NGS and phenotypic ontology-based approaches increase the diagnostic yield in syndromic retinal diseases.

Syndromic retinal diseases (SRDs) are a group of complex inherited systemic disorders, with challenging molecular underpinnings and clinical management. Our main goal is to improve clinical and molecular SRDs diagnosis, by applying a structured phenotypic ontology and next-generation sequencing (NGS)-based pipelines. A prospective and retrospective cohort study was performed on 100 probands with an a priori diagnosis of non-Usher SRDs, using available clinical data, including Human Phenotype Ontology annotation, and further classification into seven clinical categories (ciliopathies, specific syndromes and five others). Retrospective molecular diagnosis was assessed using different molecular and bioinformatic methods depending on availability. Subsequently, uncharacterized probands were prospectively screened using other NGS approaches to extend the number of analyzed genes. After phenotypic classification, ciliopathies were the most common SRD (35%). A global characterization rate of 52% was obtained, with six cases incompletely characterized for a gene that partially explained the phenotype. An improved characterization rate was achieved addressing prospective cases (83%) and well-recognizable syndrome (62%) subgroups. The 27% of the fully characterized cases were reclassified into a different clinical category after identification of the disease-causing gene. Clinical-exome sequencing is the most appropriate first-tier approach for prospective cases, whereas whole-exome sequencing and bioinformatic reanalysis increases the diagnosis of uncharacterized retrospective cases to 45%, mostly those with unspecific symptoms. Our study describes a comprehensive approach to SRDs in daily clinical practice and the importance of thorough clinical assessment and selection of the most appropriate molecular test to be used to solve these complex cases and elucidate novel associations.

Polymorphisms in histone deacetylases improve the predictive value of IL-28B for chronic hepatitis C therapy.

Histone deacetylases (HDACs) influence many cellular processes, including the modulation of signal transducer and activator of transcription activity (STAT) in response to interferon (IFN). To identify genetic markers that help optimize the IL-28B prediction of chronic hepatitis C (CHC) sustained virological response (SVR), we evaluated 27 single-nucleotide polymorphisms (SNPs) in HDAC1-11. Three SNPs, rs3778216, rs976552 and rs368328 in HDAC2, HDAC3 and HDAC5, respectively, were independently associated with SVR (P<0.05). The addition of these three HDAC's SNPs to the IL-28B predictive model (area under the curve (AUC)=0.630) rendered an important improvement of AUC-receiver operating characteristic value (AUC=0.747, P=0.021). Chi-squared Automatic Interaction Detector (CHAID) analysis denoted the significance of the rs3778216 C/C genotype in identifying a group of good responders despite carrying IL-28B T allele (79.2% of SVR), whereas HDAC5 G allele characterized a subgroup with poor response rate (25.5%). However, HDAC3 rs976552 did not display a relevant role for the hierarchical classification of patients. Variables related to SVR in hepatitis C virus genotype 1 (HCV-1) cohort were the same of those obtained for the overall population. Interestingly, in non-HCV-1 patients (n=56) the HDAC2 C/C genotype was the unique predictive variable related to SVR (AUC=0.733, P<0.007). Thus, these preliminary results suggest the potential usefulness of combined IL-28B and HDAC genotyping for the CHC patients' classification by likelihood of an SVR.

Genetic variants of interferon-stimulated genes and IL-28B as host prognostic factors of response to combination treatment for chronic hepatitis C.

Chronic hepatitis C (CHC) is a worldwide health problem that is highly related to liver fibrosis, cirrhosis, and hepatocellular carcinoma. The achievement of response to the current standard of care-pegylated interferon plus ribavirin-has recently been described to be associated with single-nucleotide polymorphisms (SNPs) near the IL-28B gene. Additionally, baseline expression levels of genes involved in interferon (IFN)-stimulated genes (ISGs) have been found to be related to treatment outcome. In the present study, 285 patients were genotyped for 63 SNPs within genes of the IFN signaling pathway (IPGs) and ISGs. Two ISG polymorphisms-OASL rs12819210 (odds ratio (OR)=2.1, P=0.03) and IFIT1 rs304478 (OR=2.5, P=0.01)-were found to be independent predictive factors of sustained virological response (SVR) after adjusting for other clinical covariates. Furthermore, the predictive value of IL-28B SNP was notably improved by simultaneous genotyping of rs12819210 and rs304478, particularly in patients with the worst prognosis (viral genotype 1, area under the curve (AUC)=0.74). In conclusion, ISG SNPs could constitute a valuable tool for individualizing CHC therapy.

Peripheral blood monocyte subsets predict antiviral response in chronic hepatitis C.

