THE EFFECTS OF REALSIL (SILYBIN-PHOSPHOLIPID-VITAMIN E COMPLEX) ON LIVER ENZYMES IN PATIENTS WITH NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) OR NON-ALCOHOLIC STEATO-HEPATITIS (NASH): A SYSTEMATIC REVIEW AND META-ANALYSIS OF RCTS.

BACKGROUND: The aim of the present study was to systematically review the effects of Realsil (silybin-phospholipid-vitamin E complex) on liver enzymes in patients with NAFLD or NASH. METHODS: We searched Web of Science, MEDLINE, Google Scholar, Cochrane Library, Science Direct, ProQuest, Scopus, and 1868 articles were found up to December 2018. Four studies that examined the effect of Realsil intake on liver enzymes among NAFLD or NASH patients were included. Exclusion criteria include: animal studies, studies with the design other than clinical trials, studies on non-adult individuals, studies that assess the effect of vitamin E, silybin, or phospholipid solely, studies that examined the effect of Realsil on other outcomes, or studies with insufficient data. RESULTS: The analysis demonstrated that Realsil intake led to a significant decrease in Gamma-Glutamyl Transpeptidase (GGT) levels (standardized mean difference (SMD) =-0.37; 95% confidence interval (CI]): -0.68 to -0.06). Realsil intake non-significantly decrease alanine transaminase (ALT) levels (SMD=-1.02 U/L; 95% CI: -2.23 to 0.20) and non-significantly increase aspartate aminotransferase (AST) levels (SMD = 0.17 U/L; 95% CI: -0.26-0.61). CONCLUSION: Realsil intake was associated with a significantly decreased circulating GGT level without any significant effect on AST and ALT levels.

Impact of systemic or mucosal immunity to adenovirus on Ad-based Ebola virus vaccine efficacy in guinea pigs.

BACKGROUND: Approximately 35% of the North American population and an estimated 90% of the sub-Saharan African population have antibodies against adenovirus serotype 5 (AdHu5) that are capable of neutralizing AdHu5-based vaccines. In mice, intranasal delivery of AdHu5 expressing the Zaire ebolavirus glycoprotein human adenovirus serotype 5 (Ad) containing the genes for the Zaire ebolavirus glycoprotein (ZGP) under the expressional control of a cytomegalovirus immediate early promoter (CMV)) can bypass systemic preexisting immunity, resulting in protection against mouse-adapted Zaire ebolavirus (Mayinga 1976). METHODS: Guinea pigs administered an adenovirus-based Ebola virus vaccine either intramuscularly or intranasally in the presence of systemically or mucosally induced adenovirus immunity were challenged with a lethal dose of guinea pig-adapted Zaire ebolavirus (Mayinga 1976) (GA-ZEBOV). The humoral immune response was assayed to determine the effect of vaccine delivery route and preexisting immunity. RESULTS: Intramuscular or intranasal vaccination fully protected guinea pigs against a lethal GA-ZEBOV challenge. However, intramuscular vaccination in animals with systemically induced preexisting immunity resulted in low survival following challenge. Interestingly, intranasal vaccination protected guinea pigs with systemic preexisting immunity to AdHu5. Mucosal adenoviral immunity induced by intranasal administration of AdHu5 decreased protection following intranasal vaccination with the first-generation but not with the second-generation vaccine. CONCLUSIONS: Intranasal vaccination is an effective vaccine delivery route in the presence of systemic and, to a lower extent, mucosal preexisting immunity to the vaccine vector in guinea pigs.

VPAC1 is a cellular neuroendocrine receptor expressed on T cells that actively facilitates productive HIV-1 infection.

