in vitro and in vivo. The issue of bioavailability of resveratrol is of paramount importance and is determined by its rapid elimination and the fact that its absorption is highly effective, but the first hepatic step leaves little free resveratrol. Clarifying aspects like stability and pharmacokinetics of resveratrol metabolites would be fundamental to understand and apply the therapeutic properties of resveratrol.

Allopurinol prevents cardiac and skeletal muscle damage in professional soccer players.

Xanthine oxidase (XO), a free radical-generating enzyme, is involved in tissue damage produced during exhaustive exercise. Our aim was to test whether allopurinol, a powerful inhibitor of XO, may be effective in preventing exercise-induced tissue damage in soccer players. Twelve soccer players were randomized into two experimental groups. One received allopurinol, before a match of the premier Spanish Football League, and the other placebo. Allopurinol prevented the exercise-induced increase in all the markers of skeletal muscle damage analyzed: creatine kinase, lactate dehydrogenase, aspartate aminotransferase, and myoglobin. Creatine kinase-MB isoenzyme and highly sensitive troponin T, specific biomarkers of myocardial injury, increased significantly in the placebo but not in the allopurinol-treated group after the football match. We also found that the exercise-induced lipid peroxidation, as reflected by malondialdehyde measurements, was prevented after allopurinol administration. However, inhibition of XO did not prevent the increment in the activity of alanine aminotransferase found after the match. No changes in the serum gamma glutamyltransferase activity was found after the match on either the placebo and the allopurinol groups. These two enzymes were determined as biomarkers of liver injury. Allopurinol represents an effective and inexpensive pharmacological agent to prevent tissue damage in soccer players.

Growth hormone replacement therapy prevents sarcopenia by a dual mechanism: improvement of protein balance and of antioxidant defenses.

The aim of our study was to elucidate the role of growth hormone (GH) replacement therapy in three of the main mechanisms involved in sarcopenia: alterations in mitochondrial biogenesis, increase in oxidative stress, and alterations in protein balance. We used young and old Wistar rats that received either placebo or low doses of GH to reach normal insulin-like growth factor-1 values observed in the young group. We found an increase in lean body mass and plasma and hepatic insulin-like growth factor-1 levels in the old animals treated with GH. We also found a lowering of age-associated oxidative damage and an induction of antioxidant enzymes in the skeletal muscle of the treated animals. GH replacement therapy resulted in an increase in the skeletal muscle protein synthesis and mitochondrial biogenesis pathways. This was paralleled by a lowering of inhibitory factors in skeletal muscle regeneration and in protein degradation. GH replacement therapy prevents sarcopenia by acting as a double-edged sword, antioxidant and hypertrophic.

Impact of exercise training on neuroplasticity-related growth factors in adolescents.

OBJECTIVES: We aimed to determine the effect of exercise training on plasma levels of brain-derived neurotrophic factor (BDNF), and serum insulin-like growth factor-1 (IGF-1) as well as cAMP response element-binding (CREB) activation in peripheral blood mononuclear cells (PBMCs) in adolescents. METHODS: Nine trained and seven sedentary male adolescents, matched in age (14.0±2.2 years), were recruited for the study. Trained boys performed higher physical activity levels (expressed both as total energy expenditure and as physical activity energy expenditure) and showed significant bradycardia when compared with sedentary ones. RESULTS: We found that BDNF and IGF-1 levels were significantly higher in trained adolescents than in sedentary ones. However, no effect of training was found in the activation of CREB in PBMCs. CONCLUSIONS: We demonstrated the increase of neuroplasticity-related proteins due to exercise training in adolescents. Our results emphasize the significance and impact of exercise in this developmental period.

Epigenetic biomarkers: A new perspective in laboratory diagnostics.

Epigenetics comprises the study of chemical modifications in the DNA and histones that regulates the gene expression or cellular phenotype. However, during the last decade this term has evolved after the elucidation of different mechanisms (microRNAs and nuclear organization of the chromosomes) involved in regulating gene expression. Epigenetics and the new designed technologies capable to analyze epigenetic changes (e.g., methylated DNA, miRNAs expression, post-translational modifications on histones among others) have disclosed an appealing scenario that will offer for the biomedical sciences new biomarkers for the study of neurodegenerative diseases, multifactorial complex diseases, rare diseases and cancer. Moreover, new technologies adapted for epigenetic studies will offer promising applications that in the next years will be common technologies in clinical laboratories. In this review we discuss epigenetic modifications used as possible biomarkers in several diseases. We also present the potential of methodologies to purify histones, and high throughput technologies as candidates to be set in clinical laboratories for their high potential analyzing epigenetic processes.

Exercise acts as a drug; the pharmacological benefits of exercise.

