Genes involved in the metabolism of fatty acids and risk for Crohn's disease in children: a candidate gene study

Contexte - La prévalence de la maladie de Crohn (MC), une maladie inflammatoire chronique du tube digestif, chez les enfants canadiens se situe parmi les plus élevées au monde. Les interactions entre les réponses immunes innées et acquises aux microbes de l'hôte pourraient être à la base de la transition de l’inflammation physiologique à une inflammation pathologique. Le leucotriène B4 (LTB4) est un modulateur clé de l'inflammation et a été associé à la MC. Nous avons postulé que les principaux gènes impliqués dans la voie métabolique du LTB4 pourrait conférer une susceptibilité accrue à l'apparition précoce de la MC. Dans cette étude, nous avons exploré les associations potentielles entre les variantes de l'ADN des gènes ALOX5 et CYP4F2 et la survenue précoce de la MC. Nous avons également examiné si les gènes sélectionnés montraient des effets parent-d'origine, influençaient les phénotypes cliniques de la MC et s'il existait des interactions gène-gène qui modifieraient la susceptibilité à développer la MC chez l’enfant. Méthodes – Dans le cadre d’une étude de cas-parents et de cas-témoins, des cas confirmés, leurs parents et des contrôles ont été recrutés à partir de trois cliniques de gastro-entérologie à travers le Canada. Les associations entre les polymorphismes de remplacement d'un nucléotide simple (SNP) dans les gènes CYP4F2 et ALOX5 ont été examinées. Les associations allélique et génotypiques ont été examinées à partir d’une analyse du génotype conditionnel à la parenté (CPG) pour le résultats cas-parents et à l’aide de table de contingence et de régression logistique pour les données de cas-contrôles. Les interactions gène-gène ont été explorées à l'aide de méthodes de réduction multi-factorielles de dimensionnalité (MDR). Résultats – L’étude de cas-parents a été menée sur 160 trios. L’analyse CPG pour 14 tag-SNP (10 dans la CYP4F2 et 4 dans le gène ALOX5) a révélé la présence d’associations alléliques ou génotypique significatives entre 3 tag-SNP dans le gène CYP4F2 (rs1272, p = 0,04, rs3093158, p = 0.00003, et rs3093145, p = 0,02). Aucune association avec les SNPs de ALOX5 n’a pu être démontrée. L’analyse de l’haplotype de CYP4F2 a montré d'importantes associations avec la MC (test omnibus p = 0,035). Deux haplotypes (GAGTTCGTAA, p = 0,05; GGCCTCGTCG, p = 0,001) montraient des signes d'association avec la MC. Aucun effet parent-d'origine n’a été observé. Les tentatives de réplication pour trois SNPs du gene CYP4F2 dans l'étude cas-témoins comportant 225 cas de MC et 330 contrôles suggèrent l’association dans un de ceux-ci (rs3093158, valeur non-corrigée de p du test unilatéral = 0,03 ; valeur corrigée de p = 0.09). La combinaison des ces deux études a révélé des interactions significatives entre les gènes CYP4F2, ALOX et NOD2. Nous n’avons pu mettre en évidence aucune interaction gène-sexe, de même qu’aucun gène associé aux phénotypes cliniques de la MC n’a pu être identifié. Conclusions - Notre étude suggère que la CYP4F2, un membre clé de la voie métabolique LTB4 est un gène candidat potentiel pour MC. Nous avons également pu mettre en évidence que les interactions entre les gènes de l'immunité adaptative (CYP4F2 et ALOX5) et les gènes de l'immunité innée (NOD2) modifient les risques de MC chez les enfants. D'autres études sur des cohortes plus importantes sont nécessaires pour confirmer ces conclusions.Background - The rates of Crohn’s disease (CD) a chronic inflammatory disease of the gastrointestinal tract, among Canadian children are the world’s highest. Interactions between the host microbial–innate-immune-responses are thought to underplay transition from physiological to pathological inflammation. Leukotriene B4 (LTB4) is a key modulator of inflammation and has been shown to be associated with CD. We postulated that key genes involved in the LTB4 metabolic pathway could confer susceptibility for early-onset CD. In this study we implemented a candidate gene approach to test for associations between DNA variants in the ALOX5 and CYP4F2 genes and early-onset of CD. We also explored whether the selected genes demonstrated parent-of-origin effects, influenced CD clinical phenotypes and whether there were gender-gene and gene-gene interactions that determined CD susceptibility. Methods – The study consisted of an exploratory phase (case-parent design) followed by a replication phase (case-control design). Confirmed cases, parents and controls were recruited from three tertiary gastroenterology clinics across Canada. Associations between tag-single nucleotide polymorphisms in the CYP4F2 and ALOX5 genes were examined. Allelic and/or genotype associations were examined using conditional on parental genotype (CPG) analysis for the case-parent data and contingency table and logistic regression for the case-control data. Gene-gene interactions were explored using multi-factor dimensionality reduction (MDR) methods. Results – The first phase of the study was based on 160 trios (case-parent design). CPG analysis for 14 tag-SNPs (i.e. 10 in the CYP4F2 and 4 in the ALOX5 gene, respectively) revealed significant allelic or genotypic associations between 3 tag-SNPs in the CYP4F2 gene (rs1272, p=0.04, rs3093158, p=0.00003, and rs3093145, p=0.02). No associations with ALOX5 tag-SNPs were evident. CYP4F2-haplotype analysis showed significant associations with CD (omnibus test p-value=0.035). Two specific haplotypes (GAGTTCGTAA, p=0.05; GGCCTCGTCG, p=0.001) showed evidence for association with CD. No parent-of-origin effects were observed. The second phase of the study retested the three CYP4F2 SNPs that showed association in the first stage and was based on 223 CD cases and 330 controls. Some indications of association with one SNP i.e. rs3093158 were present (genotypic uncorrected 1-sided p-value=0.03); however this genotype association did not withstand correction. Combining cases from the two phases of the study revealed significant interactions between the CYP4F2, ALOX and NOD2 genes. No gene-gender interactions were obvious nor were the study genes associated with specific clinical phenotypes of CD. Conclusions - Our study suggests that the CYP4F2, a key member of the LTB4 metabolic pathway is a potential candidate gene for CD. Furthermore there was evidence that interactions between adaptive immunity genes (CYP4F2 and ALOX5) and innate immunity genes (NOD2) genes modify risk for CD in children. Further studies on larger cohorts are required to confirm these findings

