Utilization of Enzymatically Hydrolyzed Soybean Protein and Crystalline Amino Acid Diets by Rats with Exocrine Pancreatic Insufficiency

ABSTRACT Exocrine pancreatic-deficient rats (PD) were prepared by cannulation and ligation of the common duct in a way which permitted bile, but not pancreatic juice, to enter the intestine. After surgery the PD rats were fed purified diets containing a high quality nitrogen source in the form of crystalline amino acids (AA), an enzymatic hydrolysate of soybean protein supplemented with essential amino acids (EH) or intact soybean protein with an essential amino acid supplement (SP). PD rats fed SP failed to regain any of their surgically-induced weight loss during the 10-day postoperative period. PD rats fed AA did not resume weight gains until after the sixth postoperative day while those fed diet EH resumed growth by the third postoperative day and grew at a rate which was nearly identical to that observed in sham-operated controls. The three diets afforded almost identical growth rates in weanling rats and in sham-operated rats used as controls for the PD rats. The amino acid compositions of AA and EH were nearly identical. Thus, the better utilization of diet EH in the PD rats was attributed to the fact that approximately 85% of the nitrogen in EH was in the form of oligopeptides. The results indicate that pancreatic enzymes are not required for the terminal stages of protein digestion and suggest that enzymatic-ally hydrolyzed proteins are utilized more efficiently than mixtures of amino acids in the absence of exocrine pancreatic function. J. Nutr. 104: 793-801, 1974 The results of recent studies in man patients with cystinuria and Hartnup dissuggest that the end-product of protein di-ease, two inherited diseases in which the gestion within the intestinal lumen is a mix-absorptive mechanisms for certain dietary ture consisting primarily of oligopeptides essential amino acids in the free form are with lesser amounts of free amino acids greatly impaired, the ability to absorb es-(1, 2). Although the terminal events in-sential amino acids in the form of peptides volved in transporting the peptides into is considered to be important for survival the enterocytes are not fully understood, (9-11). there is direct evidence from human There is now evidence indicating that studies indicating that hydroxyproline pep-defects in amino acid absorption may be tides ( 3 ) and glycylglycine ( 4 ) are taken found in association with other clinical conup from the gut lumen intact and are trans-ditions. Thus, DiMagno et al.1 have shown ported as such to the portal blood. While that there is a marked impairment in the the amount of peptide material actually ability of patients with nontropical sprue entering the portal blood is not large, these to absorb mixtures of essential amino acids, findings do support the contention that Adibì and Allen (12) reported a reduction some peptides are absorbed from the in-jn the rates of essential amino acid absorptestinal lumen intact (5-8)

A developmental approach to predicting neuronal connectivity from small biological datasets: a gradient-based neuron growth model.

PMCID: PMC3931784 Open Access article: BB/G006652/1 and BB/G006369/1.Relating structure and function of neuronal circuits is a challenging problem. It requires demonstrating how dynamical patterns of spiking activity lead to functions like cognitive behaviour and identifying the neurons and connections that lead to appropriate activity of a circuit. We apply a "developmental approach" to define the connectome of a simple nervous system, where connections between neurons are not prescribed but appear as a result of neuron growth. A gradient based mathematical model of two-dimensional axon growth from rows of undifferentiated neurons is derived for the different types of neurons in the brainstem and spinal cord of young tadpoles of the frog Xenopus. Model parameters define a two-dimensional CNS growth environment with three gradient cues and the specific responsiveness of the axons of each neuron type to these cues. The model is described by a nonlinear system of three difference equations; it includes a random variable, and takes specific neuron characteristics into account. Anatomical measurements are first used to position cell bodies in rows and define axon origins. Then a generalization procedure allows information on the axons of individual neurons from small anatomical datasets to be used to generate larger artificial datasets. To specify parameters in the axon growth model we use a stochastic optimization procedure, derive a cost function and find the optimal parameters for each type of neuron. Our biologically realistic model of axon growth starts from axon outgrowth from the cell body and generates multiple axons for each different neuron type with statistical properties matching those of real axons. We illustrate how the axon growth model works for neurons with axons which grow to the same and the opposite side of the CNS. We then show how, by adding a simple specification for dendrite morphology, our model "developmental approach" allows us to generate biologically-realistic connectomes

Hypoxia Disruption of Vertebrate CNS Pathfinding through EphrinB2 Is Rescued by Magnesium

