ABCG2 polymorphism and rivaroxaban pharmacokinetics in healthy individuals after a single dose.

Rivaroxaban is a direct factor Xa inhibitor. Its interindividual variability is large and may be connected to the occurrence of adverse drug reactions or drug inefficacy. Pharmacogenetics studies concentrating on the reasons underlying rivaroxaban's inadequate response could help explain the differences in treatment results and medication safety profiles. Against this background, this study evaluated whether polymorphisms in the gene encoding the ABCG2 transporter modify the pharmacokinetic characteristics of rivaroxaban. A total of 117 healthy volunteers participated in two bioequivalence experiments with a single oral dose of 20 mg rivaroxaban, with one group fasting and the other being fed. Ultra-high-performance liquid chromatography coupled with mass spectrometry was employed to determine the plasma concentrations of rivaroxaban, and the WinNonlin program was used to calculate the pharmacokinetics parameters. In the fasting group, the rivaroxaban pharmacokinetic parameters of Vd (508.27 vs 334.45 vs 275.59 L) and t1/2 (41.04 vs 16.43 vs 15.47 h) were significantly higher in ABCG2 421 A/A genotype carriers than in ABCG2 421 C/C and 421 C/A genotype carriers (P<0.05). The mean values of Cmax (145.81 vs 176.27 vs 190.19 ng/mL), AUC0-t (1193.81 vs 1374.69 vs 1570.77 ng/mL·h), and Cl (11.82 vs 14.50 vs 13.01 mL/h) for these groups were lower, but this difference was not statistically significant (P>0.05). These findings suggested that the ABCG2 421 A/A genotype may impact rivaroxaban parameters after a single dose in healthy subjects. This finding must be validated before it is applied in clinical practice.

Biobancos en otorrinolaringología / Biobanks in otolaryngology

Resumen Los biobancos son una innovadora herramienta biotecnológica y un recurso fundamental para el continuo avance en la investigación científica biomédica, y para el advenimiento de la medicina de precisión. Se han desarrollado de forma exponencial durante los últimos 20 años en el mundo, como también a nivel de nuestro país, con la creación de 10 biobancos desde el año 2004. En ellos se almacenan y organizan distintos tipos de muestras biológicas, asociadas a datos epidemiológicos y genéticos de donantes voluntarios. Todos los especímenes almacenados deben ser preservados con estándares de calidad garantizados, a modo de asegurar trazabilidad, integridad y calidad de las muestras. A pesar de que la mantención de un biobanco puede significar altos costos, a fin de cuentas, abaratan costos de los estudios clínicos, dado que es precisamente el biobanco quien se encarga de la obtención de datos y muestras clínicas confiables, permitiendo realizar múltiples estudios a partir de las mismas muestras. A través de este proceso, los biobancos permiten mantener una fuente confiable de recur-sos para la investigación en diversas áreas de la medicina, dentro de ellas la otorrinolaringología. En otorrinolaringología, los biobancos han significado un gran avance, facilitando la investigación en relación con hipoacusia, presbiacusia y tinnitus, así como en el área oncológica. En un futuro, se espera que la comunidad científica haga uso de este recurso, pudiendo expandir su utilidad no solo en el área médica, sino también en otras profesiones de la salud, maximizando así su gigantesco potencial.

Abstract Biobanks are novel biotechnological tools and a fundamental resource for the constant development of biomedical research, as much as for the growing practice of precision medicine. They have proliferated worldwide over the past 20 years and Chile has not been left behind with the creation of 10 bio-banks since 2004. Biobanks store and organize different types of biological samples associated with epidemiological and genetic data from volunteer donors. These samples are stored and preserved under guaranteed quality standards to ensure their traceability, integrity, and quality. Even though the price of maintaining a biobank may seem high, after all, they reduce the costs of research, since biobanks are responsible of the acquisition and storage of data and samples, allowing the performance of multiple studies from the same collection of specimens. In this direction, biobanks grant a constant source of well-founded scientific material for investigation in a wide range of medical fields, such as otolaryngology among them. In otolaryngology, the biobanks have meant a great improvement, facilitating investigations related to deafness, presbycusis, tinnitus and oncology. In the future we hope the scientific community will expand the use this innovative tool over a broader medical field and towards other health-related professions, making the most of its enormous potential.

Postoperative complications and waiting time for surgical intervention after radiologically guided drainage of intra-abdominal abscess in patients with Crohn's disease.

