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The potential of ketogenic approaches to regulate energy balance has recently gained attention since ketones may influence both energy expenditure and energy intake. In this narrative review, we summarized the most relevant evidence about the role of ketosis on energy expenditure, substrate utilization, and energy intake in humans. We considered different strategies to induce ketosis, such as fasting, dietary manipulation, and exogenous ketone sources. In general, ketosis does not have a major influence on energy expenditure but promotes a shift in substrate utilization towards ketone body oxidation. The strategies to induce ketosis by reduction of dietary carbohydrate availability (e.g., ketogenic diets) do not independently influence energy intake, being thus equally effective for weight loss as diets with higher carbohydrate content. In contrast, the intake of medium-chain triglycerides and ketone esters induces ketosis and appears to increase energy expenditure and reduce energy intake in the context of high carbohydrate availability. These latter strategies lead to slightly enhanced weight loss. Unfortunately, distinguishing the effects of the various ketogenic strategies per se from the effects of other physiological responses is not possible with the available human data. Highly controlled, inpatient studies using targeted strategies to isolate the independent effects of ketones are required to adequately address this knowledge gap.

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Ketogenic diet therapy (KDT) is a nonpharmacological treatment that has been demonstrated to be effective in reducing seizures in patients with drug-resistant epilepsy. As the majority of patients on KDT are also receiving anti-seizure medications (ASMs), questions about their combination often arise. KDT is typically implemented as an add-on, and not a substitute for ASMs. Drug monitoring and specific laboratory studies may be helpful in specific cases of cotherapy. Valproate, topiramate, zonisamide, and lamotrigine may be potentially problematic with KDT, but the evidence for this is not conclusive. ASM reduction is usually attempted after 1 month of KDT if a child is showing seizure reduction (but weaning ASMs does not require seizure freedom). Failure to wean an ASM does not mean KDT has failed and adding a new ASM may be beneficial in those cases after several months of KDT fine-tuning. The purpose of this review was to discuss the evidence for possible negative (or positive) pharmacodynamic interactions between KDT and ASMs. In addition, practical suggestions for the weaning or adding of ASMs in patients on KDT are provided.

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A cetose, conhecida também como acetonemia, é um distúrbio metabólico que afeta principalmente vacas leiteiras de alta produção. A elevação anormal de corpos cetônicos nos tecidos e fluidos corporais do animal ocorre devido a um déficit de energia. A quantidade de alimento/nutrientes ingeridos não é suficiente para suprir a demanda corporal do mesmo, assim como a eficiência reprodutiva que está diretamente ligada à saúde, condição corporal e sua capacidade de produção. Animais de alta produção possuem um desafio muito grande de aumentar a produção a cada lactação, com isso, estão susceptíveis a mudanças metabólicas, entre elas a cetose, clínica ou subclínica. Tal enfermidade ocorre devido a uma má adaptação metabólica do animal a sua nova condição de lactante. A elevada incidência de doenças uterinas no pós-parto de vacas leiteiras é responsável por inúmeros prejuízos para a atividade, principalmente pela redução da eficiência reprodutiva das vacas acometidas por infecções. Contudo, visto que a cetose subclínica prevalece nos rebanhos leiteiros de alta produção, o objetivo desta revisão de literatura é apresentar a patogenia e os efeitos que esse distúrbio metabólico têm sobre a reprodução das vacas de aptidão leiteira no após o parto, utilizando de indicadores como taxa de prenhez, taxa de concepção, retorno a ciclicidade, intervalo entre partos e intervalo entre parto e estro.(AU)

Ketosis, also known as acetonemia, is a metabolic disorder that primarily affects high-yielding dairy cows. The abnormal elevation of ketone bodies in the animal's tissues and body fluids occurs due to an energy deficit. The amount of food/nutrients ingested are not enough to supply the body's demand, as well as the reproductive efficiency that is directly linked to health, body condition and its production capacity. High production animals have a very big challenge to increase production with each lactation, therefore, they are susceptible to metabolic changes, including clinical or subclinical ketosis. Such a disease occurs due to a poor metabolic adaptation of the animal to its new lactating condition. The high incidence of uterine diseases in the postpartum period of dairy cows is responsible for numerous losses to the activity, mainly for the reduction of the reproductive efficiency of cows affected by infections. However, since subclinical ketosis prevails in high production dairy herds, the objective of this literature review is to present the pathogenesis and the effects that this metabolic disorder has on the reproduction of dairy cows in the postpartum period, using indicators such as pregnancy rate, conception rate, return to cyclicity, calving interval and calving-estrus interval.(AU)

