Elisa Colombo

Targeted next-generation sequencing appoints c16orf57 as clericuzio-type poikiloderma with neutropenia gene.

Next-generation sequencing is a straightforward tool for the identification of disease genes in extended genomic regions. Autozygosity mapping was performed on a five-generation inbred Italian family with three siblings affected with Clericuzio-type poikiloderma with neutropenia (PN [MIM %604173]), a rare autosomal-recessive genodermatosis characterised by poikiloderma, pachyonychia, and chronic neutropenia. The siblings were initially diagnosed as affected with Rothmund-Thomson syndrome (RTS [MIM #268400]), with which PN shows phenotypic overlap. Linkage analysis on all living subjects of the family identified a large 16q region inherited identically by descent (IBD) in all affected family members. Deep sequencing of this 3.4 Mb region previously enriched with array capture revealed a homozygous c.504-2 A>C mismatch in all affected siblings. The mutation destroys the invariant AG acceptor site of intron 4 of the evolutionarily conserved C16orf57 gene. Two distinct deleterious mutations (c.502A>G and c.666_676+1del12) identified in an unrelated PN patient confirmed that the C16orf57 gene is responsible for PN. The function of the predicted C16orf57 gene is unknown, but its product has been shown to be interconnected to RECQL4 protein via SMAD4 proteins. The unravelled clinical and genetic identity of PN allows patients to undergo genetic testing and follow-up.

Plant Food Supplements with Anti-Inflammatory Properties: A Systematic Review (II)

The aim of this systematic review is to summarize the evidence for or against the efficacy of plant food supplements (PFS) for coping inflammatory conditions by considering epidemiological and human intervention studies. The review considers six botanical species commonly used as food supplements/medicinals: Urtica dioica L., Symphytum officinalis L., Calendula officinalis L., Curcuma longa L., Boswellia serrata Roxb., and Harpagophytum procumbens L. The search retrieved 579 publications. By removing the duplicates and applying the inclusion/exclusion criteria, the final number of papers was 47. No epidemiological data were found. The bibliographic search found no paper regarding the anti-inflammatory effects of Calendula officinalis L. and Symphytum officinalis L. by oral use. In spite of the long-term traditional use for inflammatory disorders, Curcuma longa L. and Harpagophytum procumbens L. warrant further investigation, whereas the efficacy of Urtica dioica L, even if the available data on hard endpoints are promising, requires other trials. Boswellia serrata Roxb. was found to be the most promising, since it shows the best efficacy for the treatment of pain/inflammatory conditions. In conclusion, it is advisable to conduct further studies with more homogeneous population and larger number of subjects by avoiding the heterogeneity of the herbal preparations considered.

Ellagitannins from Rubus Berries for the Control of Gastric Inflammation: In Vitro and In Vivo Studies

Ellagitannins have shown anti-inflammatory and anti-Helicobacter pylori properties; however, their anti-inflammatory activity at gastric level was not previously investigated. The aim of this research was to evaluate the effects of ellagitannins from Rubus berries on gastric inflammation. Ellagitannin enriched extracts (ETs) were prepared from Rubus fruticosus L. (blackberry) and Rubus idaeus L. (raspberry). The anti-inflammatory activity was tested on gastric cell line AGS stimulated by TNF-α and IL-1β for evaluating the effect on NF-kB driven transcription, nuclear translocation and IL-8 secretion. In vivo the protective effect of ellagitannins was evaluated in a rat model of ethanol-induced gastric lesions. Rats were treated orally for ten days with 20 mg/kg/day of ETs, and ethanol was given one hour before the sacrifice. Gastric mucosa was isolated and used for the determination of IL-8 release, NF-kB nuclear translocation, Trolox equivalents, superoxide dismutase and catalase activities. In vitro, ETs inhibited TNF-α induced NF-kB driven transcription (IC50: 0.67–1.73 µg/mL) and reduced TNF-α-induced NF-kB nuclear translocation (57%–67% at 2 µg/mL). ETs inhibited IL-8 secretion induced by TNF-α and IL-1β at low concentrations (IC50 range of 0.7–4 µg/mL). Sanguiin H-6 and lambertianin C, the major ETs present in the extracts, were found to be responsible, at least in part, for the effect of the mixtures. ETs of blackberry and raspberry decreased Ulcer Index by 88% and 75% respectively and protected from the ethanol induced oxidative stress in rats. CINC-1 (the rat homologue of IL-8) secretion in the gastric mucosa was reduced in the animals receiving blackberry and raspberry ETs. The effect of ETs on CINC-1 was associated to a decrease of NF-κB nuclear translocation in ETs treated animals. The results of the present study report for the first time the preventing effect of ETs in gastric inflammation and support for their use in dietary regimens against peptic ulcer.