BACKGROUND: In patients with active Crohn's disease (CD), treatment of intra-abdominal abscess usually comprises antibiotics and radiologically guided percutaneous drainage (PD) preceding surgery. The aim of this study was to investigate the risk of postoperative complications and identify the optimal time interval for surgical intervention after PD. METHODS: A multicentre, international, retrospective cohort study was carried out. Details of patients with diagnosis of CD who underwent ultrasonography- or CT-guided PD were retrieved from hospital records using international classification of disease (ICD-10) diagnosis code for CD combined with procedure code for PD. Clinical variables were retrieved and the following outcomes were measured: 30-day postoperative overall complications, intra-abdominal septic complications, unplanned intraoperative adverse events, surgical-site infections, sepsis and pathological postoperative ileus, in addition to abscess recurrence. Patients were categorized into three groups according to the length of the interval from PD to surgery (1-14 days, 15-30 days and more than 30 days) for comparison of outcomes. RESULTS: The cohort comprised 335 CD patients with PD followed by surgery. Median age was 33 (i.q.r. 24-44) years, 152 (45.4 per cent) were females, and median disease duration was 9 (i.q.r. 3.6-15) years. Overall, the 30-day postoperative complications rate was 32.2 per cent and the mortality rate was 1.5 per cent. After adjustment for co-variables, older age (odds ratio 1.03 (95 per cent c.i. 1.01 to 1.06), P < 0.012), residual abscess after PD (odds ratio 0.374 (95 per cent c.i. 0.19 to 0.74), P < 0.014), smoking (odds ratio 1.89 (95 per cent c.i. 1.01 to 3.53), P = 0.049) and low serum albumin concentration (odds ratio 0.921 (95 per cent c.i. 0.89 to 0.96), P < 0.001) were associated with higher rates of postoperative complications. A short waiting interval, less than 2 weeks after PD, was associated with a high incidence of abscess recurrence (odds ratio 0.59 (95 per cent c.i. 0.36 to 0.96), P = 0.042). CONCLUSION: Smoking, low serum albumin concentration and older age were significantly associated with postoperative complications. An interval of at least 2 weeks after successful PD correlated with reduced risk of abscess recurrence.

The soluble glycoprotein NMB (GPNMB) produced by macrophages induces cancer stemness and metastasis via CD44 and IL-33.

In cancer, myeloid cells have tumor-supporting roles. We reported that the protein GPNMB (glycoprotein nonmetastatic B) was profoundly upregulated in macrophages interacting with tumor cells. Here, using mouse tumor models, we show that macrophage-derived soluble GPNMB increases tumor growth and metastasis in Gpnmb-mutant mice (DBA/2J). GPNMB triggers in the cancer cells the formation of self-renewing spheroids, which are characterized by the expression of cancer stem cell markers, prolonged cell survival and increased tumor-forming ability. Through the CD44 receptor, GPNMB mechanistically activates tumor cells to express the cytokine IL-33 and its receptor IL-1R1L. We also determined that recombinant IL-33 binding to IL-1R1L is sufficient to induce tumor spheroid formation with features of cancer stem cells. Overall, our results reveal a new paracrine axis, GPNMB and IL-33, which is activated during the cross talk of macrophages with tumor cells and eventually promotes cancer cell survival, the expansion of cancer stem cells and the acquisition of a metastatic phenotype.

Correction to: Inflammatory bowel disease position statement of the Italian Society of Colorectal Surgery (SICCR): ulcerative colitis.

The affiliation of the author Silvio Danese has been incorrectly published in the original publication.

Correction to: Inflammatory bowel disease (IBD) position statement of the Italian Society of Colorectal Surgery (SICCR): general principles of IBD management.

The affiliation of the author Silvio Danese has been incorrectly published in the original publication. The complete correct affiliation should read as follows.

Correction to: Inflammatory bowel disease position statement of the Italian Society of Colorectal Surgery (SICCR): Crohn's disease.

The affiliation of the author Silvio Danese has been incorrectly published in the original publication.

Inflammatory bowel disease position statement of the Italian Society of Colorectal Surgery (SICCR): ulcerative colitis.

The Italian Society of Colorectal Surgery (SICCR) promoted the project reported here, which consists of a Position Statement of Italian colorectal surgeons to address the surgical aspects of ulcerative colitis management. Members of the society were invited to express their opinions on several items proposed by the writing committee, based on evidence available in the literature. The results are presented, focusing on relevant points. The present paper is not an alternative to available guidelines; rather, it offers a snapshot of the attitudes of SICCR surgeons about the surgical treatment of ulcerative colitis. The committee was able to identify some points of major disagreement and suggested strategies to improve the quality of available data and acceptance of guidelines.