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ABSTRACT: This study evaluated milk fat to protein ratio (FPR) in the first test-day after calving of dairy cows in Paraná State. Data from 257,847 first monthly test-days after calving of 114,162 cows were submitted to analysis after the data edition. Procedures MIXED, CORR and STEPWISE from SAS were used in the data analysis. In order to validate FPR, a herd with regular postpartum monitoring of blood β-hydroxybutyrate (BHB) was used to estimate the correlation with FPR. There was a strong positive correlation between FPR and fat content (r = 0.85; P < 0.01) and a weak negative correlation between FPR and protein content (r = - 0.23; P < 0.01). The regression equation that best fitted FPR was 1.1806 + 0.3304*%F - 0.3877*%P (R2 = 0.98), where the variable with the greatest influence was milk fat content (partial R2 = 0.72). Animals of 4th and 5th or more lactations had higher (P < 0.01) FPR, followed by animals of third, first, and second lactations. Jersey cows had higher (P < 0.01) FPR than Holsteins and Brown Swiss animals. Cows milked twice daily had higher (P < 0.01) FPR than animals milked three times daily. There were small positive correlations between milk FPR and blood BHB on days 4, 7 and 12 after calving (0.07, 0.13, and 0.14, respectively). In conclusion, milk fat content was reported to be the most important variable affecting FPR changes, but the milk FPR has limited value to evaluate hyperketonemia incidence during the transition period.

RESUMO: Este estudo teve como objetivo avaliar a relação gordura:proteína (RGP) no primeiro controle leiteiro no pós-parto de vacas no estado do Paraná. Dados de 257.847 controles de 114.162 vacas leiteiras, realizados no primeiro controle mensal após o parto foram submetidos à análise estatística após edição dos dados. Os procedimentos MIXED, CORR e STEPWISE do programa estatístico SAS 9.4 foram utilizados. A fim de validar a RGP, um rebanho com monitoramento regular de β-hidroxibutirato (BHB) no sangue foi utilizado para estimar a correlação com RGP. Observou-se uma correlação forte e positiva entre a RGP e teor de gordura no leite (r = 0,85; P < 0,01) e uma correlação fraca e negativa entre a RGP e o teor de proteína (r = -0,23; P < 0,01). A equação de regressão que melhor se ajusta à RGP foi 1,1806 + 0,3304*%G - 0,3877*%P (R2 = 0,98), na qual a variável com maior influência foi a porcentagem de gordura (R2 = 0,72). Animais de 4ª e 5ª lactações ou mais, apresentaram maior (P < 0,01) RGP, seguidos dos animais de terceira, primeira e segunda lactações, com menores RGP. Vacas da raça Jersey apresentaram maior (P < 0,01) RGP que vacas da raça Holandesa e Pardo-Suíça. Animais com duas ordenhas diárias apresentaram maior (P < 0,01) RGP que os animais ordenhados três vezes ao dia. Observaram-se correlações positivas, mas de pequena magnitude, entre a RGP do leite e BHB no sangue no quarto, sétimo e 12 dias pós-parto (0,07, 0,13 e 0,14; respectivamente). Concluindo, o teor de gordura é o fator que mais impacta as variações da RGP do leite, mas a RGP tem valor limitado na avaliação da incidência de hipercetonemia no período de transição.

