High Fat Diet Exaggerate Metabolic and Reproductive PCOS Features by Promoting Oxidative Stress: An Improved EV Model in Rats.

Background and Objectives: Polycystic ovary syndrome (PCOS) is a frequent multifactorial endocrinopathy affecting women in the reproductive period, often associated with infertility and metabolic disorders. The use of animal models helps to better understand etiopathogenesis, enabling the examination of the effects of certain drugs in order to discover the best possible therapeutic approach. We tried to investigate the additional effect of estradiol-valerate (EV) and high-fat diet (HFD) in female rats to explore PCOS-related alterations with special focus on oxidative stress. Materials and Methods: Animals were divided into three groups: control group (CTRL, n = 6), estradiol-valerate group (EV, n = 6), and estradiol-valerate group on HFD (EV + HFD, n = 6). PCOS was induced by single subcutaneous injection of long-acting EV in a dose of 4 mg/per rat. We tried to improve the metabolic characteristics of the PCOS animal model by adding HFD, so the CTRL and EV group had a regular diet, while the EV + HFD group had HFD during the induction period of 60 days. Results: We observed alterations of anthropometric parameters and hormonal disturbances, along with estrus cycle impairment reassembly to obese-type PCOS phenotype. Moreover, glucose metabolism was impaired after addition of HFD to EV protocol, contrary to EV administered alone. Histological analysis confirmed more numerous cystic follicles after the combination of EV and HFD protocol. The alterations of oxidative stress markers could be related to and serve as the mechanistic base for development of PCOS-related endocrine, reproductive, and metabolic properties. Conclusions: The additive effect of EV and HFD was obvious in the majority of the parameters observed. Our study strongly demonstrated metabolic as well as reproductive properties of PCOS in rats.

Dietary supplementation of ß-hydroxy-ß-methylbutyrate in animals - a review.

The leucine metabolite ß-hydroxy-ß-methylbutyrate (HMB) has been studied by many researchers over the last two decades. In particular, the utility of HMB supplementation in animals has been shown in numerous studies, which have demonstrated enhanced body weight gain and carcass yield in slaughter animals; positive immunostimulatory effect; decreased mortality; attenuation of sarcopenia in elderly animals; and potential use in pathological conditions such as glucocorticoid-induced muscle loss. The aim of this study was to summarize the body of research on HMB supplementation in animals and to examine possible mechanisms of HMB action. Furthermore, while the safety of HMB supplementation in animals is well documented, studies demonstrating efficacy are less clear. The possible reasons for differences in these findings will also be examined.

Effect of HMB supplementation on body composition, fitness, hormonal profile and muscle damage indices.

There is a huge market for ergogenic supplements for athletes. However, only a few products have been proven to have ergogenic effects and to be effective at improving muscle strength and body composition. One such supplement is beta-hydroxy beta-methylbutyrate (HMB). Derived from the amino acid leucine and its keto acid alpha-ketoisocaproate (KIC), HMB has been well documented as an oral ergogenic supplement commonly used by athletes. Several studies have shown that combining exercise training with HMB supplementation leads to increased muscle mass and strength, and there is some anecdotal evidence of aerobic improvement. However, HMB supplementation has been found to be effective mainly for untrained individuals. While previous reviews have emphasized three main pathways for HMB's mode of action: 1) enhancement of sarcolemmal integrity via cytosolic cholesterol, 2) inhibition of protein degradation via proteasomes, and 3) increased protein synthesis via the mTOR pathway, more recent studies have suggested additional possible mechanisms for its physiological effects. These include decreased cell apoptosis and enhanced cell survival, increased proliferation, differentiation and fusion via the MAPK/ERK and PI3K/Akt pathways, and enhanced IGF-I transcription. These are described here, and hormonal interactions are discussed, along with HMB dosage and safety issues.

A prospective trial to evaluate treatment effects of a ß-hydroxy-ß-methylbutyrate containing nutrient for leakage at the anastomotic site after esophagectomy.

