Synthesis of triheptanoin and formulation as a solid diet for rodents

Triheptanoin-enriched diets have been successfully used in the experimental treatment of various metabolic disorders. Maximal therapeutic effect is achieved in the context of a ketogenic diet where triheptanoin oil provides 3040% of the daily caloric intake. However, pre-clinical studies using triheptanoin-rich diets are hindered by the difficulty of administering to laboratory animals as a solid foodstuff. In the present study, we successfully synthesized triheptanoin to the highest standards of purity from glycerol and heptanoic acid, using sulfonated charcoal as a catalyst. Triheptanoin oil was then formulated as a solid, stable and palatable preparation using a ketogenic base and a combination of four commercially available formulation agents: hydrophilic fumed silica, hydrophobic fumed silica, microcrystalline cellulose, and talc. Diet compliance and safety was tested on C57Bl/6 mice over a 15-week period, comparing overall status and body weight change. Practical applications: This work provides a complete description of (i) an efficient and cost-effective synthesis of triheptanoin and (ii) its formulation as a solid, stable, and palatable ketogenic diet (triheptanoin-rich; 39% of the caloric intake) for rodents. Triheptanoin-rich diets will be helpful on pre-clinical experiments testing the therapeutic efficacy of triheptanoin in different rodent models of human diseases. In addition, using the same solidification procedure, other oils could be incorporated into rodent ketogenic diet to study their dosage and long-term effects on mammal health and development. This approach could be extremely valuable as ketogenic diet is widely used clinically for epilepsy treatment.

Synthesis of triheptanoin and formulation as a solid diet for rodents

Triheptanoin-enriched diets have been successfully used in the experimental treatment of various metabolic disorders. Maximal therapeutic effect is achieved in the context of a ketogenic diet where triheptanoin oil provides 3040% of the daily caloric intake. However, pre-clinical studies using triheptanoin-rich diets are hindered by the difficulty of administering to laboratory animals as a solid foodstuff. In the present study, we successfully synthesized triheptanoin to the highest standards of purity from glycerol and heptanoic acid, using sulfonated charcoal as a catalyst. Triheptanoin oil was then formulated as a solid, stable and palatable preparation using a ketogenic base and a combination of four commercially available formulation agents: hydrophilic fumed silica, hydrophobic fumed silica, microcrystalline cellulose, and talc. Diet compliance and safety was tested on C57Bl/6 mice over a 15-week period, comparing overall status and body weight change. Practical applications: This work provides a complete description of (i) an efficient and cost-effective synthesis of triheptanoin and (ii) its formulation as a solid, stable, and palatable ketogenic diet (triheptanoin-rich; 39% of the caloric intake) for rodents. Triheptanoin-rich diets will be helpful on pre-clinical experiments testing the therapeutic efficacy of triheptanoin in different rodent models of human diseases. In addition, using the same solidification procedure, other oils could be incorporated into rodent ketogenic diet to study their dosage and long-term effects on mammal health and development. This approach could be extremely valuable as ketogenic diet is widely used clinically for epilepsy treatment.

Some common indexes of group diversity: upper boundaries

Workgroup diversity can be conceptualized as variety, separation, or disparity. Thus, the proper operationalization of diversity depends on how a diversity dimension has been defined. Analytically, the minimal diversity must be obtained when there are no differences on an attribute among the members of a group, however maximal diversity has a different shape for each conceptualization of diversity. Previous work on diversity indexes indicated maximum values for variety (e.g., Blau"s index and Teachman"s index), separation (e.g., standard deviation and mean Euclidean distance), and disparity (e.g., coefficient of variation and the Gini coefficient of concentration), although these maximum values are not valid for all group characteristics (i.e., group size and group size parity) and attribute scales (i.e., number of categories). We demonstrate analytically appropriate upper boundaries for conditional diversity determined by some specific group characteristics, avoiding the bias related to absolute diversity. This will allow applied researchers to make better interpretations regarding the relationship between group diversity and group outcomes.

Synthesis of triheptanoin and formulation as a solid diet for rodents

Triheptanoin-enriched diets have been successfully used in the experimental treatment of various metabolic disorders. Maximal therapeutic effect is achieved in the context of a ketogenic diet where triheptanoin oil provides 3040% of the daily caloric intake. However, pre-clinical studies using triheptanoin-rich diets are hindered by the difficulty of administering to laboratory animals as a solid foodstuff. In the present study, we successfully synthesized triheptanoin to the highest standards of purity from glycerol and heptanoic acid, using sulfonated charcoal as a catalyst. Triheptanoin oil was then formulated as a solid, stable and palatable preparation using a ketogenic base and a combination of four commercially available formulation agents: hydrophilic fumed silica, hydrophobic fumed silica, microcrystalline cellulose, and talc. Diet compliance and safety was tested on C57Bl/6 mice over a 15-week period, comparing overall status and body weight change. Practical applications: This work provides a complete description of (i) an efficient and cost-effective synthesis of triheptanoin and (ii) its formulation as a solid, stable, and palatable ketogenic diet (triheptanoin-rich; 39% of the caloric intake) for rodents. Triheptanoin-rich diets will be helpful on pre-clinical experiments testing the therapeutic efficacy of triheptanoin in different rodent models of human diseases. In addition, using the same solidification procedure, other oils could be incorporated into rodent ketogenic diet to study their dosage and long-term effects on mammal health and development. This approach could be extremely valuable as ketogenic diet is widely used clinically for epilepsy treatment.