OBJECTIVE: A lack of productive HIV-1 infection of Kit225 compared to Jurkat T cells, despite similar levels of CD4 and HIV-1 chemokine co-receptors, was found to correlate with the expression of vasoactive intestinal peptide/pituitary adenylate cyclase activating polypeptide receptor-1 (VPAC1). We therefore examined a role for this seven-transmembrane G protein-coupled neuroendocrine receptor in modulating HIV-1 infection. METHODS: Reverse transcription-PCR was used to show the level of VPAC1 expression in different T-cell lines. A signal-blocking antibody to VPAC1 was used to examine its inhibiting effect on HIV-1 infection. Transfection of VPAC1 cDNA in both sense and anti-sense orientation was used to assess the role of VPAC1 in HIV-1 infection. HIV-1 infection was monitored by gag p24 ELISA using HIV-1IIIB or by luciferase activity using pseudo envelope-typed HXB2-NL4-3-luciferase. Analysis of HIV-1 gag DNA and 2-LTR circles was utilized to examine a possible mechanism for the effect of VPAC1. RESULTS: Using VPAC1 signal blocking antibody, we showed that up to 80% of productive infection with HIV-1IIIB was inhibited. We also demonstrated that HIV-1 gp120 has sequence similarity to the natural ligand for VPAC1 and postulate that it can activate this receptor directly. Transfection of VPAC1 cDNA in the anti-sense orientation resulted in a significant loss, up to 50% of productive infection. In contrast, transfection of cells with VPAC1 in the sense orientation increased the productive infection by more than 15-fold and caused a profound increase in syncytium formation. Furthermore, stimulation of VPAC1 on primary cells facilitated in vitro infection with HIV-1 HXB2-NL4-3. Analysis of HIV-1 gag DNA indicated that VPAC1 does not affect viral entry; however, cells that show negligible expression of VPAC1 may not be productively infected as indicated by a lack of 2-LTR circle formation. CONCLUSION: We have discovered a cellular receptor, VPAC1, that is a novel and potent facilitator of HIV-1 infection and thus, is a potentially important new target for therapeutic intervention.

Lesioning and recovery of the serotoninergic hippocampal afferents: differential effects of GM1 ganglioside.

The effects of administration of GM1 ganglioside on the content of 5-HT and of 5-HIAA in the hippocampus after two different types of lesions of the serotoninergic afferents to the hippocampus were studied. The first type of lesion consisted in severing the dorsal hippocampal afferents. This caused a monolateral decrease of the content of 5-HT and of 5-HIAA in the hippocampal by 60 and 38%, respectively. Since a partial spontaneous recovery occurred after 40-60 days, this model has been used in the past to study sprouting phenomena in the 5-HT system. Daily intraperitoneal administration of GM1 ganglioside (30 mg/kg), for up to 60 days, did not modify this partial recovery. The second lesion consisted of electrolytic damage to a mesencephalic area, where scattered 5-HT cells projecting to the hippocampus are known to be located. The content of 5-HT and 5-HIAA in the hippocampus, ipsilateral to this lesion, decreased by 37 and by 26%, respectively. Administration of GM1 ganglioside (30 mg/kg/day for 6-14 days) partially antagonized the decrease of both 5-HT and 5-HIAA induced by the lesion. These data are in agreement with the view that gangliosides may reduce neuronal injury after mechanical lesions, with a mechanism which is probably not related to neuronal sprouting.

Modelling strategies for controlling SARS outbreaks.

Severe acute respiratory syndrome (SARS), a new, highly contagious, viral disease, emerged in China late in 2002 and quickly spread to 32 countries and regions causing in excess of 774 deaths and 8098 infections worldwide. In the absence of a rapid diagnostic test, therapy or vaccine, isolation of individuals diagnosed with SARS and quarantine of individuals feared exposed to SARS virus were used to control the spread of infection. We examine mathematically the impact of isolation and quarantine on the control of SARS during the outbreaks in Toronto, Hong Kong, Singapore and Beijing using a deterministic model that closely mimics the data for cumulative infected cases and SARS-related deaths in the first three regions but not in Beijing until mid-April, when China started to report data more accurately. The results reveal that achieving a reduction in the contact rate between susceptible and diseased individuals by isolating the latter is a critically important strategy that can control SARS outbreaks with or without quarantine. An optimal isolation programme entails timely implementation under stringent hygienic precautions defined by a critical threshold value. Values below this threshold lead to control, but those above are associated with the incidence of new community outbreaks or nosocomial infections, a known cause for the spread of SARS in each region. Allocation of resources to implement optimal isolation is more effective than to implement sub-optimal isolation and quarantine together. A community-wide eradication of SARS is feasible if optimal isolation is combined with a highly effective screening programme at the points of entry.

Heparin adsorbing capacities at physiological pH of three poly(amido-amine) resins, and of poly(amido-amine)-surface-grafted glass microspheres.

Three poly(amido-amine)s of similar structure in the form of highly hydrophilic crosslinked resins, have been prepared, and tested for their heparin-adsorbing capacity at physiological pH. They showed different capacities, and their capacities were related to their basicities. One of the same polymers was grafted on the surface of glass microspheres. After treatment, it was shown that the microspheres could adsorb significant amounts of heparin. In all cases most of the adsorbed heparin was hardly eluted with saline, plasma, or blood, but could be recovered by eluting with 0.1 M NaOH. The resins were found to have some haemolytic properties, but no haemolysis was observed with the grafted microspheres.

Differential actions of neurotrophic factors on lesion-induced damage of the serotonergic neurons projecting to the hippocampus.

