Short-chain fatty acids and FFAR2 as suppressors of bone resorption.

Short-chain fatty acids (SCFAs) exert a variety of immune and metabolic functions by binding to G-protein-coupled receptors, mainly free fatty acid receptor 2 (FFAR2). However, the effects of SCFAs and FFARs on bone remodeling, especially in alveolar bone, have been less explored. In this study, we investigated the influence of the SCFA/FFAR2 axis on alveolar bone. Bone samples from wild-type (WT) and FFAR2-deficient mice (FFAR2-/-) were analyzed using micro-CT, histology and qPCR. WT and FFAR2-/- animals received a high-fiber diet (HFD) reported to increase circulating levels of SCFAs. Additionally, we analyzed the effects of SCFAs and a synthetic FFAR2 agonist, phenylacetamide-1 (CTMB), on bone cell differentiation. The participation of histone deacetylase inhibitors (iHDACs) in the effects of SCFAs was further assessed in vitro. CTMB treatment was also evaluated in vivo during orthodontic tooth movement (OTM). FFAR2-/- mice exhibited deterioration of maxillary bone parameters. Consistent with this, FFAR2-/- mice exhibited a significant increase of OTM and changes in bone cell numbers and in the expression of remodeling markers. The HFD partially reversed bone loss in the maxillae of FFAR2-/- mice. In WT mice, the HFD induced changes in the bone markers apparently favoring a bone formation scenario. In vitro, bone marrow cells from FFAR2-/- mice exhibited increased differentiation into osteoclasts, while no changes in osteoblasts were observed. In line with this, differentiation of osteoclasts was diminished by SCFAs and CTMB. Moreover, CTMB treatment significantly reduced OTM. Pretreatment of osteoclasts with iHDACs did not modify the effects of SCFAs on these cells. In conclusion, SCFAs function as regulators of bone resorption. The effects of SCFAs on osteoclasts are dependent on FFAR2 activation and are independent of the inhibition of HDACs. FFAR2 agonists may be useful to control bone osteolysis.

High-refined carbohydrate diet promotes detrimental effects on alveolar bone and femur microarchitecture.

The impact of high-refined carbohydrate (HC) diet on fat accumulation, adipokines secretion and systemic inflammation is well described. However, it remains unclear whether these processes affect bone remodeling. OBJECTIVE: To investigate the effects of HC diet in the alveolar bone and femur parameters. METHODS: BalbC mice were fed with conventional chow or HC diet for 12 weeks. After experimental time maxillae, femur, blood and white adipose tissue samples were collected. RESULTS: The animals feed with HC diet exhibited considerable increase of adiposity index and adipose tissue levels of TNF-α, IL-6, IL-10, IL-1ß, TGF-ß and leptin. Microtomography analysis of maxillary bone revealed horizontal alveolar bone loss and disruption of trabecular bone in mice feed with HC diet. These deleterious effects were correlated with a disturbance in bone cells and an augmented expression of Rankl/Opg ratio. Consistently, similar effects were observed in femurs, which also exhibited a reduction in bone maximum load and stiffness. CONCLUSION: Our data indicates that HC diet consumption disrupts bone remodeling process, favoring bone loss. Underlying mechanisms relies on fat tissue accumulation and also in systemic and local inflammation.

Representation of the cardinality principle: early conception of error in a counterfactual test.

There is debate over how the integration of non-verbal quantifying and verbal counting relates to the representation of number principles. A stringent representational test would be one in which a child obeyed a number principle where it ran counter to a characteristic procedure. We devised a test relying on the uniqueness principle for using evidence from a miscount in inferring a counterfactual cardinal number. All the 5-year-olds passed, as did half the preschoolers. Subtests probed associated number-skills. We suggest that a crucial preschool step is to start conceptualising error by categorising relations between counting and miscounting. That step is taken at a similar age to passing a representational theory of mind test but the two were uncorrelated.

Hypercapnic-hypoxemic chronic obstructive pulmonary disease (COPD): influence of severity of COPD on nutritional status.