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This study evaluated milk fat to protein ratio (FPR) in the first test-day after calving of dairy cows in Paraná State. Data from 257,847 first monthly test-days after calving of 114,162 cows were submitted to analysis after the data edition. Procedures MIXED, CORR and STEPWISE from SAS were used in the data analysis. In order to validate FPR, a herd with regular postpartum monitoring of blood ß-hydroxybutyrate (BHB) was used to estimate the correlation with FPR. There was a strong positive correlation between FPR and fat content (r = 0.85; P < 0.01) and a weak negative correlation between FPR and protein content (r = - 0.23; P < 0.01). The regression equation that best fitted FPR was 1.1806 + 0.3304*%F - 0.3877*%P (R2 = 0.98), where the variable with the greatest influence was milk fat content (partial R2 = 0.72). Animals of 4th and 5th or more lactations had higher (P < 0.01) FPR, followed by animals of third, first, and second lactations. Jersey cows had higher (P < 0.01) FPR than Holsteins and Brown Swiss animals. Cows milked twice daily had higher (P < 0.01) FPR than animals milked three times daily. There were small positive correlations between milk FPR and blood BHB on days 4, 7 and 12 after calving (0.07, 0.13, and 0.14, respectively). In conclusion, milk fat content was reported to be the most important variable affecting FPR changes, but the milk FPR has limited value to evaluate hyperketonemia incidence during the transition period.

Este estudo teve como objetivo avaliar a relação gordura:proteína (RGP) no primeiro controle leiteiro no pós-parto de vacas no estado do Paraná. Dados de 257.847 controles de 114.162 vacas leiteiras, realizados no primeiro controle mensal após o parto foram submetidos à análise estatística após edição dos dados. Os procedimentos MIXED, CORR e STEPWISE do programa estatístico SAS 9.4 foram utilizados. A fim de validar a RGP, um rebanho com monitoramento regular de ß-hidroxibutirato (BHB) no sangue foi utilizado para estimar a correlação com RGP. Observou-se uma correlação forte e positiva entre a RGP e teor de gordura no leite (r = 0,85; P < 0,01) e uma correlação fraca e negativa entre a RGP e o teor de proteína (r = -0,23; P < 0,01). A equação de regressão que melhor se ajusta à RGP foi 1,1806 + 0,3304*%G - 0,3877*%P (R2 = 0,98), na qual a variável com maior influência foi a porcentagem de gordura (R2 = 0,72). Animais de 4ª e 5ª lactações ou mais, apresentaram maior (P < 0,01) RGP, seguidos dos animais de terceira, primeira e segunda lactações, com menores RGP. Vacas da raça Jersey apresentaram maior (P < 0,01) RGP que vacas da raça Holandesa e Pardo-Suíça. Animais com duas ordenhas diárias apresentaram maior (P < 0,01) RGP que os animais ordenhados três vezes ao dia. Observaram-se correlações positivas, mas de pequena magnitude, entre a RGP do leite e BHB no sangue no quarto, sétimo e 12 dias pós-parto (0,07, 0,13 e 0,14; respectivamente). Concluindo, o teor de gordura é o fator que mais impacta as variações da RGP do leite, mas a RGP tem valor limitado na avaliação da incidência de hipercetonemia no período de transição.

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Metabolic stress conditions caused by negative energy balance (NEB) have been associated with reduced fertility in cows. ß-hydroxybutyrate (BHBA) is the main circulating ketone body, which accumulates within follicular fluid. The aim of this study was to evaluate the effects of BHBA on follicle growth and on ovulatory mechanisms in cattle. At 72 h after intrafollicular injection, there was a decrease in follicular diameter in BHBA group compared to control (P = 0.02). Furthermore, follicle growth rate was reduced post-treatment with BHBA in comparison to the control group (P < 0.03). The BHBA intrafollicular injection in follicles ≥ 12 mm, however, did not affect E2 and P4 concentrations in the follicular fluid. In addition, the relative abundance of genes involved in the ovulatory cascade (ADAM 17, AREG, EREG, PTGS2), steroidogenesis (CYP19A1, 3BHSD, STAR), cellular stress (SOD1, CAT, GPX1, HSPA5, XBP1s, XBP1u, ATF4, ATF6), monocarboxylic acid transporters (SLC16A1, SLC16A7) and apoptosis (XIAP) was similar between groups. In conclusion, the results of this study indicate that the increase in intrafollicular concentrations of BHBA affects follicular growth, but it does not compromise the ovulatory cascade and cellular homeostasis in bovine granulosa cells.

