Bilberry pomace in rabbit nutrition: effects on growth performance, apparent digestibility, caecal traits, bacterial community and antioxidant status.

Agricultural by-products could be used as alternative raw materials in rabbit nutrition as they have been found to be highly nutritious and low cost feeding sources. The aim of this study was to estimate the nutritive value and potential use of bilberry pomace (BP) for growing rabbits. A total of 144 Grimaud rabbits (35 days old) were allotted to four groups and fed with a diet containing increasing level of BP: BP0 (basal diet), BP5, BP10 and BP15 containing 0, 50, 100 and 150 g/kg respectively. Growth trial lasted 48 days; apparent digestibility was evaluated, starting at 46 days of age, over 4 consecutive days. The nutritive value of BP was measured using the mean digestibility of the experimental diets. At 83 days of age, rabbits were slaughtered: blood, and liver and kidney samples were collected in order to determine the blood parameters and the antioxidant enzyme activities of the tissues. Moreover, caecal content was sampled and gut microbiota assessed by means of amplicon-based high-throughput 16S rRNA sequencing and PCR-denaturing gradient gel electrophoresis. The digestible protein was estimated to 104 g/kg of DM while digestible energy to 9.44 MJ/kg DM for incorporation rate up to 150 g/kg. During the finishing period, average daily feed intake and feed conversion ratio showed linear response to BP increase (P=0.008 and <0.001, respectively). During all the period, both parameters decreased linearly and quadratically with increasing BP inclusion levels (P<0.001) up to 100 g/kg of BP. A significant effect of the antioxidant status was found in the kidneys and liver (P<0.05) where the glutathione peroxidase activity increased as the BP increased. As far as gut microbiota is concerned, BP increased the relative abundance of the Clostridium, Oscillospira, Ruminococcus and Ruminococcaceae species which were clearly associated with the BP inclusion level. In conclusion, BP showed a potential use as an alternative protein and fibre sources for growing rabbits.

Effects of dietary Tenebrio molitor meal inclusion in free-range chickens.

Insects are currently being considered as a novel protein source for animal feeds, because they contain a large amount of protein. The larvae of Tenebrio molitor (TM) have been shown to be an acceptable protein source for broiler chickens in terms of growth performance, but till now, no data on histological or intestinal morphometric features have been reported. This study has had the aim of evaluating the effects of dietary TM inclusion on the performance, welfare, intestinal morphology and histological features of free-range chickens. A total of 140 medium-growing hybrid female chickens were free-range reared and randomly allotted to two dietary treatments: (i) a control group and (ii) a TM group, in which TM meal was included at 75 g/kg. Each group consisted of five pens as replicates, with 14 chicks per pen. Growth performance, haematological and serum parameters and welfare indicators were evaluated, and the animals were slaughtered at the age of 97 days. Two birds per pen (10 birds/treatment) were submitted to histological (liver, spleen, thymus, bursa of Fabricius, kidney, heart, glandular stomach and gut) and morphometric (duodenum, jejunum and ileum) investigations. The inclusion of TM did not affect the growth performance, haematological or serum parameters. The morphometric and histological features were not significantly affected either, thus suggesting no influence on nutrient metabolization, performance or animal health. Glandular stomach alterations (chronic flogosis with epithelial squamous metaplasia) were considered paraphysiological in relation to free-range farming. The observed chronic intestinal flogosis, with concomitant activation of the lymphoid tissue, was probably due to previous parasitic infections, which are very frequently detected in free-range chickens. In conclusion, the findings of this study show that yellow mealworm inclusion does not affect the welfare, productive performances or morphological features of free-range chickens, thus confirming that TM can be used safely in poultry diets.

[The videolaparoscopic treatment of cholecystic common bile duct lithiasis: review of 827 cases]. / Il trattamento videolaparoscopico della litiasi colecisti-coledocica. Studio retrospettivo su 827 casi.

BACKGROUND: The aim of this retrospective study is to verify the progress of the results in 827 patients submitted to videolaparoscopic treatment for cholecysto-choledochus lithiasis during the period >March 1994 - September 2000. METHODS: All the patients had recurring biliary colic, dyspepsia and pain in the upper abdominal quadrants. All clinical forms of cholecystitis were treated. RESULTS: The laparotomic conversions in the case of lithiasis of the gallbladder alone were 8 (0.9%) and 13 (1.5%) as it occured simultaneously with lithiasis of the common bile duct. Mortality was null and morbidity was found in 4 cases, equal to 0.4%. CONCLUSIONS: On the basis of the results obtained cholecystectomy can be implemented on a large scale to include patients of all ages and those in the high risk groups provided that the operating team include expert and skilled surgeons in the laparoscopic method as well as the conventional methods.