In 90 patients with hypercapnic-hypoxemic chronic obstructive pulmonary disease (COPD), noninvasive anthropometric and biochemical nutritional indices were measured to assess the prevalence and features of malnutrition in COPD and to analyze the relationship between nutritional depletion and the severity of the disease. A significant inverse relationship was found between PaCO2 and body weight; a parallel decrease of both somatic proteins and body-energy stores of fat appears to be paired with decreasing body weight. Deterioration of nutritional status occurred in the COPD patients considered despite seemingly adequate calorie and protein intakes, although in patients with more severe impairment of pulmonary gas exchange, calorie intake was significantly lower compared with basal energy expenditure. In the course of hypercapnic-hypoxemic COPD malnutrition is common, it is related to the severity of the disease as judged by the need for hospitalization and degree of impairment of gas exchange, and it may be present despite apparently adequate nutrient intake.

Intracellular acid-base and electrolyte metabolism in skeletal muscle of patients with chronic obstructive lung disease and acute respiratory failure.

Quadriceps femoris muscle needle biopsies were performed in 21 patients with chronic obstructive lung disease (COLD) and acute respiratory failure (ARF) and in 21 age-matched healthy control subjects. Muscle samples were analysed to obtain intracellular bicarbonate and pH values from total acid-labile carbon dioxide content. Muscle potassium, magnesium and sodium content were also determined, as well as water compartments. Skeletal muscle of COLD patients with ARF showed intracellular acidosis and reduced potassium and magnesium content. Total muscle water increase was linked to extracellular water increment. It was concluded that in COLD patients with ARF an overall derangement of skeletal muscle metabolism is present.

Muscle energy metabolism in uremia.

Energy-rich phosphagens were measured in 11 patients with end-stage chronic renal failure and 11 nonuremic subjects. A significant decrease of ATP, phosphocreatine, total adenine nucleotides, lactate, and energy charge was found. The present results can be referred both to glycolytic sequence disturbances and to the lack of substrates characteristic of uremia.

Effects of low flux-low pressure cardiopulmonary bypass on intracellular acid-base and water metabolism.

In eight patients undergoing open heart surgery for elective myocardial revascularization, extra-intracellular acid-base and water metabolism parameters were studied before and after cardiopulmonary bypass procedures. All patients presented a different degree of metabolic acidosis related to plasma lactate increase. Intracellular acid-base indexes did not change significantly, though all but one patient showed an intracellular buffers consumption. Both total muscle and extracellular water increased, while intracellular water did not change. It was concluded that low flux-low pressure perfusion CPB was related to a substantial preservation of cell integrity.

Uremic acidosis and intracellular buffering.

Skeletal muscle biopsies were performed in 16 controls and 15 non-dialysed end-stage chronic renal failure (CRF) patients presenting untreated metabolic acidosis. Intracellular bicarbonate, pH, water compartments and electrolytes were determined. In 8 of 15 patients muscle ATP and lactate were measured. Intracellular bicarbonate (HCO3i) and pH (pHi) were obtained by means of muscle total carbon dioxide method: a significant (p less than 0.001) reduction in both intracellular acid--base indexes was found in all patients (pHi 6.82 +/- 13 vs. 7.04 +/- 0.05; HCO3i 6.28 +/- 2.07 vs. 11.86 +/- 0.87). Total muscle as well as extracellular water was increased. Muscle sodium and chloride contents were also increased, while no change in potassium and magnesium was detected. A significant decrease of both muscle ATP and lactate was found. The data lead to the conclusion that chronic retention of acids in CRF results in a depletion of the muscle buffer pool and consequently in intracellular acidosis: the latter could be the main cause of the cell energy metabolism derangement described in uremia.

Intracellular bicarbonate and pH of skeletal muscle in chronic renal failure.

In 11 controls and 10 patients suffering from untreated uraemic acidosis intracellular bicarbonate and skeletal muscle pH (needle biopsy) were determined. In all patients a significant intracellular acidosis, not related to any extracellular indices was found. It is concluded that the chronic proton load is able to effect intracellular buffer composition; moreover the action of other factors such as derangements of cell metabolism and nutritional imbalance could be operating.