Pharmacognostical analysis and seasonal variation of triterpenic and phenolic compounds from birch (Betula pendula Roth.) leaves

Universitatea de Medicină şi Farmacie ,,Carol Davila”, Facultatea de Farmacie, Bucureşti, România, Universitatea Bucureşti, Facultatea de Biologie, România, Universitatea ,,A.I. Cuza”, Facultatea de Biologie, Iaşi, RomâniaObiective. Scopul studiului constă în analiza farmacognostică şi determinarea dinamicii de acumulare a compuşilor fenolici şi triterpenici din frunzele speciei Betula pendula Roth. (mesteacăn). Material şi metode. Ca material s-au utilizat frunze de mesteacăn recoltate în anul 2011, din localitatea Morăreşti, judeţul Argeş, în diferite stadii de dezvoltare – lunile mai, iunie, iulie şi sfârşitul lunii august. Metodele utilizate au fost: analiza farmacognostică – examen macroscopic (la stereomicroscop), microscopic (pe secţiuni transversale, pulberi clarificate cu chloralhidrat şi prin microscopie electronică), chimic calitativ, cromatografie în strat subţire (CSS) şi determinarea spectrofotometrică (pe baza unor curbe etalon) a conţinutului de derivaţi fenolici (flavone – g% hiperozidă, acizi fenolcarboxilici – g% acid clorogenic, taninuri – g% pirogalol, proantociani – g% clorură de cianidol) şi triterpenici (forme libere, heterozidate şi esterificate – g% acid betulinic). Rezultate. Caracteristicile macroscopice ale produselor vegetale din toate loturile au coincis cu datele din literatura de specialitate consultată. Examenul microscopic efectuat pe secţiuni transversale şi pe pulberi clarificate a evidenţiat prezenţa de elemente specifice produsului vegetal de tip folium (fragmente de epidermă, stomate de tip anomocitic, peri tectori şi glandulari, teşut palisadic, clorofilian şi lacunar). Prin microscopie electronică s-au observat particularităţile formaţiunilor secretoare (glande peltate), dependent de gradul de dezvoltare al frunzelor (în frunzele tinere celulele secretoare sunt complet acoperite de cuticulă, iar spre sfârşitul perioadei de vegetaţie acestea degenerează). Prin analiza CSS s-au identificat următorii constituenţi: hiperozidă, quercitrozidă, quercetol, kaempferol, miricetol, acid clorogenic, acid ursolic/oleanolic şi betulinol. Conţinutul de acizi triterpenici (forme libere, esterificate şi heterozidate) scade odată cu maturizarea frunzelor (de la 11,7818 g%; 10,9276 g%; 4,3568 g% în luna mai la 4,9641 g%; 4,3038 g%; 2,1586 ± g% în luna august). Frunzele tinere (recoltate în luna mai) au cel mai mare conţinut de flavone (5,1885 g%), acizi fenolcarboxilici (3,4667g%) şi taninuri (3,2100 g%). Cantitatea de proantociani creşte odată cu maturizarea frunzelor, probabil datorită condensării cu taninurile. Concluzii. Frunzele de mesteacăn recoltate la începutul perioadei de vegetaţie (luna mai) au un conţinut ridicat de flavone, taninuri, acizi fenolcarboxilici şi derivaţi triterpenici. Scăderea conţinutului de principii active odată cu maturizarea produsului vegetal se corelează cu observaţiile microscopice asupra formaţiunilor secretoare, dependent de gradul de dezvoltare al frunzelor