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BACKGROUND: Ischemic kidney injury is a common clinical condition resulting from transient interruption of the kidney's normal blood flow, leading to oxidative stress, inflammation, and kidney dysfunction. The ketogenic diet (KD), a low-carbohydrate, high-fat diet that stimulates endogenous ketone body production, has potent antioxidant and anti-inflammatory effects in distinct tissues and might thus protect the kidney against ischemia and reperfusion (IR) injury. MAIN METHODS: Male Wistar rats were fed a KD or a control diet (CD) for three days before analyzing metabolic parameters or testing nephroprotection. We used two different models of kidney IR injury and conducted biochemical, histological, and Western blot analyses at 24 h and two weeks after surgery. KEY FINDINGS: Acute KD feeding caused protein acetylation, liver AMPK activation, and increased resistance to IR-induced kidney injury. At 24 h after IR, rats on KD presented reduced tubular damage and improved kidney functioning compared to rats fed with a CD. KD attenuated oxidative damage (protein nitration, 4-HNE adducts, and 8-OHdG), increased antioxidant defenses (GPx and SOD activity), and reduced inflammatory intermediates (IL6, TNFα, MCP1), p50 NF-κB expression, and cellular infiltration. Also, KD prevented interstitial fibrosis development at two weeks, up-regulation of HSP70, and chronic Klotho deficiency. SIGNIFICANCE: Our findings demonstrate for the first time that short-term KD increases tolerance to experimental kidney ischemia, opening the opportunity for future therapeutic exploration of a dietary preconditioning strategy to convey kidney protection in the clinic.

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Background: Ketosis is the most important metabolic disease with prevalence from 15 to 45%. Ketosis is diagnosed using a metabolic profile. Due to the high prevalence, it is necessary to determine a large number of metabolic profiles within farm, which represents an additional cost, so the implementation of pooled serum in assessing the metabolic status of cows was examined. The aim of this study was to validate and evaluate the influence of the relative position (Z-score) of the value of pooled sample metabolic parameters within the known reference value of healthy cows in the detection of ketosis in herd during early lactation. Materials, Methods & Results: The experiment has been carried out using blood samples collected by puncture of coccygeal vein from 50 ketotic and 50 healthy cows. Laboratory analysis includes determination of beta-hydroxybutyrate-BHB, non-esterified fatty acids-NEFA, cholesterol-CHOL, triglycerides-TGC, glucose-GLU, albumin-ALB, total protein-TPROT, UREA, Ca, P, total bilirubin-TBIL and aspartat aminotransferase-AST. The pooled serum was made from 10 individual samples originating from 10 different cows. A serum aliquot of 0.1 mL was taken from each sample, and a 1 mL volume of pooled serum was finally formed. Three types of serum pools were made: 1) 30 pooled sample were from ketosis; 2) 30 pooled sample were from healthy cows and 3) 60 pooled samples containing mixed sera of healthy cows and cows with ketosis were made as follows: 10 pools contain 10% to 60% of ketotic cows (1/10 to 6/10 samples). Statistical analysis includes: a) difference in metabolite concentration and Z-score in pooled sample and arithmetic mean individual sample in healthy and ketotic cow, b) correlation between Z-score of pooled sample and arithmetic mean of individual sample, c) ability of Z-score of metabolite to divide ketotic from healthy cow, d) correlation between Z-score and % of ketotic cow in pooled sample; and e) calculation of 95%CI of pooled sample Z-scores for each % of ketotic cow in pools. Z-score and all analysis were calculated for each metabolic parameter. The results of the study show that the mean values and Zscores of the pool and the calculated average value of the individual samples participating in that pool differ significantly in healthy cows and cows in ketosis, except for TPROT and Ca. A higher value and a higher Z-score were found for BHB, NEFA, UREA, TBIL and AST, and a lower value and a lower Z-score for TGC, CHOL, GLU, ALB and P in ketotic cows compared to healthy cows. The value of the Z-score of the pooled sample and the calculated mean values of individual samples participating in the pool are highly correlated with each other (coefficient of determination over 99%). Z-score of metabolites in the pooled sample can be used to distinguish healthy from ketotic cows (ROC AUC= 0.711 to 0.989), except for TPROT and Ca. The Z-score value of the pooled sample shows a linear correlation with the percentage of ketotic cows in the pool and the reference ranges of Z-scores change significantly as a function of the percentage of ketosis cows. Discussion: Modern research on the metabolic profile in cows requires obtaining a large amount of information from as few samples as possible. The advantages of using the Z-score are reflected in the following: this score does not depend on the absolute value of the metabolite, but on the position within the known population reference value, Z-score of sample and the arithmetic mean of individual samples included in the same pool are almost identical, the Z-score of these 2 groups of results is ideally correlated, the Z-score significantly correlates with the % of ketosis samples in the pooled sample. The use of pooled sample Z-score can be a useful in a herd level assessment of metabolic status and detection of ketosis as most important metabolic disease in dairy cows.