Anastomotic leakage after esophagectomy is associated with prolonged hospitalization and increased medical cost. Additionally, it sometimes leads to a fatal condition and impaired postoperative quality of life. During the process of wound healing, ß-hydroxy-ß-methylbutyrate (HMB) is important for collagen biosynthesis. An open-label prospective intervention trial has been designed to evaluate the treatment effect of an enteral nutrient containing HMB with arginine and glutamine (Abound, Abbott Japan Co., Ltd.) for leakage at the anastomotic site after esophagectomy. Patients in whom leakage at the anastomotic site developed within 14 days after esophagectomy are eligible and Abound (24 g) is administered for 14 days through an enteral feeding tube. The target sample size is 10. The primary endpoint is duration between diagnosis and cure of leakage. Surgical procedure, safety, length of fasting, drainage placement and hospital stay, and nutritional status are determined as secondary endpoints. A historical control consisting of 20 patients who had leakage at the anastomotic site after esophagectomy between 2005 and 2018 at Nagoya University Hospital is compared with enrolled patients.

Oxidative and inflammatory effects of pulmonary rehabilitation in patients with bronchiectasis. A prospective, randomized study.

INTRODUCTION: Background: systemic inflammation and oxidative stress are important factors in the pathogenesis of bronchiectasis. Pulmonary rehabilitation (PR) is recommended for bronchiectasis, but there is no data about its effect on the inflammatory and REDOX status of these patients. Aims: to investigate the effect of PR in non-cystic-fibrosis bronchiectasis (NCFB) patients, and to compare it with the effect of PR plus a hyperproteic oral nutritional supplement (PRS) enriched with beta-hydroxy-beta-methylbutyrate (HMB) on serum inflammatory and oxidative biomarkers. Materials and methods: this was an open randomized, controlled trial. Thirty individuals (65 years old or younger with a body mass index over 18.5, older than 65 years with a body mass index over 20) were recruited from September 2013 to September 2014, and randomly assigned to receive PR or PRS. Total neutrophils, and inflammatory and oxidative biomarker levels were measured at baseline, and then at 3 and 6 months. Results: in the PRS group neutrophil levels were decreased from baseline at 6 months. A significantly different fold change was found between the PR and PRS groups. In the PR group, IL-6 and adiponectin were increased by the end of the study while TNFα levels were decreased from baseline at 6 months. REDOX biomarkers remained stable throughout the study except for 8-isoprostane levels, which were increased from baseline at 6 months in both groups of patients. Conclusions: a PR program induced a pro-oxidative effect accompanied by changes in circulating inflammatory cytokine levels in NCFB patients. Our results would also suggest a possible beneficial effect of the HMB enriched supplement on neutrophil level regulation in these patients. The information provided in this study could be useful for choosing the right therapeutic approach in the management of bronchiectasis.

INTRODUCCIÓN: Introducción: la inflamación sistémica y el estrés oxidativo son factores importantes en la patogénesis de la bronquiectasia. La rehabilitación pulmonar (PR) está recomendada en los sujetos con bronquiectasias, pero no hay datos sobre sus posibles efectos sobre el estado inflamatorio y REDOX de estos pacientes. Objetivos: investigar el efecto de la PR en pacientes con bronquiectasias no asociadas a fibrosis quística (NCFB) sobre los biomarcadores oxidativos e inflamatorios, y compararlo con los efectos de la PR junto con la suplementación oral de un suplemento hiperproteico (PRS) enriquecido con beta-hidroxi-beta-metilbutirato (HMB). Material y métodos: ensayo clínico abierto, aleatorizado y controlado. Treinta pacientes (de 65 años o menos con un índice de masa corporal por encima de 18,5, y mayores de 65 años con un índice de masa corporal de más de 20) se aleatorizaron para recibir PR o PRS. Los niveles circulantes de neutrófilos totales y los de biomarcadores de estado inflamatorio y oxidativo se determinaron al inicio del estudio y a los 3 y 6 meses. Resultados: los niveles de neutrófilos en el grupo de PRS se redujeron desde el inicio a los 6 meses, presentando una tasa de cambio significativamente diferente según el tratamiento. En el grupo de PR, la IL-6 y la adiponectina aumentaron al final del estudio, mientras que los niveles de TNFα disminuyeron desde el inicio a los 6 meses. Los biomarcadores de estrés oxidativo se mantuvieron estables durante todo el estudio excepto por los niveles de 8-isoprostano, que aumentaron desde el inicio a los 6 meses en ambos grupos de pacientes. Conclusión: el programa de PR indujo un efecto pro-oxidativo acompañado de cambios en los niveles de citoquinas inflamatorias circulantes en pacientes con NCFB. Nuestros resultados también sugieren un posible efecto beneficioso del suplemento nutricional sobre la regulación de los niveles de neutrófilos de estos pacientes.