Pharmacological profile of the novel inotropic agent (E,Z)-3-((2-aminoethoxy)imino)androstane-6,17-dione hydrochloride (PST2744).

The novel Na(+)/K(+)-ATPase inhibitor (E,Z)-3-((2-aminoethoxy)imino)androstane-6,17-dione hydrochloride (PST2744) was characterized for its inotropic and toxic properties. Inhibition potency on dog kidney Na(+)/K(+)-ATPase was comparable (0.43 microM) to that of digoxin (0.45 microM). PST2744 concentration-dependently increased force of contraction in guinea pig atria and twitch amplitude in isolated guinea pig myocytes; in the latter, aftercontractions developed significantly less than with digoxin. Intravenous infusion of 0.2 mg/kg/min PST2744 in anesthetized guinea pigs exerted an immediate and long-lasting inotropic effect (ED(80) of 1.89 +/- 0.37 mg/kg) without causing lethal arrhythmias up to a cumulative dose of 18 mg/kg. Conversely, an equieffective infusion of digoxin (0.016 mg/kg/min; ED(80) of 0.32 mg/kg) caused lethal arrhythmias at a cumulative dose of 0.81 mg/kg. At a higher rate (0.4 mg/kg/min), PST2744 induced lethal arrhythmias, with a lethal dose/ED(80) ratio significantly greater than digoxin (20.2 +/- 6.3 versus 3.23 +/- 0.55, p < 0.05). Decay of the inotropic effect (t(1/2), min) was significantly faster for PST2744 (6.0 +/- 0.39) than for digoxin (18.3 +/- 4.5, p < 0.05). In anesthetized dogs, PST2744 dose-dependently increased maximum velocity of pressure rise (+dP/dt(max)) in the range 32 to 500 microg/kg i.v. and was safer than digoxin. In conscious dogs with a healed myocardial infarction, PST2744 significantly increased resting values of +dP/dt(max), left ventricular pressure, and SPB, and increased +dP/dt(max) throughout treadmill exercise while reverting the increase in left ventricular end diastolic pressure seen in control animals. Digoxin significantly decreased basal heart rate, while not affecting the hemodynamic response to exercise. Thus, PST2744 represents a new class of Na(+)/K(+)-ATPase inhibitors endowed with inotropic activity comparable with that of digitalis but having greater safety.

[Laparoscopical marsupialization of symptomatic lymphoceles following kidney trans-plantation]. / Marsupializzazione videolaparascopica di linfocele sintomatico secondario a trapianto renale.

Personal experience in the laparoscopic treatment of a lymphocele following kidney transplantation and a review of the literature are presented. We have treated a symptomatic lymphocele, which occurred a month after renal transplantation. It compressed the iliac vessels and obstructed the urine flow. Physical examinations revealed it consisted of two chambers; it measured 12 x 8 x 6 cm. A US-guided puncture was performed and a drainage tube out in place. A continuous flow of lymphatic liquid derived, and therefore we decided on surgical intervention, which was conducted in laparoscopy. A puncture of blue through the drainage tube was performed; under US-guidance, we made an opening in the peritoneal wall and in the wall of the lymphocele. A cauterization of the edges was conducted. An immediate improvement in subjective and objective symptoms was achieved. A four-month follow-up showed minimal residual effusion, slowly disappearing. Literature data and clinical evolution of the patient show that the laparoscopic approach is to be considered the "gold standard" for the treatment of symptomatic lymphocele following kidney transplantation. The authors recommend the use of US-guidance to single out anatomic structures, particularly for surgeons not trained in this procedure.

17 alpha-O-(aminoalkyl)oxime derivatives of 3 beta,14 beta-dihydroxy-5 beta-androstane and 3 beta-hydroxy-14-oxoseco-D-5 beta-androstane as inhibitors of Na(+),K(+)-ATPase at the digitalis receptor.

The synthesis and binding affinities to the digitalis Na(+),K(+)-ATPase receptor of a series of 3 beta,14 beta-dihydroxy-5 beta-androstane and 3 beta-hydroxy-14-oxoseco-D-5 beta-androstane derivatives bearing a 17 alpha-(aminoalkoxy)imino chain are reported; some derivatives were also studied for their inotropic activity. Our recently proposed model of interaction of molecules with the digitalis receptor was used to design these compounds. On that basis, the possibility to design novel potent inhibitors of Na(+),K(+)-ATPase without being constrained by the stereochemistry of the classical digitalis skeleton in the D-ring region was predicted. The binding affinities of the most potent compounds in the two series, (EZ)-17 alpha-[2-[(2-aminoethoxy)imino]ethyl]-5 beta-androstane-3 beta,14 beta-diol (6f) and (EZ)-3 beta-hydroxy-17 alpha-[2-[(2-aminoethoxy)imino]ethyl]-14,15-seco-5 beta-androstan-14-one (24c) are higher than that of the potent natural compound digitoxigenin, despite the unusual alpha-exit of the substituent in position 17 of 6f or the disruption of the D-ring in 24c. These results further support the validity of our recently proposed model of binding at the digitalis receptor. Results of the inotropic tests on guinea pig atrium deserve further investigation on the pharmacological profile of these derivatives.