Comparative study on metal versus zirconium dioxide infrastructure manufacturing in prosthetic rehabilitation in the maxillary frontal zone

Prosthetic rehabilitation of the maxillary front teeth is an extremely laborious problem for the dental team, consisting of the dentist and the dental technician. If for the physiognomic component the most recommended materials are the ceramic masses, for the resistance substrate there are several variants. Conventional technologies using dental alloys and modern ones involving the use of zirconium dioxide can be used successfully in performing fixed prosthetic restorations in the maxillary frontal area, both options having both advantages and disadvantages, as we will describe in this material

Extradural autologous temporal muscle graft mimicking a meningioma: Case report

Meningiomas are the most common dural tumour, but there are also many other dural masses which mimic their appearances, such as neoplastic and non-neoplastic lesions. In this paper we report another mass which may mimic a dural lesion, namely a muscle graft harvested from the temporal site and left in situ, used to achieve haemostasis in a posttraumatic temporal extradural hematoma in a young male patient. Solid knowledge of differentiating neuroimaging characteristics of dural masses, as well as its corroboration with the patient’s medical history are extremely helpful in establishing an accurate diagnostic

Клинико-морфопатологические аспекты красного плоского лишая полости рта.

Oral lichen planus is a chronic, mucocutaneous condition with an unidentified etiology. Women between the ages of 30 and 60 are most affected. The incidence rate for the entire population is 1-2%. Bilateral lesions are typically whitish, sometimes ulcerated. The importance of this condition is related to the frequency of occurrence, the clinical resemblance to other diseases of the mucosa, sometimes with persistent pain and the possible relationship with squamous cell carcinoma. There are several hypotheses regarding the etiology of these diseases, they include: the genetic factor, infectious, psychogenic and autoimmune. The diagnosis of oral plan lichen is made on the basis of clinical and morphopathological examination where information on changes in tissue and cells is obtained.Lichen plan oral este o afecțiune cronică, mucocutanată cu o etiologie needentificată. Cel mai mult sunt afectate femeile cu vârsta cuprinsă între 30 și 60 ani. Rata incidenței pe întreaga populație este de 1-2%. Tipic sunt prezente leziuni bilaterale, albicioase, uneori poartă un caracter ulceros. Importanța acestei afecțiuni este legată de frecvența apariției, de asemănarea clinică cu alte boli ale mucoasei, uneori prezentând dureri persistente și de posibila relație cu carcinomul scuamos. Există câteva ipot eze în ceea ce privește etiologia aceste maladii, din ele fac parte: factorul genetic, infecțios, psihogenic și autoimun. Stabilirea diagnosticului lichenului plan oral se efectuează în baza examenului clinic și morfopatologic unde se obține informație privind schimbări la nivel de țesut și celule.Красный плоский лишай полости рта представляет собой хроническое кожно-слизистое заболевание с неустановленной этиологией. Больше всего страдают женщины в возрасте от 30 до 60 лет. Заболеваемость всего населения составляет 1-2%. Двусторонние поражения обычно беловатые, иногда изъязвленные. Важность этого состояния связана с частотой встречаемости, клиническим сходством с другими заболеваниями слизистой оболочки, иногда с упорным болевым синдромом и возможной связью с плоскоклеточным раком. Существует несколько гипотез относительно этиологии этих заболеваний, к ним относятся: генетическая факторная, инфекционная, психогенная и аутоиммунная. Диагноз плоского лишая полости рта ставится на основании клинического и морфопатологического обследования, при котором получают информацию об изменениях в тканях и клетках

Dentists, members of the French Resistance movement during the World War II

The Resistance was a reaffirmation of France's independence and individuality, as well as a struggle to regain freedom and, above all, national integrity. In fact, many historians appreciate that the French Resistance could have achieved more if it had been more effectively integrated into Allied plans and strategies. Thus, in this material we tried to present some short biographies of dentists who worked in the French Resistance against the German occupation troops, some of them even paying with their lives for the courage they showed