Year-long changes in protein metabolism in elderly men and women supplemented with a nutrition cocktail of beta-hydroxy-beta-methylbutyrate (HMB), L-arginine, and L-lysine.

BACKGROUND: A major contributing factor to the loss of mobility in elderly people is the gradual and continuous loss of lean body mass. OBJECTIVES: To determine whether supplementation of an amino acid cocktail daily for 1 year could improve the age-associated changes in protein turnover and lean body mass in elderly people. DESIGN: Elderly (76+/-1.6 years) women (n=39) and men (n=38) were recruited for a double-blinded controlled study. Study participants were randomly assigned to either an isonitrogenous control-supplement (n=37) or a treatment-supplement (HMB/Arg/Lys) consisting of beta-hydroxy-beta-methylbutyrate, L-arginine, and L-lysine (n=40) for the 1-year study. Lean tissue mass was measured using both bioelectrical-impedance analysis (BIA) and dual energy x-ray absorptiometry (DXA). Rates of whole-body protein turnover were estimated using primed/intermittent oral doses of 15N-glycine. RESULTS: In subjects taking the HMB/Arg/Lys supplement, lean tissue increased over the year of study while in the control group, lean tissue did not change. Compared with control, HMB/Arg/Lys increased body cell mass (BIA) by 1.6% (P=.002) and lean mass (DXA) by 1.2% (P=.05). The rates of protein turnover were significantly increased 8% and 12% in the HMB/Arg/Lys-supplemented group while rates of protein turnover decreased 11% and 9% in the control-supplemented subjects (P<.01), at 3 and 12 months, respectively. CONCLUSIONS: Consumption of a simple amino acid-related cocktail increased protein turnover and lean tissue in elderly individuals in a year-long study.

Cost-Effectiveness of a Specialized Oral Nutritional Supplementation for Malnourished Older Adult Patients in Spain.

Malnutrition has been related to prolonged hospital stays, and to increases in readmission and mortality rates. In the NOURISH (Nutrition effect On Unplanned Readmissions and Survival in Hospitalized patients) study, administering a high protein oral nutritional supplement (ONS) containing beta-hydroxy-beta-methylbutyrate (HP-HMB) to hospitalised older adult patients led to a significant improvement in survival compared with a placebo treatment. The aim of this study was to determine whether HP-HMB would be cost-effective in Spain. We performed a cost-effectiveness analysis from the perspective of the Spanish National Health System using time horizons of 90 days, 180 days, 1 year, 2 years, 5 years and lifetime. The difference in cost between patients treated with HP-HMB and placebo was €332.75. With the 90 days time horizon, the difference in life years gained (LYG) between both groups was 0.0096, resulting in an incremental cost-effectiveness ratio (ICER) of €34,700.62/LYG. With time horizons of 180 days, 1 year, 2 years, 5 years and lifetime, the respective ICERs were €13,711.68, €3377.96, €2253.32, €1127.34 and €563.84/LYG. This analysis suggests that administering HP-HMB to older adult patients admitted to Spanish hospitals during hospitalisation and after discharge could be a cost-effective intervention that would improve survival with a reduced marginal cost.

Proteins and amino acid supplementation in sports: are they truly necessary?

Although dietary protein supplementation is commonly used by both athletes and people engaged in recreational sports, the data supporting its wide use are still limited. Some evidence supports the use of creatine and possibly HMB as ergogenic aids in specific situations [8], however this is also based on limited data. The use of supplements for the healthy, non-competitive adult engaged in recreational sports is usually not warranted.

Light and electron microscopy of liver in hyperlipoproteinemic patients under long-term gemfibrozil treatment.