A point mutation in the N-terminal coiled-coil domain releases c-Fes tyrosine kinase activity and survival signaling in myeloid leukemia cells.

The c-fes locus encodes a 93-kDa non-receptor protein tyrosine kinase (Fes) that regulates the growth and differentiation of hematopoietic and vascular endothelial cells. Unique to Fes is a long N-terminal sequence with two regions of strong homology to coiled-coil oligomerization domains. We introduced leucine-to-proline substitutions into the coiled coils that were predicted to disrupt the coiled-coil structure. The resulting mutant proteins, together with wild-type Fes, were fused to green fluorescent protein and expressed in Rat-2 fibroblasts. We observed that a point mutation in the first coiled-coil domain (L145P) dramatically increased Fes tyrosine kinase and transforming activities in this cell type. In contrast, a similar point mutation in the second coiled-coil motif (L334P) was without effect. However, combining the L334P and L145P mutations reduced transforming and kinase activities by approximately 50% relative to the levels of activity produced with the L145P mutation alone. To study the effects of the coiled-coil mutations in a biologically relevant context, we expressed the mutant proteins in the granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent myeloid leukemia cell line TF-1. In this cellular context, the L145P mutation induced GM-CSF independence, cell attachment, and spreading. These effects correlated with a marked increase in L145P protein autophosphorylation relative to that of wild-type Fes. In contrast, the double coiled-coil mutant protein showed greatly reduced kinase and biological activities in TF-1 cells. These data are consistent with a role for the first coiled coil in the negative regulation of kinase activity and a requirement for the second coiled coil in either oligomerization or recruitment of signaling partners. Gel filtration experiments showed that the unique N-terminal region interconverts between monomeric and oligomeric forms. Single point mutations favored oligomerization, while the double point mutant protein eluted essentially as the monomer. These data provide new evidence for coiled-coil-mediated regulation of c-Fes tyrosine kinase activity and signaling, a mechanism unique among tyrosine kinases.

17beta-O-Aminoalkyloximes of 5beta-androstane-3beta,14beta-diol with digitalis-like activity: synthesis, cardiotonic activity, structure-activity relationships, and molecular modeling of the Na(+),K(+)-ATPase receptor.

A series of digitalis-like compounds with a 17-aminoalkoxyiminoalkyl or -alkenyl substituent was synthesized and evaluated for inhibition of Na(+),K(+)-ATPase and for inotropic activity. The highest inhibition was found with compounds having the substituent in configuration 17beta and the amino group at a distance of 6 or 7 bonds from C(17) of the digitoxigenin skeleton. The presence of the oxime function strengthens the interaction with the receptor, more if alpha,beta-unsaturated, thus mimicking the electronic situation of the unsaturated lactone in natural digitalis compounds. The most active compounds showed Na(+),K(+)-ATPase inhibitory potencies (IC(50)) 17-25 times higher than the standards digitoxigenin and digoxin and 3-11 times higher inotropic potencies (EC(50)) in isolated guinea pig left atria. These features are supported by a molecular model suggesting the possible interactions of the groups described above with particular amino acid residues in the H1-H2 domains of Na(+),K(+)-ATPase. Some interactions are the classical ones already described in the literature; a new, very strong interaction of the basic group with the Cys138 was found and adds new possibilities to design compounds interacting with this region of the receptor. The most interesting compounds were also studied in vivo in the anesthetized guinea pig for evaluating their inotropic effect versus the lethal dose. Compounds 9 and 12 showed a slightly higher safety ratio than digoxin and deserve further evaluation.

Gastroprokinetic properties of the benzimidazolone derivative BIMU 1, an agonist at 5-hydroxytryptamine4 and antagonist at 5-hydroxytryptamine3 receptors.

