Analgesia induced by the epigenetic drug, L-acetylcarnitine, outlasts the end of treatment in mouse models of chronic inflammatory and neuropathic pain

Background: L-acetylcarnitine, a drug marketed for the treatment of chronic pain, causes analgesia by epigenetically up-regulating type-2 metabotropic glutamate (mGlu2) receptors in the spinal cord. Because the epigenetic mechanisms are typically long-lasting, we hypothesized that analgesia could outlast the duration of L-acetylcarnitine treatment in models of inflammatory and neuropathic pain. Results: A seven-day treatment with L-acetylcarnitine ( 100 mg/kg, once a day, i.p.) produced an antiallodynic effect in the complete Freund adjuvant mouse model of chronic inflammatory pain. L-Acetylcarnitine-induced analgesia persisted for at least 14 days after drug withdrawal. In contrast, the analgesic effect of pregabalin, amitryptiline, ceftriaxone, and N-acetylcysteine disappeared seven days after drug withdrawal. L-acetylcarnitine treatment enhanced mGlu2/3 receptor protein levels in the dorsal region of the spinal cord. This effect also persisted for two weeks after drug withdrawal and was associated with increased levels of acetylated histone H3 bound to the Grm2 gene promoter in the dorsal root ganglia. A long-lasting analgesic effect of L-acetylcarnitine was also observed in mice subjected to chronic constriction injury of the sciatic nerve. In these animals, a 14-day treatment with pregabalin, amitryptiline, tramadol, or L-acetylcarnitine produced a significant antiallodynic effect, with pregabalin displaying the greatest efficacy. In mice treated with pregabalin, tramadol or L-acetylcarnitine the analgesic effect was still visible 15 days after the end of drug treatment. However, only in mice treated with L-acetylcarnitine analgesia persisted 37 days after drug withdrawal. This effect was associated with an increase in mGlu2/3 receptor protein levels in the dorsal horns of the spinal cord. Conclusions: Our findings suggest that L-acetylcarnitine has the unique property to cause a long-lasting analgesic effect that might reduce relapses in patients suffering from chronic pain

Microcystin Contamination in Sea Mussel Farms from the Italian Southern Adriatic Coast following Cyanobacterial Blooms in an Artificial Reservoir

An experimental study was performed in 2009-2010 to investigate the polluting effect of eutrophic inland waters communicating with the sea coast. The study was planned after a heavy and long-lasting Planktothrix rubescens bloom occurred in the Lake Occhito, an artificial reservoir. The waters of the reservoir flow into the southern Adriatic Sea, near several marine breeding of Mytilus galloprovincialis mussels, a typical seafood from the Apulia region (Southern Italy). A monitoring study of water and mussels from the sea coast of northern Apulia region and on the Occhito reservoir was carried out over twelve months, to get more information regarding the contamination by cyanobacteria and related cyanotoxins. Elisa immunoassay analyses estimated total microcystin amounts from 1.73 to 256 ng/g in mussels, up to 0.61 μg/L in sea water and up to 298.7 μg/L in lake water. Analyses of some samples of free-living marine clams as well as of marine and freshwater fish proved microcystin contamination. Selective confirmatory analyses by LC/ESI-Q-ToF-MS/MS on some mussel samples identified the microcystin desMe-MC-RR as the major toxin; this compound has been reported in the literature as a specific marker toxin of Planktothrix rubescens blooms. Our study describes for the first time the direct relationship between environmental pollution and food safety, caused by seafood contamination from freshwater toxic blooms

Microcystin Contamination in Sea Mussel Farms from the Italian Southern Adriatic Coast following Cyanobacterial Blooms in an Artificial Reservoir

An experimental study was performed in 2009-2010 to investigate the polluting effect of eutrophic inland waters communicating with the sea coast. The study was planned after a heavy and long-lastingPlanktothrix rubescensbloom occurred in the Lake Occhito, an artificial reservoir. The waters of the reservoir flow into the southern Adriatic Sea, near several marine breeding ofMytilus galloprovincialismussels, a typical seafood from the Apulia region (Southern Italy). A monitoring study of water and mussels from the sea coast of northern Apulia region and on the Occhito reservoir was carried out over twelve months, to get more information regarding the contamination by cyanobacteria and related cyanotoxins. Elisa immunoassay analyses estimated total microcystin amounts from 1.73 to 256 ng/g in mussels, up to 0.61 μg/L in sea water and up to 298.7 μg/L in lake water. Analyses of some samples of free-living marine clams as well as of marine and freshwater fish proved microcystin contamination. Selective confirmatory analyses by LC/ESI-Q-ToF-MS/MS on some mussel samples identified the microcystin desMe-MC-RR as the major toxin; this compound has been reported in the literature as a specific marker toxin ofPlanktothrix rubescensblooms. Our study describes for the first time the direct relationship between environmental pollution and food safety, caused by seafood contamination from freshwater toxic blooms

Inner tubing technique used for the treatment of anastomotic aneurism

The authors report the case of a 66-year-old male patient diagnosed with a pseudoaneurysm of the distal aorto-aortic anastomosis treated with the inner tubing technique. The patient had been operated on 1 year before when he had an aortic prosthesis implanted as treatment for a ruptured abdominal aortic aneurysm. The inner tubing technique was developed to facilitate the treatment in bifurcated vascular lesions, where endovascular conventional prosthesis is not availabl

mGlu1 Receptors Monopolize the Synaptic Control of Cerebellar Purkinje Cells by Epigenetically Down-Regulating mGlu5 Receptors

