CX3CR1+ Cell–Mediated Salmonella Exclusion Protects the Intestinal Mucosa during the Initial Stage of Infection

During Salmonella Typhimurium infection, intestinal CX3CR1(+) cells can either extend transepithelial cellular processes to sample luminal bacteria or, very early after infection, migrate into the intestinal lumen to capture bacteria. However, until now, the biological relevance of the intraluminal migration of CX3CR1(+) cells remained to be determined. We addressed this by using a combination of mouse strains differing in their ability to carry out CX3CR1-mediated sampling and intraluminal migration. We observed that the number of S. Typhimurium traversing the epithelium did not differ between sampling-competent/migration-competent C57BL/6 and sampling-deficient/migration-competent BALB/c mice. In contrast, in sampling-deficient/migration-deficient CX3CR1(-/-) mice the numbers of S. Typhimurium penetrating the epithelium were significantly higher. However, in these mice the number of invading S. Typhimurium was significantly reduced after the adoptive transfer of CX3CR1(+) cells directly into the intestinal lumen, consistent with intraluminal CX3CR1(+) cells preventing S. Typhimurium from infecting the host. This interpretation was also supported by a higher bacterial fecal load in CX3CR1(+/gfp) compared with CX3CR1(gfp/gfp) mice following oral infection. Furthermore, by using real-time in vivo imaging we observed that CX3CR1(+) cells migrated into the lumen moving through paracellular channels within the epithelium. Also, we reported that the absence of CX3CR1-mediated sampling did not affect Ab responses to a noninvasive S. Typhimurium strain that specifically targeted the CX3CR1-mediated entry route. These data showed that the rapidly deployed CX3CR1(+) cell-based mechanism of immune exclusion is a defense mechanism against pathogens that complements the mucous and secretory IgA Ab-mediated system in the protection of intestinal mucosal surface

Platelet Rich Plasma Enhancement of Skin Regeneration in an ex-vivo Human Experimental Model

An original ex vivo wounded skin culture protocol using autologous Platelet Rich Plasma (PRP) and enriched Dulbecco's Modified Eagle's Medium demonstrated a favourable modulation of the epithelial cells and fibroblasts proliferation, a relevant antiinflammatory action and a favourable modulation of the re-organization of collagen and elastic fibres. The step by step regenerative effects of PRP on human skin wound repair and regeneration process was observed over a period of 10 days

Increased levels of interleukin-6 exacerbate the dystrophic phenotype in mdx mice

Duchenne muscular dystrophy (DMD) is characterized by progressive lethal muscle degeneration and chronic inflammatory response. The mdx mouse strain has served as the animal model for human DMD. However, while DMD patients undergo extensive necrosis, the affected muscles of adult mdx mice rapidly regenerates and regains structural and functional integrity. The basis for the mild effects observed in mice compared with the lethal consequences in humans remains unknown. In this study, we provide evidence that interleukin-6 (IL-6) is causally linked to the pathogenesis of muscular dystrophy. We report that forced expression of IL-6, in the adult mdx mice, recapitulates the severe phenotypic characteristics of DMD in humans. Increased levels of IL-6 exacerbate the dystrophic muscle phenotype, sustaining inflammatory response and repeated cycles of muscle degeneration and regeneration, leading to exhaustion of satellite cells. The mdx/IL6 mouse closely approximates the human disease and more faithfully recapitulates the disease progression in humans. This study promises to significantly advance our understanding of the pathogenic mechanisms that lead to DMD

Hyperalgesic activity of kisspeptin in mice.

BACKGROUND: Kisspeptin is a neuropeptide known for its role in the hypothalamic regulation of the reproductive axis. Following the recent description of kisspeptin and its 7-TM receptor, GPR54, in the dorsal root ganglia and dorsal horns of the spinal cord, we examined the role of kisspeptin in the regulation of pain sensitivity in mice. RESULTS: Immunofluorescent staining in the mouse skin showed the presence of GPR54 receptors in PGP9.5-positive sensory fibers. Intraplantar injection of kisspeptin (1 or 3 nmol/5 μl) induced a small nocifensive response in naive mice, and lowered thermal pain threshold in the hot plate test. Both intraplantar and intrathecal (0.5 or 1 nmol/3 μl) injection of kisspeptin caused hyperalgesia in the first and second phases of the formalin test, whereas the GPR54 antagonist, p234 (0.1 or 1 nmol), caused a robust analgesia. Intraplantar injection of kisspeptin combined with formalin enhanced TRPV1 phosphorylation at Ser800 at the injection site, and increased ERK1/2 phosphorylation in the ipsilateral dorsal horn as compared to naive mice and mice treated with formalin alone. CONCLUSION: These data demonstrate for the first time that kisspeptin regulates pain sensitivity in rodents and suggest that peripheral GPR54 receptors could be targeted by novel drugs in the treatment of inflammatory pain.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Metabotropic Glutamate Receptors in Glial Cells: A New Potential Target for Neuroprotection?

