Alessandra D’Amico

Protective role of palmitoylethanolamide in contact allergic dermatitis

To cite this article: Petrosino S, Cristino L, Karsak M, Gaffal E, Ueda N, Tüting T, Bisogno T, De Filippis D, D’Amico A, Saturnino C, Orlando P, Zimmer A, Iuvone T, Di Marzo V. Protective role of palmitoylethanolamide in contact allergic dermatitis. Allergy 2010; 65: 698–711.

Levels of endocannabinoids and palmitoylethanolamide and their pharmacological manipulation in chronic granulomatous inflammation in rats

The endocannabinoids anandamide and 2-arachidonoylglycerol, and the anandamide-congener, palmitoylethanolamide, are all substrates for the enzyme fatty acid amide hydrolase, and are endowed with anti-inflammatory actions exerted via cannabinoid receptors or, in the case of palmitoylethanolamide, also via other targets. We investigated the role of the endocannabinoid system during granuloma formation, a model of chronic inflammation sustained by neoangiogenesis, in rats. Granuloma was induced by subcutaneous lambda-carrageenin-soaked sponge implants on the back of male Wistar rats. After 96h, granulomas were detached and tissue formation was evaluated as wet weight; the endocannabinoid system was evaluated by the measurement of endocannabinoid levels, by LC-MS, and of cannabinoid receptor expression, by western blot analysis. Moreover, angiogenesis was evaluated by the measurement of both hemoglobin content and CD31 protein expression. Arachidonoylserotonin (AA-5-HT, 12.5-50mug/ml), an inhibitor of FAAH, and palmitoylethanolamide (PEA, 200-800mug/ml) were given locally only once at the time of implantation. Granuloma formation was accompanied by a significant decrease in endocannabinoid and palmitoylethanolamide levels paralleled by increased levels of the fatty acid amide hydrolase, responsible for their breakdown. Moreover, an increase of cannabinoid receptor expression was also observed. Pharmacological elevation of endocannabinoids and palmitoylethanolamide, obtained separately by arachidonoylserotonin and exogenous palmitoylethanolamide treatment, dose-dependently reduced inflammatory hallmarks including tumor necrosis factor-alpha as well as granuloma-dependent angiogenesis. The effect of arachidonoylserotonin was accompanied by near-normalization of 2-arachidonoylglycerol and palmitoylethanolamide levels in the tissue. These findings suggest that chronic inflammation might develop also because of endocannabinoid and palmitoylethanolamide tissue concentration impairment, the correction of which might be exploited to develop new anti-inflammatory drugs.

Cannabinomimetic Control of Mast Cell Mediator Release: New Perspective in Chronic Inflammation

The present review aims to elucidate the emerging role played by cannabinomimetic compounds in the control of mast cell activation. Mast cells are immune competent cells strategically localised at the sites directly interfacing with the external environment, which, in case of injury, regulate the immune response by the release of a plethora of both pre‐formed and newly‐synthesised mediators. However, although the main goal of mast cell activation is to initiate the inflammatory reaction, and thus maintain internal homeostasis, the consequences of dysregulated mast cell activation could be to chronically activate the inflammatory response as occurs in arthritis, inflammatory bowel diseases, atherosclerosis and asthma. Therefore, much effort has been made to develop compounds that act to prevent mast cell degranulation. Cannabinomimetic compounds (i.e. agents able to modulate endocannabinoid function) are considered as an emerging class of regulators of mast cell behaviour. We focus on the evidence for a cannabinomimetic control of both acute and chronic inflammatory disease, recognising a common mast cell origin for problems such as dermatitis, inflammatory gastrointestinal syndrome and granuloma formation. Special emphasis is provided for the recent promising results obtained with palmitoylethanolamide in human studies. In the light of evidence suggesting that the control of mast cell activation at an early time during an inflammatory process may account for its resolution, it is reasonable to propose that cannabinomimetic compounds, including palmitoylethanolamide and its congeners, could represent possible candidates for treating several chronic inflammatory diseases.

Adelmidrol, a palmitoylethanolamide analogue, reduces chronic inflammation in a carrageenin-granuloma model in rats

Palmitoylethanolamide (PEA) and some of its analogues have shown great efficacy in the treatment of pain and inflammation. Adelmidrol – the International Nonproprietary Name (INN) of the di‐amide derivative of azelaic acid – is one of these analogues. The anti‐inflammatory and analgesic effects of PEA and adelmidrol are hypothesized to be mediated, at least in part, by mast cell down‐modulation. Mast cell mediators released at early stage of the inflammatory process drive the inflammatory reaction to chronicity as it happens in X‐carrageenin‐induced granulomatous tissue formation. In the present study, the choice of testing adelmidrol depends upon the physicochemical properties of the compound, i.e. the amphipatic feature, that make it more easily soluble than PEA. In this study, we investigated the effect of adelmidrol on granuloma formation induced by λ‐carrageenin‐soaked sponge implant in rats. Our results show that the local administration of the compound under study significantly decreases weight and neo‐angiogenesis in granulomatous tissue. The anti‐inflammatory effect was due to the modulation of mast cells degranulation, as shown by histological analysis and by the inhibition of the release of several pro‐inflammatory and pro‐angiogenic enzymes (e.g. iNOS, chymase and metalloproteinase MMP‐9), and mediators (e.g. nitric oxide and TNF‐α). The results indicate that adelmidrol, given locally, may represent a potential therapeutic tool in controlling chronic inflammation.