The changes induced by nerve growth factor (NGF) and by GM1-ganglioside administration on serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and tryptophan content and on choline acetyltransferase activity, were studied in the central nervous system of rats undergoing electrolytic damage of a mesencephalic area, located near the nucleus interpeduncularis. This lesion selectively reduced the content of 5-HT and 5-HIAA in the ipsilateral hippocampus. Daily intraperitoneal injection of GM1-ganglioside (30 mg/kg/day for 6-14 days) significantly reduced the injury-induced loss of hippocampal 5-HT and 5-HIAA content. On the contrary NGF, administered at a dose (10 micrograms/rat i.c.v. twice a week for 2 weeks) which was able to increase, in the same animals, the cortical choline acetyltransferase activity, failed to affect the lesion-induced reduction of 5-HT and of 5-HIAA in the hippocampus.

Lesioning and recovery of the serotoninergic projections to the hippocampus.

The time course of the changes of the hippocampal 5-hydroxytryptamine (5-HT) system after a lesion of the dorsal afferents to this brain area was studied by measuring the content of 5-HT and of 5-hydroxyindoleacetic acid (5-HIAA) in the dorsal, medial and ventral hippocampus. Furthermore, the binding sites for [3H]5-HT, [3H]ketanserin, [3H]imipramine and [3H]mianserin and a 5-HT-mediated behavior (head-twitch responses) were studied in controls and in animals bearing such a lesion. The contents of 5-HT and of 5-HIAA are higher in the ventral than in the dorsal hippocampus. Seven days after the lesion the 5-HT content decreases by 78% in the dorsal and by 50% in the ventral hippocampus. However, 60 days later, a partial recovery, possibly due to a collateral sprouting, does occur. The ratios between 5-HIAA and 5-HT are also increased 10, 14 and 21 days after the lesion, suggesting an increased utilization of the amine by the remaining neuronal terminals. The Bmax of the recognition sites for [3H]5-HT and [3H]mianserin, but not those for [3H]ketanserin are increased 10 days after the lesion and this increase lasts at least 30 days. Finally, starting 10 days after surgery and lasting for 40 days, a 5-HT-mediated behavior (head-twitch responses) shows supersensitivity. These results suggest that important changes occur in the 5-HT innervation of the hippocampus after a mechanical lesion: among these we showed a slow collateral sprouting, an increased utilization of the amine and a supersensitivity of 5-HT receptors.

Decrease in rat cerebral quinolinic acid concentration following chronic hydrocortisone treatment.

The effects of acute or repeated hydrocortisone administration were studied on the content of quinolinic acid (QUIN), 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) assessed by mass fragmentography (QUIN) and high-performance liquid chromatography (5-HT and 5-HIAA) in various brain areas of the rat. Acute administration of the steroid did not significantly modify the brain content of these tryptophan metabolites while, when repeatedly administered at doses of 5 or 50 mg/kg i.p., hydrocortisone significantly reduced the cortical content of QUIN (by 28%, P less than 0.05 and 21%, P less than 0.05 respectively) and the utilization of 5-HT (as evaluated from the ratio 5-HIAA/5-HT by 22%, P less than 0.05 at 50 mg/kg). These data confirm that hydrocortisone administration affects tryptophan metabolism in the rat.

A new endogenous anxiolytic agent: L-pyroglutamic acid.

By use of a simple anticonflict procedure (Vogel test), it was demonstrated that L-pyroglutamic acid (L-pyrrolidone carboxylic acid [L-PCA]), an amino acid naturally occurring in mammalian tissues and fluids, possesses anxiolytic activity. This tissues and fluids, possesses anxiolytic activity. This effect was stereospecific (D-PCA was inactive) and, in the rat, it was not associated with a decrease in motor activity. Ro 15-1788, a benzodiazepine antagonist, did not modify L-PCA actions. Furthermore, anxiolytic doses of the amino acid did not change the content of 5-hydroxytryptamine (5-HT) or of 5-hydroxyindoleacetic acid (5-HIAA) in the rat cortex and hippocampus. These results suggest that the mechanism of the anxiolytic activity of L-PCA is different from that of the benzodiazepines and of 5-HT1a agonists.

Omeprazole in patients with mild or moderate reflux esophagitis induces lower relapse rates than ranitidine during maintenance treatment.