Inflammatory bowel disease position statement of the Italian Society of Colorectal Surgery (SICCR): Crohn's disease.

The Italian Society of Colorectal Surgery (SICCR) promoted the project reported here, which consists of a position statement of Italian colorectal surgeons to address the surgical aspects of Crohn's disease management. Members of the society were invited to express their opinions on several items proposed by the writing committee, based on evidence available in the literature. The results are presented, focusing on relevant points. The present paper is not an alternative to available guidelines; rather, it offers a snapshot of the attitudes of SICCR surgeons about the surgical treatment of Crohn's disease. The committee was able to identify some points of major disagreement and suggested strategies to improve quality of available data and acceptance of guidelines.

Prevalence of cervical HPV and attitude towards cervical screening in IBD patients under immunomodulatory treatment: a multidisciplinary management experience.

OBJECTIVE: Therapeutic strategies for Inflammatory Bowel Diseases (IBD: Crohn's disease and Ulcerative Colitis) have improved but the risk for HPV infection in patients under immunomodulatory/biologic treatment is unclear. Objective of the study is to identify the attitude of patients and caregivers to cervical screening. To determine the prevalence of HPV and cervical lesions in IBD patients receiving immunomodulatory/biological treatment. PATIENTS AND METHODS: IBD patients treated with immunomodulators were enrolled from November 2016 to September 2017, thanks to a multidisciplinary cooperation. A survey was administered to enrolled patients as well as to a selected network of IBD expert physicians. Patients who consented underwent gynecological examination, smear, HPV DNA test, colposcopy, vaginal and cervical microbiological swabs. RESULTS: 294 patients from AMICI Onlus Association, 119 patients from the hospital clinic, 30 doctors from national IBD centers participated to the survey. 19 patients from the IBD clinic underwent cervical screening. More than 90% of doctors consider their patients at risk of cervical cancer. A low prevalence of high-risk genotypes and related HPV lesions and an increased prevalence of bacterial vaginosis emerged in the studied population. CONCLUSIONS: Biological drugs could lead to a positive immunomodulation towards HPV infection. In IBD patients an alteration of the vaginal and intestinal microbiota seems to be coexisting.

Inflammatory bowel disease (IBD) position statement of the Italian Society of Colorectal Surgery (SICCR): general principles of IBD management.

The Italian Society of Colorectal Surgery (SICCR) promoted the project reported here, which consists of a Position Statement of Italian colorectal surgeons to address the surgical aspects of inflammatory bowel disease management. Members of the society were invited to express their opinions on several items proposed by the writing committee, based on evidence available in the literature. The results are presented, focusing on relevant points. The present paper is not an alternative to available guidelines; rather, it offers a snapshot of the attitudes of SICCR surgeons about the general principles of surgical treatment of inflammatory bowel disease. The committee was able to identify some points of major disagreement and suggested strategies to improve quality of available data and acceptance of guidelines.

Correlation of the in vitro biotransformation of H3B-6527 in dog and human hepatocytes with the in vivo metabolic profile of 14C-H3B-6527 in a dog mass balance study.

1. H3B-6527 is an orally available covalent small molecule inhibitor of FGFR4 undergoing evaluation in adults with hepatocellular carcinoma. Absorption, metabolism, transport and elimination of H3B-6527 were investigated in vitro and in a 14C-H3B-6527 beagle dog mass balance study.2. Following intravenous dosing in dogs, unchanged 14C-H3B-6527 represents only 1.6% of the total dose in excreta. The low amount of radioactivity in the dog urine (4.9% of the administered dose), suggests that renal elimination is a minor pathway of clearance for H3B-6527. A majority of the radioactivity was observed in the feces up to 5 days after dose administration, suggesting that drug-related material was secreted in the bile, and that H3B-6527 clearance was mostly driven by metabolism.3. In vitro, H3B-6527 is a substrate of GSTs, CYP3A and P-glycoprotein.4. The major pathways of metabolism were similar in human and dog hepatocytes, and occurred via glutathione (GSH) conjugations and sequential hydrolysis, N-deethylation and hydroxylation.5. The metabolic profile of H3B-6527 was qualitatively similar in dog hepatocytes and plasma/excreta.