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Postpartum cows, mainly with metabolic diseases, such as ketosis, usually experience an increased number of services per conception. During ketosis, high concentrations of ß-hydroxybutyrate (BHBA) in follicular, uterine and oviductal fluid have been considered to cause subfertility in cows. However, the effect of sperm exposure to an environment with high BHBA concentration is not known. This study investigated the influence of high levels of BHBA on kinetics, oxidative status and morphology of bovine spermatozoa. To assess the effect of BHBA after sperm selection, bovine spermatozoa were incubated (180 min) with different BHBA concentrations: 0 (Control), 0.8, 2.4 or 5 mM. Sperm kinetics was evaluated after 30, 60, 120 and 180 min, and oxidative status and morphology were analysed at 180 min. Oxidative status was evaluated through the production of reactive oxidative species (ROS), total antioxidant capacity and lipid peroxidation. High concentrations of BHBA decreased the curvilinear velocity, straight line velocity, mean path velocity, linearity, straightness and hyperactivity of spermatozoa. However, there was no effect of BHBA on oxidative and antioxidant capacity as well as on sperm morphology. In conclusion, exposure of bovine spermatozoa to high levels of BHBA impairs sperm kinetics without altering oxidative and antioxidant mechanisms.

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Tuberculosis remains a significant infectious disease of farm animals and humans worldwide. The objective of this study was to assess various risk factors associated with testing positive for bovine tuberculosis (bTB) in high-yielding Holstein cows in an intensive dry-lot dairy operation. In a retrospective observational study, 9312 records from Holstein cows from a large dairy herd in northern Mexico were used. The incidence rate of lactating cows reactor to bTB was 7.3 cases/100 cow years (95% CI = 6.7-7.9%). Multiple logistic regression models indicated that cows with total milk yield during the first lactation >10,200 kg were 1.3 times (95% confidence intervals (CI) for odds ratio (OR) = 1.2-1.6) more likely to be detected as bTB reactors than cows with total milk yield <10,200 kg (8.2 vs. 6.4%; P < 0.01). The risk of being reactor to bTB increased with x̅ total milk yield/lactation >11,500 kg (OR=2.7, 95% CI = 2.3-3.3; 10.4 vs. 4.2%) compared with cows with x̅ total milk yield/lactation <11,500 kg. Cows with >10,200 kg 305-day milk yield in the last lactation was associated (P < 0.01) with 1.3 times higher odds (95% CI for OR = 1.1-1.5) of being classed as reactors than cows with <10,200 kg. Cows with peak milk yield >48 kg were 1.9 times (95% CI for OR = 1.6-2.2) more likely to be reactor to bTB than cows with peak milk yield <48 kg (9.2 vs. 5.1%; P < 0.01). Cows with either puerperal metritis (OR = 0.07, 95% CI = 0.5-0.9) or carrying twins (OR = 0.05, 95% CI = 0.01-0.19) had a protective role for being reactor to bTB. This study showed that increased milk production was associated with a higher risk of becoming positive to tuberculin skin test in high-yielding Holstein cows.

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