In cerebellar Purkinje cells (PCs) type-1 metabotropic glutamate (mGlu1) receptors play a key role in motor learning and drive the refinement of synaptic innervation during postnatal development. The cognate mGlu5 receptor is absent in mature PCs and shows low expression levels in the adult cerebellar cortex. Here we found that mGlu5 receptors were heavily expressed by PCs in the early postnatal life, when mGlu1α receptors were barely detectable. The developmental decline of mGlu5 receptors coincided with the appearance of mGlu1α receptors in PCs, and both processes were associated with specular changes in CpG methylation in the corresponding gene promoters. It was the mGlu1 receptor that drove the elimination of mGlu5 receptors from PCs, as shown by data obtained with conditional mGlu1α receptor knockout mice and with targeted pharmacological treatments during critical developmental time windows. The suppressing activity of mGlu1 receptors on mGlu5 receptor was maintained in mature PCs, suggesting that expression of mGlu1α and mGlu5 receptors is mutually exclusive in PCs. These findings add complexity to the the finely tuned mechanisms that regulate PC biology during development and in the adult life and lay the groundwork for an in-depth analysis of the role played by mGlu5 receptors in PC maturation

Antimicrobial, cytotoxic and insulin‐releasing activities of the amphibian host‐defense peptide ocellatin‐3N and its L‐lysine‐substituted analogs

The host-defense peptide ocellatin-3N (GIFDVLKNLAKGVITSLAS.NH2), first isolated from the Caribbean frog Leptodactylus nesiotus, inhibited growth of clinically relevant Gram-positive and Gram-negative bacteria as well as a strain of the major emerging yeast pathogen Candida parapsilosis. Increasing cationicity while maintaining amphipathicity by the substitution Asp(4)-> Lys increased potency against the microorganisms by between 4- and 16-fold (MIC <= 3 mu M) compared with the naturally occurring peptide. The substitution Ala(18)-> Lys and the double substitution Asp(4)-> Lys and Ala(18)-> Lys had less effects on potency. The [D4K] analog also showed 2.5- to 4-fold greater cytotoxic potency against non-small-cell lung adenocarcinoma A549 cells, breast adenocarcinoma MDA-MB-231 cells, and colorectal adenocarcinoma HT-29 cells (LC50 values in the range of 12-20 mu M) compared with ocellatin-3N but was less hemolytic to mouse erythrocytes. However, the peptide showed no selectivity for tumor-derived cells [LC50 = 20 mu M for human umbilical vein endothelial cells (HUVECs)]. Ocellatin-3N and [D4K]ocellatin-3N stimulated the release of insulin from BRIN-BD11 clonal beta-cells at concentrations >= 1 nM, and [A18K]ocellatin-3N, at concentrations >= 0.1 nM. No peptide stimulated the release of lactate dehydrogenase at concentrations up to 3 mu M, indicating that plasma membrane integrity had been preserved. The three peptides produced an increase in intracellular [Ca2+] in BRIN-BD11 cells when incubated at a concentration of 1 mu M. In view of its high insulinotropic potency and relatively low hemolytic activity, the [A18K] ocellatin analog may represent a template for the design of agents with therapeutic potential for the treatment of patients with type 2 diabetes

SOGS-RA gambling scores and substance use in adolescents

Background and aims There is a well-established association between pathological gambling and substance use disorders in adolescents. The aim of this study was to shed light on the association between adolescents’ different levels of involvement in gambling activities and substance use (smoking tobacco and cannabis and drinking alcoholic beverages), based on a large sample. Methods A survey was conducted in 2013 on 34,746 students attending 619 secondary schools, who formed a representative sample of the Italian 15- to 19-year-old population. The prevalence of different categories of gamblers was estimated by age group and gender. A multiple correspondence analysis (CA) was conducted to explain the multivariate associations between substance use and gambling. Results The prevalence of problem gambling was 2.7% among the 15- to 17-year-olds, and rose to 3.6% among the 18- and 19-year-olds. Multiple CA revealed that, even when it does not reach risk-related or problem levels, gambling is associated with the use of alcohol and tobacco. In particular, the analysis showed that non-problem gambling levels were associated with alcohol and tobacco use at least once in the previous month, and that higher-risk gambling levels related to the use of cannabis and episodes of drunkenness at least once in the previous month. Conclusion This study found that any gambling behavior, even below risk-related or problem levels, was associated with some degree of substance use by youths, and that adolescents’ levels of gambling lay along a continuum of the categories of substance use

Renal function and volume of infants born with a very low birth-weight: a preliminary cross-sectional study.

AIM: The aim of our study was to compare the function and volumes of kidneys of very low birth-weight (VLBW) and of extremely low birth-weight (ELBW) infants at pre-school ages.PATIENTS AND METHODS: We did a revision of the neonatal records of infants born in our hospital that weighed < or =1500 g at birth. The children were divided into two groups according to their weight at birth: ELBW (<1000 g) and VLBW (1000-1500 g). At the age of 5.7 +/- 1.4 years, the children underwent clinical, laboratory and ultrasound renal assessments.RESULTS: Sixty-nine children fulfilled the requirements for the study. The rate of neonatal treatment with aminoglycosides was higher in ELBW preterms. Renal function parameters, i.e. estimated glomerular filtration rate and albuminuria, did not differ between the two groups of children. Urinary alpha1-microglobulin excretion was significantly higher and kidneys were significantly smaller in the ELBW group than in the VLBW group.CONCLUSION: No impairment or differences in renal parameters were found in pre-school children born ELBW compared with those born with VLBW, except for differences in kidney volume, renal cortical thickness and urinary alpha1-microglobulin excretion. Thus, patients born with ELBW would require a longer follow-up period