Risk Factors for Small Bowel Obstruction After Laparoscopic Ileal Pouch-Anal Anastomosis for Inflammatory Bowel Disease: A Multivariate Analysis in Four Expert Centres in Europe.

BACKGROUND AND AIMS: Although laparoscopy is associated with a reduction in adhesions, no data are available about the risk factors for small bowel obstruction [SBO] after laparoscopic ileal pouch-anal anastomosis [IPAA]. Our aims here were to identify the risk factors for SBO after laparoscopic IPAA for inflammatory bowel disease [IBD]. METHODS: All consecutive patients undergoing laparoscopic IPAA for IBD in four European expert centres were included and divided into Groups A [SBO during follow-up] and B [no SBO]. RESULTS: From 2005 to 2015, SBO occurred in 41/521 patients [Group A; 8%]. Two-stage IPAA was more frequently complicated by SBO than 3- and modified 2-stage IPAA [12% vs 7% and 4%, p = 0.04]. After multivariate analysis, postoperative morbidity (odds ratio [OR] = 3, 95% confidence interval [CI] = 1.5-7, p = 0.002), stoma-related complications [OR = 3, 95% CI = 1-6, p = 0.03] and long-term incisional hernia [OR = 6, 95% CI = 2-18, p = 0.003] were predictive factors for SBO, while subtotal colectomy as first surgery was an independent protective factor [OR = 0.4, 95% CI = 0.2-0.8, p = 0.002]. In the subgroup of patients receiving restorative proctocolectomy as first operation, stoma-related or other surgical complications and long-term incisional hernia were predictive of SBO. In the patient subgroup of subtotal colectomy as first operation, postoperative morbidity and long-term incisional hernia were predictive of SBO, whereas ulcerative colitis and a laparoscopic approach during the second surgical stage were protective factors. CONCLUSIONS: We found that SBO occurred in less than 10% of patients after laparoscopic IPAA. The study also suggested that modified 2-stage IPAA could potentially be safer than procedures with temporary ileostomy [2- and 3-stage IPAA] in terms of SBO occurrence.

Genetics of ncHH: from a peculiar inheritance of a novel GNRHR mutation to a comprehensive review of the literature.

BACKGROUND: Normosmic congenital hypogonadotropic hypogonadism (ncHH) is caused by the deficient production, secretion, or action of gonadotropin-releasing hormone (GnRH). Its typical clinical manifestation is delayed puberty and azoospermia. Homozygous and compound heterozygous mutations in the GNRHR gene (4q13.2) are the most frequent genetic causes of ncHH. OBJECTIVES: (i) Characterization at the molecular level (genetic origin and functional effect) of a unique homozygous mutation (p.Gly99Glu) in a ncHH man; (ii) to provide a comprehensive catalog of GNRHR mutations with genotype-phenotype correlation and comparison of in vitro studies vs. in silico prediction tools. MATERIAL AND METHODS: A ncHH man and his parents, in whom we performed the following: (i) Sanger sequencing, qPCR of the GNRHR gene; (ii) chromosome 4 SNP array; and (iii) competition binding assay and inositol phosphate signaling assay. PubMed and Human Genome Mutation Database (HGMD) search for GNRHR mutations. Bioinformatic analysis of 55 reported variants. RESULTS: qPCR showed two GNRHR copies in the index case. SNP array revealed the inheritance of two homologous chromosomes 4 from the mother (maternal heterodisomy; hUPD) with two loss of heterozygosity regions, one of them containing the mutated gene (maternal isodisomy; iUPD). Functional studies for the p.Gly99Glu mutation demonstrated a right-shifted GnRH-stimulated signaling response. Bioinformatic tools show that commonly used in silico tools are poor predictors of the function of ncHH-associated GNRHR variants. DISCUSSION: Functional analysis of the p.Gly99Glu mutation is consistent with severely decreased GnRH binding affinity (a severe partial loss-of-function mutation). Complete LOF variants are associated with severe and severe/moderate phenotype, whereas partial LOF variants show wide range of clinical manifestations. CONCLUSION: This is the first ncHH patient carrying a novel causative missense mutation of GNRHR with proven 'severe pLOF' due to maternal hUPD/iUPD of chromosome 4. Our literature review shows that functional studies remain essential both for diagnostic and potential therapeutic purposes.

The natural compound 7-epiclusianone inhibits superoxide dismutase activity in Schistosoma mansoni.