Neurodegenerative disorders are characterized by excitotoxicity and neuroinflammation that finally lead to slow neuronal degeneration and death. Although neurons are the principal target, glial cells are important players as they contribute by either exacerbating or dampening the events that lead to neuroinflammation and neuronal damage. A dysfunction of the glutamatergic system is a common event in the pathophysiology of these diseases. Metabotropic glutamate (mGlu) receptors belong to a large family of G protein-coupled receptors largely expressed in neurons as well as in glial cells. They often appear overexpressed in areas involved in neurodegeneration, where they can modulate glutamatergic transmission. Of note, mGlu receptor upregulation may involve microglia or, even more frequently, astrocytes, where their activation causes release of factors potentially able to influence neuronal death. The expression of mGlu receptors has been also reported on oligodendrocytes, a glial cell type specifically involved in the development of multiple sclerosis. Here we will provide a general overview on the possible involvement of mGlu receptors expressed on glial cells in the pathogenesis of different neurodegenerative disorders and the potential use of subtype-selective mGlu receptor ligands as candidate drugs for the treatment of neurodegenerative disorders. Negative allosteric modulators (NAM) of mGlu5 receptors might represent a relevant pharmacological tool to develop new neuroprotective strategies in these diseases. Recent evidence suggests that targeting astrocytes and microglia with positive allosteric modulators (PAM) of mGlu3 receptor or oligodendrocytes with mGlu4 PAMS might represent novel pharmacological approaches for the treatment of neurodegenerative disorders

HE3286, an oral synthetic steroid, treats lung inflammation in mice without immune suppression

<p>Abstract</p> <p>Background</p> <p>17α-Ethynyl-5-androsten-3β, 7β, 17β-triol (HE3286) is a synthetic derivative of an endogenous steroid androstenetriol (β-AET), a metabolite of the abundant adrenal steroid deyhdroepiandrosterone (DHEA), with broad anti-inflammatory activities. We tested the ability of this novel synthetic steroid with improved pharmacological properties to limit non-productive lung inflammation in rodents and attempted to gauge its immunological impact.</p> <p>Methods and Results</p> <p>In mice, oral treatment with HE3286 (40 mg/kg) significantly (<it>p </it>< 0.05) decreased neutrophil counts and exudate volumes (~50%) in carrageenan-induced pleurisy, and myeloperoxidase in lipopolysaccharide-induced lung injury. HE3286 (40 mg/kg) was not found to be profoundly immune suppressive in any of the classical animal models of immune function, including those used to evaluate antigen specific immune responses <it>in vivo </it>(ovalbumin immunization). When mice treated for two weeks with HE3286 were challenged with <it>K. pneumoniae</it>, nearly identical survival kinetics were observed in vehicle-treated, HE3286-treated and untreated groups.</p> <p>Conclusions</p> <p>HE3286 represents a novel, first-in-class anti-inflammatory agent that may translate certain benefits of β-AET observed in rodents into treatments for chronic inflammatory pulmonary disease.</p

Role of CX3CR1+ cell in the protection of the intestinal mucosa

During infection intestinal CX3CR1+ cells can either extend transepithelial cellular processes to sample luminal bacteria or, very early after infection migrate into the intestinal lumen to capture bacteria. However, up to date, the biological relevance of the intraluminal migration of CX3CR1+ cells remained to be determined. We addressed this by using a combination of mouse strains differing in their ability to carry out CX3CR1-mediated sampling and intraluminal migration. We observed that, the number of S. Typhimurium traversing the epithelium did not differ between sampling-competent/migration-competent C57BL/6 and sampling-deficient/migration-competent Balb/c mice. By contrast, in sampling-deficient/migration-deficient CX3CR1-/- mice the numbers of S. Typhimurium penetrating the epithelium were significantly higher. However, in these mice the number of invading S. Typhimurium was significantly reduced after the adoptive transfer of CX3CR1+ cells directly into the intestinal lumen, consistent with intraluminal CX3CR1+ cells preventing S. Typhimurium from infecting the host. This interpretation was also supported by a higher bacterial faecal load in CX3CR1+/gfp compared to CX3CR1gfp/gfp mice following oral infection. Furthermore, by using real time in vivo imaging we observed that CX3CR1+ cells migrated into the lumen moving through paracellular channels within the epithelium. Also, we reported that the absence of CX3CR1-mediated sampling did not affect antibody responses to a non-invasive S. Typhimurium strain that specifically targeted the CX3CR1-mediated entry route. These data showed that the rapidly deployed CX3CR1+ cell-based mechanism of immune-exclusion is a defence mechanism against pathogens that complements the mucous and secretory (s)IgA antibody-mediated system in the protection of intestinal mucosal surface

Genetic variants associated with gastrointestinal symptoms in Fabry disease.