The mechanisms of hypoxic injury to the developing human brain are poorly understood, despite being a major cause of chronic neurodevelopmental impairments. Recent work in the invertebrate Caenorhabditis elegans has shown that hypoxia causes discrete axon pathfinding errors in certain interneurons and motorneurons. However, it is unknown whether developmental hypoxia would have similar effects in a vertebrate nervous system. We have found that developmental hypoxic injury disrupts pathfinding of forebrain neurons in zebrafish (Danio rerio), leading to errors in which commissural axons fail to cross the midline. The pathfinding defects result from activation of the hypoxia-inducible transcription factor (hif1) pathway and are mimicked by chemical inducers of the hif1 pathway or by expression of constitutively active hif1α. Further, we found that blocking transcriptional activation by hif1α helped prevent the guidance defects. We identified ephrinB2a as a target of hif1 pathway activation, showed that knock-down of ephrinB2a rescued the guidance errors, and showed that the receptor ephA4a is expressed in a pattern complementary to the misrouting axons. By targeting a constitutively active form of ephrinB2a to specific neurons, we found that ephrinB2a mediates the pathfinding errors via a reverse-signaling mechanism. Finally, magnesium sulfate, used to improve neurodevelopmental outcomes in preterm births, protects against pathfinding errors by preventing upregulation of ephrinB2a. These results demonstrate that evolutionarily conserved genetic pathways regulate connectivity changes in the CNS in response to hypoxia, and they support a potential neuroprotective role for magnesium

Flavaglines Alleviate Doxorubicin Cardiotoxicity: Implication of Hsp27

Background: Despite its effectiveness in the treatment of various cancers, the use of doxorubicin is limited by a potentially fatal cardiomyopathy. Prevention of this cardiotoxicity remains a critical issue in clinical oncology. We hypothesized that flavaglines, a family of natural compounds that display potent neuroprotective effects, may also alleviate doxorubicininduced cardiotoxicity. Methodology/Principal Findings: Our in vitro data established that a pretreatment with flavaglines significantly increased viability of doxorubicin-injured H9c2 cardiomyocytes as demonstrated by annexin V, TUNEL and active caspase-3 assays. We demonstrated also that phosphorylation of the small heat shock protein Hsp27 is involved in the mechanism by which flavaglines display their cardioprotective effect. Furthermore, knocking-down Hsp27 in H9c2 cardiomyocytes completely reversed this cardioprotection. Administration of our lead compound (FL3) to mice attenuated cardiomyocyte apoptosis and cardiac fibrosis, as reflected by a 50 % decrease of mortality. Conclusions/Significance: These results suggest a prophylactic potential of flavaglines to prevent doxorubicin-induce

Intestinal Epithelial Stem/Progenitor Cells Are Controlled by Mucosal Afferent Nerves

Background: The maintenance of the intestinal epithelium is of great importance for the survival of the organism. A possible nervous control of epithelial cell renewal was studied in rats and mice. Methods: Mucosal afferent nerves were stimulated by exposing the intestinal mucosa to capsaicin (1.6 mM), which stimulates intestinal external axons. Epithelial cell renewal was investigated in the jejunum by measuring intestinal thymidine kinase (TK) activity, intestinal H-3-thymidine incorporation into DNA, and the number of crypt cells labeled with BrdU. The influence of the external gut innervation was minimized by severing the periarterial nerves. Principal Findings: Luminal capsaicin increased all the studied variables, an effect nervously mediated to judge from inhibitory effects on TK activity or H-3-thymidine incorporation into DNA by exposing the mucosa to lidocaine (a local anesthetic) or by giving four different neurotransmitter receptor antagonists i.v. (muscarinic, nicotinic, neurokinin1 (NK1) or calcitonin gene related peptide (CGRP) receptors). After degeneration of the intestinal external nerves capsaicin did not increase TK activity, suggesting the involvement of an axon reflex. Intra-arterial infusion of Substance P (SP) or CGRP increased intestinal TK activity, a response abolished by muscarinic receptor blockade. Immunohistochemistry suggested presence of M3 and M5 muscarinic receptors on the intestinal stem/progenitor cells. We propose that the stem/progenitor cells are controlled by cholinergic nerves, which, in turn, are influenced by mucosal afferent neuron(s) releasing acetylcholine and/or SP and/or CGRP. In mice lacking the capsaicin receptor, thymidine incorporation into DNA and number of crypt cells labeled with BrdU was lower than in wild type animals suggesting that nerves are important also in the absence of luminal capsaicin, a conclusion also supported by the observation that atropine lowered thymidine incorporation into DNA by 60% in control rat segments. Conclusion: Enteric nerves are of importance in maintaining the intestinal epithelial barrier.Original Publication:Ove Lundgren, Mats Jodal, Madeleine Jansson, Anders T Ryberg and Lennart Svensson, Intestinal Epithelial Stem/Progenitor Cells Are Controlled by Mucosal Afferent Nerves, 2011, PLOS ONE, (6), 2, 16295.http://dx.doi.org/10.1371/journal.pone.0016295Copyright: Public Library of Science (PLoS)http://www.plos.org