We have investigated the in vivo motor stimulating and gastroprokinetic properties of the azabicycloalkyl benzimidazolone derivative BIMU 1 (3-ethyl-2,3-dihydro-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2-oxo-1H- benzimidazole-1-carboxamide hydrochloride) and its binding profile at 5-hydroxytryptamine3 and 5-hydroxytryptamine4 receptors, in an attempt to assess the serotonergic mechanism underlying its prokinetic action. BIMU 1 dose-dependently (0.01-0.3 mg/kg i.v.) increased the motility of a denervated pouch of canine stomach. This excitatory action was sensitive to muscarinic blockade. A similar stimulatory effect was exerted by the benzamidic prokinetic agent cisapride (0.03-0.3 mg/kg i.v.) but not by the 5-HT3 receptor antagonist ondansetron (up to 1 mg/kg i.v.). The significance for propulsive efficacy of the motor stimulating activity of BIMU 1 was evaluated in a model of gastric emptying of liquids in the conscious dog. The emptying rate of a non-caloric liquid meal instilled through a gastric fistula was accelerated by both BIMU 1 (0.01-1 mg/kg i.v. and 0.1-3 mg/kg p.o.) and cisapride (0.03-1 mg/kg i.v. and 0.3-10 mg/kg p.o.). Ondansetron (1 mg/kg i.v.) did not show any effect. The activity of the 5-HT4 receptor antagonist DAU 6285 was evaluated in the gastric emptying model per se and in interaction experiments on the accelerating action of BIMU 1 (0.3 mg/kg i.v.).(ABSTRACT TRUNCATED AT 250 WORDS)

Propionyl-L-carnitine limits chronic ventricular dilation after myocardial infarction in rats.

To determine whether propionyl-L-carnitine (PLC) administration ameliorates ventricular remodeling after myocardial infarction, we performed coronary occlusion in rats and examined the long-term effects of the drug 19-24 wk after surgery. In view of the well-established role of angiotensin-converting enzyme (ACE) inhibitors in the reduction of ventricular dilation after infarction, the therapeutic impact of oral PLC (60 mg/kg) was compared with that of enalapril (1 mg/kg). Infarct size measured planimetrically was found to be comparable in untreated, PLC-treated, and enalapril-treated rats, averaging 40-46% of the left ventricular free wall. Heart weight was increased 14, 16, and 11% with no treatment, with PLC, and with enalapril, respectively. The relationship between left ventricular filling pressure and chamber volume demonstrated that PLC and enalapril significantly prevented the expansion in cavitary size after infarction. These protective influences were observed throughout the range of filling pressures measured, from 0 to 30 mmHg. At a uniform reference point of filling pressure of 4 mmHg, untreated infarcted hearts showed an expansion in ventricular volume of 2.17-fold (P < 0.0001). Corresponding increases in this parameter after PLC and enalapril were 36 and 43%, respectively, both not statistically significant. Moreover, PLC was capable of reducing the alterations in myocardial compliance associated with myocardial infarction. In conclusion, PLC reduces the magnitude of decompensated eccentric hypertrophy produced by myocardial infarction in a manner similar to that found with ACE inhibition.

[Recurrent hernia of the Douglas pouch. Surgical reconstruction by the vaginal route using a mersylene net]. / Ernia del Douglas recidivante. Correzione e riparazione per via vaginale mediante l'uso di rete in Mersilene.

The paper reports an interesting case of Douglas' hernia in a patient who had previously undergone gynecological surgery using a vaginal and abdominal route. The paper is illustrated by radiographic image. The importance of the clinical, anatomical and morphological conditions of the patient is underlined in the evolution of the hernial pathology. Reconstructive surgery was performed by creating a support barrier of mersylene net in order to avoid further recurrences.

Pharmacology of mifentidine, a novel H2-receptor antagonist.

N1-[(4-Imidazolyl)-phenyl]-N2-isopropylformamidine (mifentidine, DA 4577 is a potent and selective H2 antagonist, representative of a new class of compounds, the imidazolylphenyl-formamidines, characterized by a semi-rigid structural conformation. Mifentidine appeared to be a specific and competitive antagonist of several histamine-mediated responses. Thus, in isolated guinea pig atria and ventricles it antagonized histamine chronotropic and dimaprit inotropic effects in a competitive manner providing affinity estimates (pA2) of 7.66 and 7.74, respectively. Mifentidine exerted potent antisecretory effects in: the isolated mouse stomach where it antagonized the acid promoting activity of histamine (EC50 3.28 mumol/l) but not that of bethanechol or db-cAMP (adenosine 3',5'-monophosphate); the lumen perfused stomach of the anaesthetized rat, inhibiting histamine (ED50 0.1 mumol/kg i.v.) and pentagastrin (ED50 0.2 mumol/kg i.v.) stimulated secretion; the pylorus ligated rat (ED50 1.35 mumol/kg i.v.); the gastric fistula dog, reducing the secretagogue effect of pentagastrin (ED50 96 nmol/kg i.v.); the conscious dog equipped with the Heidenhain pouch, where it was effective both following intravenous (ED50 119.7 nmol/kg) and oral administration (ED50 323.8 nmol/kg) in antagonizing histamine action. Mifentidine antisecretory effect, examined in the dog, appeared to last for a significantly longer time than that of ranitidine. Mifentidine was free of cardiovascular effects (on aortic blood pressure and heart rate) when administered repeatedly to the conscious dog at doses far above those needed to suppress acid secretion.