Psychosocial aspects and psychiatric disorders in young adult with thalassemia major

Beta-thalassemia major (TM), a chronic, genetically determined hematological disorder, has received little investigation on the psychological aspects of the disease and the psychosocial adjustment of patients with this anemia. Unfortunately, the few psychological studies referred on the literature are generally limited to the investigation of the only children with thalassemia major. The study was planned to assess the self-image, the quality of life, the way of coping and to investigate the existence of psychiatric disorders in young adults with thalassemia major. 147 patients were included in the study. Patients were psychologically investigated by three interviews: the first connects some psychosocial information, the second submits patients to the psychological test and the third gives back the results obtained by the test. The psychological test consists of the ways of coping questionnaire (WCQ), the Machover’s test, The short form 36-health survey questionnaire (SF-36) and symptom-check-list-90 revised (SCL-90-R) were performed on all patients. Vis-à-vis identity and self-image were found to be low with feeling of insufficiency and being exposed to vulnerability in 80% of patients with TM. Evaluation of mean values of symptomatological dimensions in these patients showed a personality characterized by somatization (SOM), depression (DEP) and obsessive-compulsive traits. The principal coping strategy used is escape-avoidance. No statistically significant differences occurred to relation to gender, age, level education and SCL-90-R and WCQ scores. Estimation of the SF-36 scores showed that the emotional role and social function values were considerably lower than in all of the domain. As a result, the study showed that most of the patients with TM had severe psychosocial problems. Relying on these data, it was concluded that medical therapy of these patients should be supported with psychological aid and psychiatric treatment.

Modulation of the inflammatory response in rats chronically treated with the antidepressant agomelatine

Growing evidence suggests that the activation of the inflammatory/immune system contributes to depression pathogenesis, a hypothesis that might hold strong clinical implication. Indeed more than 30% of depressed patients fail to achieve remission, which poses the necessity to identify systems that may represent novel targets for medications. Accordingly, goal of this study was to evaluate the ability of the antidepressant agomelatine to modulate specific components of the immune response in the rat brain following an inflammatory challenge with lipopolysaccharide (LPS). To this aim, adult male rats were chronically treated with agomelatine before being acutely challenged with LPS 16 h after the last drug administration. Rats were sacrificed 2, 6, or 24h after the challenge and several components of the inflammatory response have been investigated by using real-time PCR or ELISA. We found that agomelatine significantly reduced the LPS-induced up-regulation of the pro-inflammatory cytokines interleukin-1β and interleukin-6 in the rat brain as well as at peripheral level. At central level, these effects are associated to the inhibition of NF-κB translocation as well as to alterations of mechanisms responsible for microglia activation. In addition, we found that agomelatine was also able to alter the expression of enzymes related to the kynurenine pathway that are thought to represent important mediators to inflammation-related depression. These data disclose novel properties that may contribute to the therapeutic effect of agomelatine providing evidence for a crucial role of specific components of the immune/inflammatory system in the antidepressant response and thereby in depression etiopathology.

A Review on the Anti-Inflammatory Activity of Pomegranate in the Gastrointestinal Tract

Several biological activities of pomegranate have been widely described in the literature, but the anti-inflammatory effect in the gastrointestinal tract has not been reviewed till now. The aim of the present paper is to summarize the evidence for or against the efficacy of pomegranate for coping with inflammatory conditions of the gastro-intestinal tract. The paper has been organized in three parts: (1) the first one is devoted to the modifications of pomegranate active compounds in the gastro-intestinal tract; (2) the second one considering the literature regarding the anti-inflammatory effect of pomegranate at gastric level; (3) the third part considers the anti-inflammatory effect of pomegranate in the gut. In vivo studies performed on the whole fruit or juice, peel, and flowers demonstrate antiulcer effect in a variety of animal models. Ellagic acid was the main responsible for this effect, although other individual ellagitannins could contribute to the biological activity of the mixture. Different preparations of pomegranate, including extracts from peels, flowers, seeds, and juice, show a significant anti-inflammatory activity in the gut. No clinical studies have been found, thus suggesting that future clinical studies are necessary to clarify the beneficial effects of pomegranate in the gastrointestinal tract.