Material deprivation affects the management and clinical outcome of hepatocellular carcinoma in a high-resource environment

none94Aim: This study investigated how material deprivation in Italy influences the stage of hepatocellular carcinoma (HCC) at diagnosis and the chance of cure. Methods: 4114 patients from the Italian Liver Cancer database consecutively diagnosed with HCC between January 2008 and December 2018 were analysed about severe material deprivation (SMD) rate tertiles of the region of birth and region of managing hospitals, according to the European Statistics on Income and Living Conditions. The main outcomes were HCC diagnosis modalities (during or outside surveillance), treatment adoption and overall survival. Results: In more deprived regions, HCC was more frequently diagnosed during surveillance, while the incidental diagnosis was prevalent in the least deprived. Tumour characteristics did not differ among regions. The proportion of patients undergoing potentially curative treatments progressively decreased as the SMD worsened. Consequently, overall survival was better in less deprived regions. Patients who moved from most deprived to less deprived regions increased their probability of receiving potentially curative treatments by 1.11 times (95% CI 1.03 to 1.19), decreasing their mortality likelihood (hazard ratio 0.78 95% CI 0.67 to 0.90). Conclusions: Socioeconomic status measured through SMD does not seem to influence HCC features at diagnosis but brings a negative effect on the chance of receiving potentially curative treatments. Patient mobility from the most deprived to the less deprived regions increased the access to curative therapies, with the ultimate result of improving survival.openCucchetti A.; Gramenzi A.; Johnson P.; Giannini E.G.; Tovoli F.; Rapaccini G.L.; Marra F.; Cabibbo G.; Caturelli E.; Gasbarrini A.; Svegliati-Baroni G.; Sacco R.; Zoli M.; Morisco F.; Di Marco M.; Mega A.; Foschi F.G.; Biasini E.; Masotto A.; Nardone G.; Raimondo G.; Azzaroli F.; Vidili G.; Brunetto M.R.; Farinati F.; Trevisani F.; Avanzato F.; Biselli M.; Caraceni P.; Garuti F.; Neri A.; Santi V.; Pellizzaro F.; Imondi A.; Sartori A.; Penzo B.; Sanmarco A.; Granito A.; Muratori L.; Piscaglia F.; Sansone V.; Forgione A.; Dajti E.; Marasco G.; Ravaioli F.; Cappelli A.; Golfieri R.; Mosconi C.; Renzulli M.; Cela E.M.; Facciorusso A.; Cacciato V.; Casagrande E.; Moscatelli A.; Pellegatta G.; de Matthaeis N.; Allegrini G.; Lauria V.; Ghittoni G.; Pelecca G.; Chegai F.; Coratella F.; Ortenzi M.; Missale G.; Olivani A.; Inno A.; Marchetti F.; Busacca A.; Camma C.; Di Martino V.; Maria Rizzo G.E.; Franze M.S.; Saitta C.; Sauchella A.; Berardinelli D.; Bevilacqua V.; Borghi A.; Gardini A.C.; Conti F.; Dall'Aglio A.C.; Ercolani G.; Adotti V.; Arena U.; Di Bonaventura C.; Campani C.; Dragoni G.; Gitto S.; Laffi G.; Coccoli P.; Malerba A.; Guarino M.; Capasso M.; Oliveri F.; Romagnoli V.Cucchetti, A.; Gramenzi, A.; Johnson, P.; Giannini, E. G.; Tovoli, F.; Rapaccini, G. L.; Marra, F.; Cabibbo, G.; Caturelli, E.; Gasbarrini, A.; Svegliati-Baroni, G.; Sacco, R.; Zoli, M.; Morisco, F.; Di Marco, M.; Mega, A.; Foschi, F. G.; Biasini, E.; Masotto, A.; Nardone, G.; Raimondo, G.; Azzaroli, F.; Vidili, G.; Brunetto, M. R.; Farinati, F.; Trevisani, F.; Avanzato, F.; Biselli, M.; Caraceni, P.; Garuti, F.; Neri, A.; Santi, V.; Pellizzaro, F.; Imondi, A.; Sartori, A.; Penzo, B.; Sanmarco, A.; Granito, A.; Muratori, L.; Piscaglia, F.; Sansone, V.; Forgione, A.; Dajti, E.; Marasco, G.; Ravaioli, F.; Cappelli, A.; Golfieri, R.; Mosconi, C.; Renzulli, M.; Cela, E. M.; Facciorusso, A.; Cacciato, V.; Casagrande, E.; Moscatelli, A.; Pellegatta, G.; de Matthaeis, N.; Allegrini, G.; Lauria, V.; Ghittoni, G.; Pelecca, G.; Chegai, F.; Coratella, F.; Ortenzi, M.; Missale, G.; Olivani, A.; Inno, A.; Marchetti, F.; Busacca, A.; Camma, C.; Di Martino, V.; Maria Rizzo, G. E.; Franze, M. S.; Saitta, C.; Sauchella, A.; Berardinelli, D.; Bevilacqua, V.; Borghi, A.; Gardini, A. C.; Conti, F.; Dall'Aglio, A. C.; Ercolani, G.; Adotti, V.; Arena, U.; Di Bonaventura, C.; Campani, C.; Dragoni, G.; Gitto, S.; Laffi, G.; Coccoli, P.; Malerba, A.; Guarino, M.; Capasso, M.; Oliveri, F.; Romagnoli, V