Primary herpes virus infection and ischemic stroke in childhood: a new association?

We describe, to our knowledge, the first case of arterial ischemic stroke after primary herpes simplex virus type 1 (HSV1) infection in a previously healthy child, without signs of encephalitis. A 10-year-old previously healthy girl was admitted to our hospital with acute left-sided hemiparesis which involved the lower half of her face. Submandibular lymphadenitis and oral vesicular lesions were present. MRI confirmed the suspicion of an acute ischemic stroke. Immunoglobulin M antibodies to HSV1 were detected. Cerebrospinal fluid polymerase chain reaction for herpes virus was negative. She was treated with aspirin (3mg/kg) and intravenous acyclovir (10mg/kg every 8 hours) for 21 days. Immunoglobulin G antibodies to HSV1 appeared 16 days after admission. Twelve months after her hospitalization the patients examination was normal. Stroke should be considered a possible complication of HSV1 primary infection. Guidelines for the management of acute stroke in children are needed.

De novo PIK3R2 variant causes polymicrogyria, corpus callosum hyperplasia and focal cortical dysplasia

We report an 8-year-old boy with a complex cerebral malformation, intellectual disability, and complex partial seizures. Whole-exome sequencing revealed a yet unreported de novo variant in the PIK3R2 gene that was recently associated with megalencephaly–polymicrogyria–polydactyly–hydrocephalus (MPPH) syndrome and bilateral perisylvian polymicrogyria (BPP). Our patient showed cerebral abnormalities (megalencephaly, perisylvian polymicrogyria, and mega corpus callosum) that were consistent with these conditions. Imaging also showed right temporal anomalies suggestive of cortical dysplasia. Until now, only three variants (c.1117G>A (p.(G373R)), c.1126A>G (p.(K376E)) and c.1202T>C (p.(L401P))) affecting the SH2 domain of the PIK3R2 protein have been reported in MPPH and BPP syndromes. In contrast to the variants reported so far, the patient described herein exhibits the c.1669G>C (p.(D557H)) variant that affects a highly conserved residue at the interface with the PI3K catalytic subunit α. The phenotypic spectrum associated with variants in this gene and its pathway are likely to continue to expand as more cases are identified.

Phenotypic and genetic characterization of a family carrying two Xq21.1-21.3 interstitial deletions associated with syndromic hearing loss

BackgroundSensorineural hearing impairment is a common pathological manifestation in patients affected by X-linked intellectual disability. A few cases of interstitial deletions at Xq21 with several different phenotypic characteristics have been described, but to date, a complete molecular characterization of the deletions harboring disease-causing genes is still missing. Thus, the aim of this study is to realize a detailed clinical and molecular analysis of a family affected by syndromic X-linked hearing loss with intellectual disability.ResultsClinical analyses revealed a very complex phenotype that included inner ear malformations, vestibular problems, choroideremia and hypotonia with a peculiar pattern of phenotypic variability. Genomic analysis revealed, for the first time, the presence of two close interstitial deletions in the Xq21.1-21.3, harboring 11 protein coding, 9 non-coding genes and 19 pseudogenes. Among these, 3 protein coding genes have already been associated with X-linked hearing loss, intellectual disability and choroideremia.ConclusionsIn this study we highlighted the presence of peculiar genotypic and phenotypic details in a family affected by syndromic X-linked hearing loss with intellectual disability. We identified two, previously unreported, Xq21.1-21.3 interstitial deletions. The two rearrangements, containing several genes, segregate with the clinical features, suggesting their role in the pathogenicity. However, not all the observed phenotypic features can be clearly associated with the known genes thus, further study is necessary to determine regions involved.

Spectrum of lytic lesions of the skull: a pictorial essay

Lytic lesions of the skull include a wide range of diseases, ranging from benign conditions such as arachnoid granulations or vascular lacunae, to aggressive malignant lesions such as lymphomas or metastases. An early and correct characterisation of the nature of the lesion is, therefore, crucial, in order to achieve a fast and appropriate treatment option. In this review, we present the radiological appearance of the most frequent lytic lesions of the skull, describing findings from different imaging modalities (plain X-rays, CT and MRI), with particular attention to diagnostic clues and differential diagnoses.Teaching Points• Osteolytic skull lesions may be challenging to diagnose.• Association of different imaging techniques may aid image interpretation.• Clinical information and extensive knowledge of possible differential diagnoses is essential.• Some osteolytic tumours, although benign, may present as locally aggressive lesions.• Malignant lesions require accurate staging, followed by variable treatment approaches.

Brainstem arteriovenous malformation presenting with dyspraxic handwriting in a young girl

We report the case of a 11-year-old girl who developed an isolated hand-writing disorder with dysgraphia at the beginning of the school year in the sixth grade. A brain magnetic resonance angiography showed a round arteriovenous malformation sited in the left side of the midbrain extending to the ipsilateral medio-basal thalamus. Child neurologists should never neglect a thorough neurological evaluation in case of isolated worsening of handwriting, to rule out possible underlying organic causes.

Late Complications: Abscess

Patient with surgically treated right fronto-parieto-temporal glioblastoma multiforme Late postoperative MR imaging with morphologic sequences and diffusion-weighted imaging