Gaze alternation in dogs and toddlers in an unsolvable task: evidence of an audience effect

Dogs have been shown to use human-directed gazing behaviour and gaze alternation in numerous contexts; however, it is still unclear whether this behaviour can be considered an intentional and referential communicative act. In the current study, adult dogs and preverbal toddlers were tested using the classic unsolvable task paradigm, but varying the attentional stance of the participating audience (the experimenter and the caregiver). The aims were to assess (1) whether dogs and toddlers would use gaze alternation behaviour in similar manners when the task became unsolvable, and (2) whether both dogs and toddlers would take into account the attentional stance of the audience when initiating a communicative interaction. Results indicated that both toddlers and dogs increased their gaze alternation behaviour between the apparatus and caregiver when the task became unsolvable, and toddlers also showed an increase in pointing behaviour. Furthermore, both species showed a capacity to take into account the attentional stance of the audience when manifesting gaze alternation behaviours towards them. Taken together, these results suggest that gaze alternation is both an intentional and referential communicative act and that both species can take into account the need for audience attention when communicating with them.

Novel C16orf57 mutations in patients with Poikiloderma with Neutropenia: bioinformatic analysis of the protein and predicted effects of all reported mutations

BackgroundPoikiloderma with Neutropenia (PN) is a rare autosomal recessive genodermatosis caused by C16orf57 mutations. To date 17 mutations have been identified in 31 PN patients.ResultsWe characterize six PN patients expanding the clinical phenotype of the syndrome and the mutational repertoire of the gene. We detect the two novel C16orf57 mutations, c.232C>T and c.265+2T>G, as well as the already reported c.179delC, c.531delA and c.693+1G>T mutations. cDNA analysis evidences the presence of aberrant transcripts, and bioinformatic prediction of C16orf57 protein structure gauges the mutations effects on the folded protein chain.Computational analysis of the C16orf57 protein shows two conserved H-X-S/T-X tetrapeptide motifs marking the active site of a two-fold pseudosymmetric structure recalling the 2H phosphoesterase superfamily. Based on this model C16orf57 is likely a 2H-active site enzyme functioning in RNA processing, as a presumptive RNA ligase.According to bioinformatic prediction, all known C16orf57 mutations, including the novel mutations herein described, impair the protein structure by either removing one or both tetrapeptide motifs or by destroying the symmetry of the native folding.Finally, we analyse the geographical distribution of the recurrent mutations that depicts clusters featuring a founder effect.ConclusionsIn cohorts of patients clinically affected by genodermatoses with overlapping symptoms, the molecular screening of C16orf57 gene seems the proper way to address the correct diagnosis of PN, enabling the syndrome-specific oncosurveillance.The bioinformatic prediction of the C16orf57 protein structure denotes a very basic enzymatic function consistent with a housekeeping function. Detection of aberrant transcripts, also in cells from PN patients carrying early truncated mutations, suggests they might be translatable. Tissue-specific sensitivity to the lack of functionally correct protein accounts for the main cutaneous and haematological clinical signs of PN patients.

Clericuzio-type poikiloderma with neutropenia syndrome in three sibs with mutations in the C16orf57 gene: delineation of the phenotype

We report on three sibs who have autosomal recessive Clericuzio‐type poikiloderma neutropenia (PN) syndrome. Recently, this consanguineous family was reported and shown to be informative in identifying the C16orf57 gene as the causative gene for this syndrome. Here we present the clinical data in detail. PN is a distinct and recognizable entity belonging to the group of poikiloderma syndromes among which Rothmund–Thomson is perhaps the best described and understood. PN is characterized by cutaneous poikiloderma, hyperkeratotic nails, generalized hyperkeratosis on palms and soles, neutropenia, short stature, and recurrent pulmonary infections. In order to delineate the phenotype of this rare genodermatosis, the clinical presentation together with the molecular investigations in our patients are reported and compared to those from the literature.

Metabolic Syndrome and Inflammation: A Critical Review of In Vitro and Clinical Approaches for Benefit Assessment of Plant Food Supplements

Metabolic syndrome is defined as the clustering in an individual of several metabolic abnormalities associated with insulin resistance, type 2 diabetes, and obesity, in which low-grade chronic inflammatory activity is commonly observed. Part of the European Project PlantLIBRA is concerned with methods to assess the benefits of plant food supplements (PFSs) in countering inflammatory activity and metabolic syndrome. This paper summarizes the current methods used for benefit assessment of PFS, taking into consideration only in vitro, in silico, and clinical methodologies used to investigate the anti-inflammatory properties of plants. No in silico studies (using computer simulation) related to metabolic syndrome were found; these methods appear to be used exclusively for identifying or testing potentially effective compounds in drug development. Most in vitro methods for the assessment of beneficial effects of botanicals or plant food supplements in diabetes were based on a quantitative polymerase chain reaction (PCR), whereas the preferred kind of clinical study was the double-blind randomized controlled clinical trial. Only two parameters were observed to change after treatment with botanicals in both in vitro and in vivo studies: interleukin-6 and tumour necrosis factor-α, and these biomarkers should be carefully considered in future studies for PFS benefit assessment.