Genes Involved in the Metabolism of Poly-Unsaturated Fatty-Acids (PUFA) and Risk for Crohn's Disease in Children & Young Adults

Epidemiological evidence for the role of polyunsaturated fatty-acids (PUFA) in Crohn's disease (CD) is unclear, although the key metabolite leucotriene B4 (LTB(4)) is closely linked to the inflammatory process. We hypothesized that inherited variation in key PUFA metabolic enzymes may modify susceptibility for CD.A case-control design was implemented at three pediatric gastroenterology clinics in Canada. Children ≤20 yrs diagnosed with CD and controls were recruited. 19 single nucleotide polymorphisms (SNPs) across the ALOX5 (4) CYP4F3 (5) and CYP4F2 (10) genes, were genotyped. Associations between SNPs/haplotypes and CD were examined. A total of 431 cases and 507 controls were studied. The mean (±SD) age of the cases was 12.4 (±3.3) years. Most cases were male (56.4%), had ileo-colonic disease (L3±L4, 52.7%) and inflammatory behavior (B1±p, 87%) at diagnosis. One genotyped CYP4F3 SNP (rs2683037) not in Hardy-Weinberg Equilibrium was excluded. No associations with the remaining 4 CYP4F3 SNPs with CD were evident. However haplotype analysis revealed associations with a two-marker haplotype (TG) (rs3794987 & rs1290617) (p = 0.02; permuted p = 0.08). CYP4F2 SNPs, rs3093158 (OR (recessive) = 0.56, 95% CI = 0.35-0.89; p = 0.01), rs2074902 (OR (trend) = 1.26, 95% CI = 1.00-1.60; p = 0.05), and rs2108622 (OR (recessive) = 1.6, 95% CI = 1.00-2.57; p = 0.05) were significantly associated whereas rs1272 (OR (recessive) = 0.58, 95% CI = 0.30-1.13; p = 0.10) showed suggestions for associations with CD. A haplotype comprising these 4 SNPs was significantly associated (p = 0.007, permuted p = 0.02) with CD. Associations with SNP rs3780901 in the ALOX5 gene were borderline non-significant (OR (dominant) = 1.29, 95% CI = 0.99-1.67; p = 0.056). A haplotype comprising the 4 ALOX5 SNPs (TCAA, p = 0.036) was associated with CD, but did not withstand corrections for multiple comparisons (permuted p = 0.14).Inherited variation in enzymes involved in the synthesis/metabolism of LTB(4) may be associated with CD. These findings implicate PUFA metabolism as a important pathway in the CD pathogenesis

Sex difference and intra-operative tidal volume: Insights from the LAS VEGAS study

BACKGROUND: One key element of lung-protective ventilation is the use of a low tidal volume (VT). A sex difference in use of low tidal volume ventilation (LTVV) has been described in critically ill ICU patients.OBJECTIVES: The aim of this study was to determine whether a sex difference in use of LTVV also exists in operating room patients, and if present what factors drive this difference.DESIGN, PATIENTS AND SETTING: This is a posthoc analysis of LAS VEGAS, a 1-week worldwide observational study in adults requiring intra-operative ventilation during general anaesthesia for surgery in 146 hospitals in 29 countries.MAIN OUTCOME MEASURES: Women and men were compared with respect to use of LTVV, defined as VT of 8 ml kg-1 or less predicted bodyweight (PBW). A VT was deemed 'default' if the set VT was a round number. A mediation analysis assessed which factors may explain the sex difference in use of LTVV during intra-operative ventilation.RESULTS: This analysis includes 9864 patients, of whom 5425 (55%) were women. A default VT was often set, both in women and men; mode VT was 500 ml. Median [IQR] VT was higher in women than in men (8.6 [7.7 to 9.6] vs. 7.6 [6.8 to 8.4] ml kg-1 PBW, P < 0.001). Compared with men, women were twice as likely not to receive LTVV [68.8 vs. 36.0%; relative risk ratio 2.1 (95% CI 1.9 to 2.1), P < 0.001]. In the mediation analysis, patients' height and actual body weight (ABW) explained 81 and 18% of the sex difference in use of LTVV, respectively; it was not explained by the use of a default VT.CONCLUSION: In this worldwide cohort of patients receiving intra-operative ventilation during general anaesthesia for surgery, women received a higher VT than men during intra-operative ventilation. The risk for a female not to receive LTVV during surgery was double that of males. Height and ABW were the two mediators of the sex difference in use of LTVV.TRIAL REGISTRATION: The study was registered at Clinicaltrials.gov, NCT01601223