The effects of long-term gemfibrozil (Lopid) therapy on human liver structure are not known. Studies of this nature are becoming essential in determining the risk/benefit ratio since gemfibrozil is an effective agent for the control of hyperlipoproteinemia types IIa, IIb, and IV. Particularly, gemfibrozil is effective when dietary management or available therapeutic control fail to reduce serum cholesterol and triglycerides as well as normalizing the lipoprotein pattern. Percutaneous liver biopsies of 9 patients on long-term gemfibrozil therapy were evaluated by light microscopy, interference contrast optics and transmission electron microscopy. The distribution of patients according to lipoprotein phenotype was 3 Type IIa, 3 Type IIb, and 3 Type IV. Their lipoprotein patterns approached normal and the serum lipids were controlled during gemfibrozil therapy. By light microscopy, the lobular architecture and other parameters were within normal limits. Varying degrees of fatty change were found as would be expected. No preferential lobular disposition of the fat globules was evident. Coalescence of fat droplets, nuclear displacement and fatty cysts were noted. Differential interference contrast microscopy revealed several degrees of contrast amplitude in these droplets suggesting a heterogeneous lipid deposition in hepatocytes. The subcellular analysis revealed a moderate degree of glycogen deposition, absence of nuclear abnormalities and unremarkable mitochondria; the rough endoplasmic reticulum was not significantly altered and smooth surfaced membranes appeared proliferated. Detailed analysis of the peroxisome population showed matrix rarefaction, marginal plate formation and spurious densities though no significant proliferation occurred. Distribution of peroxisomes in hepatocytes varied widely from cell to cell and in different lobular areas. This study confirmed the association of hepatic fatty change with hyperlipoproteinemia irrespective of the pattern observed in circulating lipoproteins. Peroxisome proliferation, as seen in rodents when receiving gemfibrozil, did not occur and the structure of these subcellular organelles was not compromised. It was concluded that the long-term administration of this compound did not show adverse effects on the hepatocyte in hyperlipoproteinemia.

Effect of ß-hydroxy-ß-methylbutyrate (HMB) on lean body mass during 10 days of bed rest in older adults.

BACKGROUND: Loss of muscle mass due to prolonged bed rest decreases functional capacity and increases hospital morbidity and mortality in older adults. OBJECTIVE: To determine if HMB, a leucine metabolite, is capable of attenuating muscle decline in healthy older adults during complete bed rest. DESIGN: A randomized, controlled, double-blinded, parallel-group design study was carried out in 24 healthy (SPPB ≥ 9) older adult subjects (20 women, 4 men), confined to complete bed rest for ten days, followed by resistance training rehabilitation for eight weeks. Subjects in the experimental group were treated with HMB (calcium salt, 1.5 g twice daily - total 3 g/day). Control subjects were treated with an inactive placebo powder. Treatments were provided starting 5 days prior to bed rest till the end rehabilitation phase. DXA was used to measure body composition. RESULTS: Nineteen eligible older adults (BMI: 21-33; age: 60-76 year) were evaluable at the end of the bed rest period (Control n = 8; Ca-HMB n = 11). Bed rest caused a significant decrease in total lean body mass (LBM) (2.05 ± 0.66 kg; p = 0.02, paired t-test) in the Control group. With the exclusion of one subject, treatment with HMB prevented the decline in LBM over bed rest -0.17 ± 0.19 kg; p = 0.23, paired t-test). There was a statistically significant difference between treatment groups for change in LBM over bed rest (p = 0.02, ANOVA). Sub-analysis on female subjects (Control = 7, HMB = 8) also revealed a significant difference in change in LBM over bed rest between treatment groups (p = 0.04, ANOVA). However, differences in function parameters could not be observed, probably due to the sample size of the study. CONCLUSIONS: In healthy older adults, HMB supplementation preserves muscle mass during 10 days of bed rest. These results need to be confirmed in a larger trial.

Supplements and the endocrine system in athletes.

In the world of athletes' nutrition, there are many ethical concerns, because there is the suspicion that in practice, large doses of supplements in athletes are not taken for nutritional purposes. It is beyond the scope of this article to highlight the possible roles of supplements or methods of supplementation in the improvement of athletic performance in elite athletes. Instead, the author briefly reviews some of the substances taken by athletes, with particular attention to their mechanisms of action and the pathways involved. Very often, the effects of many supplements are hormone-related, or supplements influence hormone secretion. Examples of possible links between "supplements or ergogenic compounds" and the endocrine/metabolic system are addressed.

[Problems posed by the therapeutic combination of phenobarbital and sodium dipropylacetate. Apropos of a case]. / Problèmes posés par l'association thérapeutique phénobarbital-dipropylacétate de sodium. A propos d'un cas

The authors report on the observation of an epileptic woman who showed the clinical and electro-encephalographic symptoms of an overdose of barbiturates when undergoing treatment associating Depakine and Gardenal. Resumption of the treatment results in identical symptoms. The potentialisation of this association and the mechanism by which it acts are as yet unknown.