Identification of haptoglobin as an angiogenic factor in sera from patients with systemic vasculitis.

Angiogenesis is an important process in chronic inflammatory diseases. We observed that sera from patients with systemic vasculitis stimulated angiogenesis in an in vitro model using human umbilical vein endothelial cells cultured on a basement membrane (Matrigel) substrate. After 40% ammonium sulfate precipitation, angiogenic activity remained in the low molecular weight fraction and could be inactivated by heat. SDS-page of serum FPLC fractions exhibiting maximal angiogenic activity demonstrated two prominent species of 45 and 16-20 kD in patients' sera. These bands were much less apparent in sera obtained from control subjects. Amino-terminal sequencing of the 45-kD protein demonstrated that it was haptoglobin. Purified haptoglobin stimulated angiogenesis in a dose-dependent manner. The angiogenic activity of vasculitis patients' sera was partially inhibited by an antihaptoglobin antibody. Furthermore, serum haptoglobin levels in vasculitis patients correlated both with disease and angiogenic activity. Haptoglobin angiogenic activity was confirmed in two in vivo models using an implanted disc and a subcutaneous injection of basement membrane. Stimulation of angiogenesis is a newly recognized biological function of haptoglobin. The increased levels of haptoglobin found in chronic inflammatory conditions may play an important role in tissue repair. In systemic vasculitis, haptoglobin might also compensate for ischemia by promoting development of collateral vessels.

On the bicanonical map of irregular varieties

From the point of view of uniform bounds for the birationality of pluricanonical maps, irregular varieties of general type and maximal Albanese dimension behave similarly to curves. In fact Chen-Hacon showed that, at least when their holomorphic Euler characteristic is positive, the tricanonical map of such varieties is always birational. In this paper we study the bicanonical map. We consider the natural subclass of varieties of maximal Albanese dimension formed by primitive varieties of Albanese general type. We prove that the only such varieties with non-birational bicanonical map are the natural higher-dimensional generalization to this context of curves of genus $2$: varieties birationally equivalent to the theta-divisor of an indecomposable principally polarized abelian variety. The proof is based on the (generalized) Fourier-Mukai transform.

Dietary resveratrol prevents alzheimer's markers and increases life span in SAMP8

Resveratrol is a polyphenol that is mainly found in grapes and red wine and has been reported to be a caloric restriction (CR) mimetic driven by Sirtuin 1 (SIRT1) activation. Resveratrol increases metabolic rate, insulin sensitivity, mitochondrial biogenesis and physical endurance, and reduces fat accumulation in mice. In addition, resveratrol may be a powerful agent to prevent age-associated neurodegeneration and to improve cognitive deficits in Alzheimer's disease (AD). Moreover, different findings support the view that longevity in mice could be promoted by CR. In this study, we examined the role of dietary resveratrol in SAMP8 mice, a model of age-related AD. We found that resveratrol supplements increased mean life expectancy and maximal life span in SAMP8 and in their control, the related strain SAMR1. In addition, we examined the resveratrol-mediated neuroprotective effects on several specific hallmarks of AD. We found that long-term dietary resveratrol activates AMPK pathways and pro-survival routes such as SIRT1 in vivo. It also reduces cognitive impairment and has a neuroprotective role, decreasing the amyloid burden and reducing tau hyperphosphorylation.

Dietary resveratrol prevents alzheimer's markers and increases life span in SAMP8

Resveratrol is a polyphenol that is mainly found in grapes and red wine and has been reported to be a caloric restriction (CR) mimetic driven by Sirtuin 1 (SIRT1) activation. Resveratrol increases metabolic rate, insulin sensitivity, mitochondrial biogenesis and physical endurance, and reduces fat accumulation in mice. In addition, resveratrol may be a powerful agent to prevent age-associated neurodegeneration and to improve cognitive deficits in Alzheimer's disease (AD). Moreover, different findings support the view that longevity in mice could be promoted by CR. In this study, we examined the role of dietary resveratrol in SAMP8 mice, a model of age-related AD. We found that resveratrol supplements increased mean life expectancy and maximal life span in SAMP8 and in their control, the related strain SAMR1. In addition, we examined the resveratrol-mediated neuroprotective effects on several specific hallmarks of AD. We found that long-term dietary resveratrol activates AMPK pathways and pro-survival routes such as SIRT1 in vivo. It also reduces cognitive impairment and has a neuroprotective role, decreasing the amyloid burden and reducing tau hyperphosphorylation.

Effects of erythropoietin on muscle O2 transport during exercise in patients with chronic renal failure.