BACKGROUND/AIMS: Patients with reflux esophagitis have rapid relapses after treatment withdrawal. This study was designed to investigate the relapse rate of symptomatic esophagitis during maintenance treatment with omeprazole versus ranitidine after the induction of acute healing with omeprazole. METHODOLOGY: Patients with endoscopically verified acute erosive or ulcerative esophagitis (grade 2 or 3) were initially treated with 20 mg of omeprazole daily for 4, 8, or 12 weeks. After healing, the patients were randomized to maintenance treatment with omeprazole (20 mg every morning) or ranitidine (150 mg twice daily). A control endoscopy was performed at the end of the healing phase and after 6 months of maintenance treatment or symptomatic relapse. RESULTS: Of 231 initially treated patients, 223 were healed (no erosive esophagitis) and entered the maintenance study. The estimated proportions of patients in remission after 6 months of maintenance treatment with 20 mg of omeprazole once per day (n = 102) and 150 mg of ranitidine twice per day (n = 103) were 89.2% and 75.7%, respectively. The single daily dose of omeprazole worked significantly better than the doses of ranitidine (p < 0.001). The omeprazole group, in comparison to the ranitidine group, had a significantly higher number of patients without symptoms (37.8% vs 54.7%) and a lesser percentage of moderate symptoms (9.45% vs 19.8%). CONCLUSIONS: Maintenance treatment with omeprazole (20 mg once daily) is superior to ranitidine (150 mg twice daily) in keeping patients with mild to moderate erosive reflux esophagitis in remission over a 6-month period.

[Pheochromocytoma diagnosed during quinapril therapy]. / Feocromocitoma evidenziato in corso di terapia con quinapril.

A hypertensive diabetic woman, who was resistant to any pharmacological therapy, underwent to check for secondary hypertension. The treatment with the particularly active ACE inhibitor quinapril failed but it suggested a procedure for a fast differential diagnosis of disease.

Identification and measurement of kynurenic acid in the rat brain and other organs.

Kynurenic acid, a biologically active tryptophan metabolite, has been identified and measured in the rat brain and other organs using HPLC and GC/MS. Both the described methods required extraction of the compound in alkaline ethanol and initial purification on Dowex ion-exchange resins. The GC/MS approach used 3-hydroxy-2-naphthoic acid as an internal standard and a derivatization procedure with diazomethane and trifluoroacetic anhydride. The HPLC procedure was performed on a reverse-phase column using a spectrophotometric detector. Both the GC/MS and the HPLC methods had the lowest detection limit in the range of 10 pmol/injection, but the variability of the results was lower when HPLC was used. HPLC analysis showed the content of kynurenic acid to be 14 +/- 2 pmol/g wet wt in the brain, 75 +/- 7 in the heart, 87 +/- 8 in the liver, and 298 +/- 10 in the kidneys. Comparable but variable values were obtained with GC/MS.

Presence of kynurenic acid in the mammalian brain.

Kynurenic acid, a tryptophan metabolite able to antagonize the actions of the excitatory amino acids, has been identified and measured for the first time in the brain of mice, rats, guinea pigs, and humans by using an HPLC method. Its content was 5.8 +/- 0.9 in mouse brain, 17.8 +/- 2.0 in rat brain, 16.2 +/- 1.5 in guinea pig brain, 26.8 +/- 2.9 in rabbit brain, and 150 +/- 30 in human cortex (pmol/g wet wt. mean +/- SE). The regional distribution of this molecule was uneven. In rats, guinea pigs, and rabbits, the brainstem was the area richest in this compound. Tryptophan administration (100-300 mg/kg, i.p.) to rats resulted in a significant increase of the brain content of kynurenic acid. Similarly, 1 h after probenecid administration (200 mg/kg, i.p.), the brain content of kynurenate increased by fourfold, thus suggesting that its turnover rate is relatively fast.

Biochemical and behavioural studies on indole-pyruvic acid: a keto-analogue of tryptophan.

The effects of acute or repeated administration of indole-pyruvic acid (IPA), a keto-analogue of tryptophan (TRP), were studied in various brain areas of rats by measuring the changes of 5-hydroxytryptamine (5-HT) and of norepinephrine (NE) content and metabolism. The analgesic and sedative properties of the molecule were evaluated by measuring the tail-flick latency, the spontaneous activity and the potentiation of the barbiturate-induced sleep. Acute or repeated administrations of IPA (20 or 50 mg/kg) increased the utilization of 5-HT in the cortex, hippocampus, diencephalon and brain-stem of rats fed a standard laboratory diet. IPA, however, did not substitute TRP in rats fed a TRP-free diet. The administration of this keto-analogue resulted also in a decreased content of 3-methoxy-4-hydroxy-phenylglycol (MHPG) in the cortex and in the brain-stem, thus suggesting a decreased utilization of NE in these areas. Furthermore, IPA administration decreased the rats' spontaneous activity, increased the duration of barbiturate-induced sleep and increased the tail-flick time, thus indicating that it has sedative and analgesic properties.