Schistosomiasis - caused by trematodes from the genus Schistosoma - affects more than 200 million people worldwide. Growing resistance to therapy with praziquantel (PZQ) has encouraged the search for novel treatments against this neglected disease. The compound 7-epiclusianone (7-epi) - isolated from 'bacupari' (the fruit of the Gracinia brasiliensis tree) - has promising activity against Schistosoma mansoni in vitro, damaging the parasite's tegument. However, the target and mechanism of action of 7-epi have not been identified. Here, we examined the possibility that 7-epi harms the tegument by inhibiting parasite superoxide dismutase (SOD), which protects the tegument from damage by reactive oxygen species produced by host immune cells. Molecular docking analysis in silico suggested strong interactions between 7-epi and S. mansoni cytosolic superoxide dismutase (SmCtSOD) at allosteric cavities. Schistosoma mansoni couples were cultivated ex vivo with 12.44-198.96 µm 7-epi for 24 h, and then parasite extracts were tested for lipid peroxidation (as a surrogate for oxidative stress), and SOD activity and expression. Lipid peroxidation levels increased after incubation with concentrations ≥99.48 µm 7-epi, and this compound reduced SOD activity at concentrations ≥24.87 µm. However, contact with 7-epi did not alter SOD expression, by quantitative real-time polymerase chain reaction (qRT-PCR). Our results show that the inhibition of SmCtSOD is partly responsible for the tegument detachment observed after incubation with 7-epi, but is not the only cause of the antiparasitic action of this compound in vitro.

Successful neuropsychological rehabilitation in a patient with Cerebellar Cognitive Affective Syndrome.

The objective of this case study was to describe the neuropsychological rehabilitation of a 16-year-old patient who presented a Cerebellar Cognitive Affective Syndrome (CCAS) following a bilateral cerebellar hemorrhage. The patient presented severe and diffuse cognitive deficits, massive behavioral disorders, and emotion regulation difficulties. The cognitive rehabilitation was performed in the chronic phase (one year after the onset of the hemorrhage) using a transdisciplinary neurobehavioral approach based on the patient's favorite interest (soccer). A significant behavioral and cognitive improvement was observed. The patient became progressively independent in all activities of daily living and was discharged home. The Functional Independence Measure at discharge was 124/126 (vs. 37/126 at entry). The patient was able to complete his schooling despite the mild cognitive and behavioral sequelae. This first description of the use of neurobehavioral therapy in a case of chronic CCAS suggests that (a) major clinical improvement can occur more than one year after the onset of the CCAS, showing the importance of long-term and intensive neurorehabilitation; and (b) when the cerebellum cannot properly play its regulator role in cognition, neuropsychological intervention through a behavioral and cognitive approach can be of great help by acting as an external modulator to help the patient regain control over himself.

Particulate matter phagocytosis induces tissue factor in differentiating macrophages.

Airborne exposure to particulate matter with diameter < 10 mcM (PM10) has been linked to an increased risk of thromboembolic events, but the mechanisms are not completely understood. The aim of this study was to evaluate the effect of PM10 phagocytosis on the release of procoagulant molecules in human differentiating macrophages, and that of PM10 inhalation in an experimental model in rats. Human monocytes were separated from the peripheral blood by the lymphoprep method, differentiated in vitro and treated with standard PM10 or vehicle. Sprague-Dawley rats were instilled intratracheally with PM10 or vehicle alone. The outcome was expression of proinflammatory genes and of tissue factor (TF). In human differentiating macrophages, PM10 exposure upregulated inflammatory genes, but most consistently induced TF mRNA and protein levels, but not TF protein inhibitor, resulting in increased TF membrane expression and a procoagulant phenotype. Differentiation towards the anti-inflammatory M2 phenotype inhibited PM10 -mediated TF expression. TF induction required phagocytosis of PM10 , whereas phagocytosis of inert particles was less effective. PM10 phagocytosis was associated with a gene expression profile consistent with intracellular retention of iron, inducing oxidative stress. Both PM10 and iron activated the stress kinases ERK1/2 pathway, involved in the induction of TF expression. In rats, alveolar exposure to PM10 was associated with pulmonary recruitment of inflammatory cells and resulted in local, but not systemic, induction of TF expression, which was sufficient to increase circulating TF levels. In conclusion, TF induction by differentiating lung macrophages, activated following phagocytosis, contributes to the increased risk of thromboembolic complications associated with PM10 exposure.