Erythropoietin (rHuEPO) has proven to be effective in the treatment of anemia of chronic renal failure (CRF). Despite improving the quality of life, peak oxygen uptake after rHuEPO therapy is not improved as much as the increase in hemoglobin concentration ([Hb)] would predict. We hypothesized that this discrepancy is due to failure of O2 transport rates to rise in a manner proportional to [Hb]. To test this, eight patients with CRF undergoing regular hemodialysis were studied pre- and post-rHuEPO ([Hb] = 7.5 +/- 1.0 vs. 12.5 +/- 1.0 g x dl-1) using a standard incremental cycle exercise protocol. A group of 12 healthy sedentary subjects of similar age and anthropometric characteristics served as controls. Arterial and femoral venous blood gas data were obtained and coupled with simultaneous measurements of femoral venous blood flow (Qleg) by thermodilution to obtain O2 delivery and oxygen uptake (VO2). Despite a 68% increase in [Hb], peak VO2 increased by only 33%. This could be explained largely by reduced peak leg blood flow, limiting the gain in O2 delivery to 37%. At peak VO2, after rHuEPO, O2 supply limitation of maximal VO2 was found to occur, permitting the calculation of a value for muscle O2 conductance from capillary to mitochondria (DO2). While DO2 was slightly improved after rHuEPO, it was only 67% of that of sedentary control subjects. This kept maximal oxygen extraction at only 70%. Two important conclusions can be reached from this study. First, the increase in [Hb] produced by rHuEPO is accompanied by a significant reduction in peak blood flow to exercising muscle, which limits the gain in oxygen transport. Second, even after restoration of [Hb], O2 conductance from the muscle capillary to the mitochondria remains considerably below normal.

Dietary resveratrol prevents alzheimer's markers and increases life span in SAMP8

Resveratrol is a polyphenol that is mainly found in grapes and red wine and has been reported to be a caloric restriction (CR) mimetic driven by Sirtuin 1 (SIRT1) activation. Resveratrol increases metabolic rate, insulin sensitivity, mitochondrial biogenesis and physical endurance, and reduces fat accumulation in mice. In addition, resveratrol may be a powerful agent to prevent age-associated neurodegeneration and to improve cognitive deficits in Alzheimer's disease (AD). Moreover, different findings support the view that longevity in mice could be promoted by CR. In this study, we examined the role of dietary resveratrol in SAMP8 mice, a model of age-related AD. We found that resveratrol supplements increased mean life expectancy and maximal life span in SAMP8 and in their control, the related strain SAMR1. In addition, we examined the resveratrol-mediated neuroprotective effects on several specific hallmarks of AD. We found that long-term dietary resveratrol activates AMPK pathways and pro-survival routes such as SIRT1 in vivo. It also reduces cognitive impairment and has a neuroprotective role, decreasing the amyloid burden and reducing tau hyperphosphorylation.

Deciphering the global organization of clustering in real complex networks

We uncover the global organization of clustering in real complex networks. To this end, we ask whether triangles in real networks organize as in maximally random graphs with given degree and clustering distributions, or as in maximally ordered graph models where triangles are forced into modules. The answer comes by way of exploring m-core landscapes, where the m-core is defined, akin to the k-core, as the maximal subgraph with edges participating in at least m triangles. This property defines a set of nested subgraphs that, contrarily to k-cores, is able to distinguish between hierarchical and modular architectures. We find that the clustering organization in real networks is neither completely random nor ordered although, surprisingly, it is more random than modular. This supports the idea that the structure of real networks may in fact be the outcome of self-organized processes based on local optimization rules, in contrast to global optimization principles.

Gelatinase expression and proteolytic activity in giant-cell arteritis

Objectives: Gelatinases (MMP2 and MMP9) are expressed in giant-cell arteritis (GCA) and are thought to play a role in vessel disruption. However, their activation status and enzymatic activity have not been evaluated. Our aim was to investigate the distribution and proteolytic activity of gelatinases in GCA lesions at different stages. Methods: Expression of MMP2, MMP9, MMP2-activator MMP14 and their natural inhibitors TIMP1 and TIMP2 was determined by real-time PCR and immunohistochemistry in temporal artery sections from 46 patients and 12 controls. MMP activation status and enzymatic activity were assessed by gelatin and film in situ zymography. Results: Vascular smooth muscle cells from normal specimens constitutively expressed pro-MMP2 and its inhibitor TIMP2 with no resulting proteolytic activity. In GCA MMP2, MMP9 and MMP14 were strongly expressed in their active form by infiltrating leucocytes. Inflamed arteries also expressed TIMP1 and TIMP2. However, the MMP9/TIMP1 and MMP2/TIMP2 ratios were higher in patients compared with controls, indicating an increased proteolytic balance in GCA which was confirmed by in situ zymography. Maximal gelatinase expression and activity occurred at the granulomatous areas surrounding the internal elastic lamina (IEL). Myointimal cells also expressed MMPs and exhibited proteolytic activity, suggesting a role for gelatinases in vascular remodelling and repair. Conclusions: GCA lesions show intense expression of gelatinases. Activators and inhibitors are regulated to yield enhanced gelatinase activation and proteolytic activity. Distribution of expression and proteolytic activity suggests that gelatinases have a major role not only in the progression of inflammatory infiltrates and vessel destruction but also in vessel repair.