BACKGROUND: Hepatitis C virus infection evolves into chronic progressive liver disease in a significant percentage of patients. Monocytes constitute a diverse group of myeloid cells that mediate innate and adaptive immune response. In addition to proinflammatory CD16+ monocytes, a Tie-2+ subgroup - Tie-2 expressing monocytes (TEMs) - that has robust proangiogenic potential has been recently defined. AIM: To study the heterogeneity of peripheral blood monocytes in chronic hepatitis C (CHC) patients and to examine their proposed pathophysiological roles on disease progression and response to antiviral therapy. METHODS: We studied CD16+ and Tie-2+ peripheral monocyte subpopulations in 21 healthy subjects and 39 CHC patients in various stages of disease and responses to antiviral treatment using flow cytometry. Expression profiles of proangiogenic and tissue remodelling factors in monocyte supernatants were measured using ELISA and protein arrays. Intrahepatic expression of CD14, CD31 and Tie-2 was analysed using immunofluorescence. RESULTS: Increases of certain peripheral monocyte subsets were observed in the blood of CHC patients, wherein those cells with proinflammatory (CD16+) or proangiogenic (TEMs) potential expanded (P < 0.005, both). Notably, TEMs were significantly increased in nonresponders, particularly those with lower CD16 expression. In addition, many angiogenic factors were differentially expressed by peripheral monocytes from control or CHC patients, such as angiopoietin-1 and angiogenin (P < 0.05). Interestingly, intrahepatic TEMs were distinguished within portal infiltrates of CHC patients. CONCLUSIONS: These findings suggest for the first time the relevance of peripheral monocytes phenotypes for the achievement of response to treatment. Hence, the study of monocyte subset regulation might effect improved CHC prognoses and adjuvant therapies.

Effects of exercise and human contact on animal welfare in a dog shelter.

The aim of the study is to investigate the reduction of stress in dogs in municipal shelters through easy-to-implement activities, ie, 25-minute sessions of exercise and human contact, that do not require a significant investment in terms of funding, staff or time. The results demonstrate that the dogs taking part in these sessions have lower salivary cortisol levels (F=121.42; P<0.05) and achieve better scores on a behaviour test (t(17)=4.27; P=0.001). It can therefore be affirmed that the exercise and human contact protocol proposed in the present study diminishes stress and improves the welfare of dogs housed in shelters.

Pharmacogenetic relevance of the CYP2C9*3 allele in a tenoxicam bioequivalence study performed on Spaniards.

We performed a study to quantify CYP2C9 and CYP2C8 alleles influence on the variability observed in tenoxicam pharmacokinetic (PK) and implication in a bioequivalence study design performed on Spaniards. Eighteen healthy volunteers were included in an open, randomized, crossover, phase I bioequivalence study. Significant increases were found in CYP2C9*3 alleles vs. *1 and *2 in AUC(0-infinity) (median (min-max)): 256 (230-516) vs. 150 (100-268) and 169 (124-197) microg h/mL (p<0.01) and half-life time (t1/2) 102 (79-36) vs. 56 (45-94) and 64 (60-80)h (p<0.01). Non-significant differences were observed in C(max) 1.9 (1.8-2.9) vs. 2.4 (1.7-3.4), 2.5 (1.6-2.9) microg/mL or in according to CYP2C8 alleles presence. CYP2C9*3 allele is associated to a longer elimination time of tenoxicam. PK parameters calculated in bioequivalence studies (AUC(0-infinity), t1/2) may be influenced by the presence of CYP2C9*3 allele resulting in a high variability. Thus, bioequivalence studies of tenoxicam formulations should be designed considering genotype profile.

[The autoimmune hepatitis-primary biliary cirrhosis overlap syndrome: a case report]. / Síndrome overlap hepatitis autoinmune-cirrosis biliar primaria: a propósito de un caso.

The autoimmune hepatitis-primary biliary cirrhosis overlap syndrome is an entity characterized by clinical, analytical, immunological and histological manifestations of both entities. We present the case of a 26-year-old woman with a serious acute hepatitis that fulfills the diagnostic criteria of the overlap syndrome and that showed a satisfactory response to oral corticoid therapy.

[Pacemaker endocarditis]. / Endocarditis del marcapasos.

Pacemaker endocarditis is a rare but serious complication of permanent transvenous pacing. The most common presentation is fever syndrome or gram positive bacteremia. For the diagnostic it is important to performed blood cultures and an echocardiography. A retrospective study included the cases of pacemaker endocarditis diagnosed in the Internal Medicine Department of our Hospital between 1989-2003. Six patients were included. Repeated manipulation of the system and diabetes were the most frequent risk factors. The most frequently detected causative microorganisms were Staphylococci. In spite of the low sensitivity of the transthoracic echocardiography in expert hands it can improve, in this series it places in 66 %. Surgical treatment with cardiopulmonary bypass and implantation of a new system was performed in the same intervention in all patients. None relapsed and the overall mortality was 17%.

Lithium and venlafaxine interaction: a case of serotonin syndrome.

Serotonin syndrome, which occurs as a result of enhanced serotonin concentration in the central nervous system, is a well-known adverse effect of serotonin-active medications. The concomitant use of antidepressant drugs associated with lithium as a co-adjuvant seems to increase the risk of this adverse reaction. We report a case of the serotonin syndrome during treatment with lithium and venlafaxine, an antidepressant with a dual selective re-uptake inhibition mechanism, and review the literature for similar cases. A 71-year-old woman developed serotonin syndrome while receiving treatment with moderate doses of lithium and venlafaxine for refractory depression. She had been taking higher doses of venlafaxine during the previous months with no significant secondary effects. Use of the Naranjo adverse drug reaction probability algorithm indicated a probable relationship between serotonin syndrome and treatment with lithium and venlafaxine.

[Pacemaker endocarditis]. / Endocarditis del marcapasos.

In the last years an increment has taken place in the pacemaker and implantable cardioverter-defibrillator indications that will have as consequence an increase of the prevalence of endocarditis associated to intravascular devices, for what acquires special relevance for the clinician to know this entity and to include it in his differential diagnoses. The objective of this article is to describe the epidemiology, clinic characteristics, diagnosis, treatment and outcome of the pacemaker endocarditis.