The beneficial effects of regular exercise for the promotion of health and cure of diseases have been clearly shown. In this review, we would like to postulate the idea that exercise can be considered as a drug. Exercise causes a myriad of beneficial effects for health, including the promotion of health and lifespan, and these are reviewed in the first section of this paper. Then we deal with the dosing of exercise. As with many drugs, dosing is extremely important to get the beneficial effects of exercise. To this end, the organism adapts to exercise. We review the molecular signalling pathways involved in these adaptations because understanding them is of great importance to be able to prescribe exercise in an appropriate manner. Special attention must be paid to the psychological effects of exercise. These are so powerful that we would like to propose that exercise may be considered as a psychoactive drug. In moderate doses, it causes very pronounced relaxing effects on the majority of the population, but some persons may even become addicted to exercise. Finally, there may be some contraindications to exercise that arise when people are severely ill, and these are described in the final section of the review. Our general conclusion is that exercise is so effective that it should be considered as a drug, but that more attention should be paid to the dosing and to individual variations between patients.

Valoración nutricional en escolares y adolescentes ciclistas de competición. Recomendaciones dietéticas para el niño deportista / Nutritional assessment of school age children and adolescents who are high-level cycling competitors. Dietetics recommendations for the athletic child

Introducción: La promoción del deporte en la infancia es primordial para inculcar hábitos saludables y prevenir enfermedades futuras. La nutrición es un factor principal para asegurar el éxito de la práctica deportiva. Objetivos: Realizar una valoración nutricional a partir de la comparación de una muestra de niños deportistas de competición y controles. Pacientes y métodos: Se han incluido 28 ciclistas y 12 controles de 10-15 años de edad. Se calcularon los z-score del peso, la talla, el perímetro braquial, los pliegues subescapular y tricipital y el índice de masa corporal (IMC). En los deportistas la valoración se repitió en dos tiempos (al inicio y al final de la temporada). Se realizó una encuesta de conocimientos nutricionales y análisis dietético de 3 días, y se cuantificaron las calorías, las vitaminas A, D, E y C, el hierro, el calcio, el cinc y la fibra. Resultados: El análisis antropométrico puso de manifiesto que ambos grupos estaban normonutridos, con diferencias en el IMC en los deportistas entre el inicio y el final de la temporada (p <0,05). El análisis dietético mostró que los deportistas no alcanzaban sus requerimientos energéticos, y que el grupo control los sobrepasaba. En ambos grupos la ingesta de hidratos de carbono, vitaminas D y E y fibra fue inferior a las recomendaciones, la de calcio próxima a las recomendaciones, y elevadas las de proteínas, grasas, hierro, cinc y vitaminas A y C. La encuesta sobre conocimientos nutricionales reveló una educación nutricional deficiente. Conclusiones: Los hábitos dietéticos de los niños deportistas deben vigilarse, de modo que puedan desarrollar la práctica deportiva sin comprometer su crecimiento y desarrollo. Es necesario promover la educación nutricional en los ámbitos escolar y deportivo(AU)

Introduction: Promoting sports in childhood is important as a means of instilling healthy habits and prevent future illnesses. Nutrition is an important factor to consider in order of being successful in sports. Objectives: To do a nutritional assessment in a group comparing children who do sports of high competition and controls. Patients and Methods: Twenty eight cyclists have been included and twelve appropriate controls where done in children between the ages of 10 and 15. The Z-scores of weight, height, brachial perimeter (BP), subscapular and triceps skinfold thickness and body mass index were calculated. In the group of athletic children, these measures were collected twice, at the beginning and at the end of the season. A survey about nutritional knowledge and a dietary evaluation were performed, focusing on total energy intake, macronutrient distribution and intake of vitamin A, D, E and C, iron, calcium, zinc and dietary fiber. Results: Both groups had normal nutritional status according to the anthropometric analysis, with statistically differences in BMI between the beginning and end of the season in the group of cyclist (p <0.05). The dietetic analysis showed that the energy requirements were not met by athletic children and they were exceeded in the control group. In both groups, the intake of carbohydrates, vitamins D and E and dietary fiber were below the recommendations; calcium intake was near the recomendations, and vitamin C and A, fat, proteins, iron and zinc intake was higher. The survey about nutritional knowledge demonstrated a nutritional deficiency education. Conclusions: Athletic children’s nutritional habits require special supervision in order to be able to train without compromising their growth and development. Nutritional education should be promoted at school and in competition sports(AU)

Increased average longevity among the "Tour de France" cyclists.

It is widely held among the general population and even among health professionals that moderate exercise is a healthy practice but long term high intensity exercise is not. The specific amount of physical activity necessary for good health remains unclear. To date, longevity studies of elite athletes have been relatively sparse and the results are somewhat conflicting. The Tour de France is among the most gruelling sport events in the world, during which highly trained professional cyclists undertake high intensity exercise for a full 3 weeks. Consequently we set out to determine the longevity of the participants in the Tour de France, compared with that of the general population. We studied the longevity of 834 cyclists from France (n=465), Italy (n=196) and Belgium (n=173) who rode the Tour de France between the years 1930 and 1964. Dates of birth and death of the cyclists were obtained on December 31 (st) 2007. We calculated the percentage of survivors for each age and compared them with the values for the pooled general population of France, Italy and Belgium for the appropriate age cohorts. We found a very significant increase in average longevity (17%) of the cyclists when compared with the general population. The age at which 50% of the general population died was 73.5 vs. 81.5 years in Tour de France participants. Our major finding is that repeated very intense exercise prolongs life span in well trained practitioners. Our findings underpin the importance of exercising without the fear that becoming exhausted might be bad for one's health.