Gastrointestinal symptoms (GIS) are often among the earliest presenting events in Fabry disease (FD), an X-linked lysosomal disorder caused by the deficiency of α-galactosidase A. Despite recent advances in clinical and molecular characterization of FD, the pathophysiology of the GIS is still poorly understood. To shed light either on differential clinical presentation or on intervariability of GIS in FD, we genotyped 1936 genetic markers across 231 genes that encode for drug-metabolizing enzymes and drug transport proteins in 49 FD patients, using the DMET Plus platform. All nine single nucleotide polymorphisms (SNPs) mapped within four genes showed statistically significant differences in genotype frequencies between FD patients who experienced GIS and patients without GIS: ABCB11 (odd ratio (OR) = 18.07, P = 0,0019; OR = 8.21, P = 0,0083; OR=8.21, P = 0,0083; OR = 8.21, P = 0,0083),SLCO1B1 (OR = 9.23, P = 0,0065; OR = 5.08, P = 0,0289; OR = 8.21, P = 0,0083), NR1I3 (OR = 5.40, P = 0,0191) and ABCC5 (OR = 14.44, P = 0,0060). This is the first study that investigates the relationships between genetic heterogeneity in drug absorption, distribution, metabolism and excretion (ADME) related genes and GIS in FD. Our findings provide a novel genetic variant framework which warrants further investigation for precision medicine in FD

Multi-parasite infection in an immigrant from Ghana: potential for new epidemic foci.

Introduction: Imported parasitosis, which do not require an invertebrate vector, are extremely dangerous and can lead to the occurrence of disease in currently parasite free areas. In the present study we report a case of multi-parasitic infection in a young immigrant from Ghana to Italy caused by filaria, Schistosoma sp. and Strongyloides sp. Case presentation: A 27-year-old Ghanaian man attended the Hospital of Nuoro (Sardinia), Italy, at the end of August 2015, claiming pain to the kidney and hypertensive crisis; the patient presented with dyspnea and epistaxis, chronic itchy skin of the back, shoulders, arms and legs, anuria and high creatinine, metabolic acidosis and hypereosinophilic syndrome. Serological test for parasitic infections were done, and showed a marked positivity for filaria, Schistosoma sp. and Strongyloides sp. The patient started the treatment immediately with two doses per day of Bassado Antibiotic (tetracycline) for twenty days and then with a single dose of 3 mg of ivermectin that was repeated after 3 months. Conclusions: Immigrant patients from endemic areas who show clinical signs, such as a general itching on the back, shoulders and arms and legs, should have a thorough history in order to make early diagnosis and prevent further complications. Therefore, general practitioners and doctors in Europe and in other parasitosis non-endemic countries, should consider to test for parasites in any immigrant from endemic countries to aid in establishing the final diagnosis and prevent further complications

Measles outbreaks in the Emilia-Romagna Region, Italy, during 2016

Background and aim. Despite the availability of a vaccine,measles continues to be endemic in Italy, where an increase of cases was reported during 2016. This study describes the measles outbreaks in Emilia-Romagna Region (ERR), one of the Italian regions mostly affected. Materials and Methods. A total of 101 suspected cases were reported in ERR during 2016. Laboratory diagnosis by serological and/or molecular methods was performed on 142 specimens (78 urine, 19 oral fluid and 45 sera) related to 97 suspected cases. For positive cases, measles virus (MV) strains involved were identified. Results. Among 101 suspected cases, 72 (71.3%) were confirmed. Vaccination status was known for 61 (84.7%) cases, of which 56 (91.8%) were unvaccinated. The highest incidence was found in the age group 15-39 years. In addition, for the 34.7% (25/72) of confirmed cases, the transmission occurred in nosocomial settings, where healthcare workers were involved (60% of cases). Roma/Sinti population were also involved in 12.5% (9/72)or confirmed cases. Both groups are considered hard-to-reach for immunization. The phylogenetic analysis showed circulation of MV strains belonging to genotype B3 and D8 in 45 (80.4%) and 11 cases (19.6%), respectively. In 94.7% of cases, the measles endemic transmission was demonstrated. Conclusions. This data obtained through active surveillance showed the endemic transmission of MV within a population with immunity gaps including healthcare workers (20.8% of confirmed cases), among which the spread of two endemic MV strains was observed