Prolactin binding sites in rat brain and liver: effects of long-term ovariectomy and ovarian steroids

The effects of long-term ovariectomy on the levels of brain and liver lactogenic binding sites as well as plasma and liver prolactin (PRL) have been investigated in sham-operated and ovariectomized rats receiving either 17β estradiol (OVX-E), progesterone (OVX-P), or vehicle (OVX-V). The levels of lactogenic binding sites in the parietal and piriform cortices, amygdala, thalamus, hypothalamus, as well as in the liver were significantly decreased after long-term ovariectomy. Moreover, the levels of plasma and liver PRL were also significantly decreased. Exogenous estradiol and progesterone replacement restored the levels of lactogenic binding sites in the parietal cortex and hypothalamus as well as in the liver. However, plasma and liver PRL levels were significantly increased by estradiol but only restored by progesterone. These results suggest that ovarian steroids influence the levels of lactogenic binding sites and prolactin.     

Wide spectrum screening keratin as a marker of metaplastic spindle cell carcinoma of the breast: an immunohistochemical study of 24 patients

Wide spectrum screening keratin as a marker of metaplastic spindle cell carcinoma of the breast: an immunohistochemical study of 24 patients
Aims : Metaplastic spindle cell carcinomas may be difficult to distinguish histologically from other spindle cell lesions in the breast. Variable staining with cytokeratin immunomarkers has been reported for metaplastic carcinomas. We evaluated the diagnostic utility of anti-cytokeratin polyclonal antibody, wide spectrum screening keratin, to assess spindle cell breast lesions.
Methods and results : Twenty-four patients with spindle cell breast carcinoma and 31 patients with benign or malignant spindle cell tumours were studied using a panel of antibodies directed against multiple cytokeratins (AE1/AE3, CAM5.2, wide spectrum screening keratin), epithelial membrane antigen (EMA), and vimentin. Sites of origin for the 31 controls included breast, bone, and soft tissue. All but one (95.8%) metaplastic carcinomas stained positively with wide spectrum screening keratin. Only rare or focal immunoreactivity was observed with AE1/AE3 in four cases; however, sensitivity of AE1/AE3 was improved in 13 cases using steam EDTA as an antigen retrieval technique. Three cases were immunoreactive with CAM5.2 and eight cases were immunoreactive with EMA. All control cases lacked immunoreactivity with the cytokeratin panel and EMA. The spindle cells in the metaplastic breast tumours (88%) and in the controls (97%) stained with vimentin.
Conclusions : Wide spectrum screening keratin may be the most useful and convenient antibody in differentiating metaplastic spindle cell carcinoma from other spindle cell lesions in the breast.     

Prediction of cyclosporine A blood levels: an application of the adaptive-network-based fuzzy inference system (ANFIS) in assisting drug therapy

OBJECTIVE: Therapeutic drug monitoring (TDM) is a procedure in which the levels of drugs are assayed in various body fluids with the aim of individualizing the dose of critical drugs, such as cyclosporine A. Cyclosporine A assays are performed in blood. METHODS: We proposed the use of the Takagi and Sugeno-type "adaptive-network-based fuzzy inference system" (ANFIS) to predict the concentration of cyclosporine A in blood samples taken from renal transplantation patients. We implemented the ANFIS model using TDM data collected from 138 patients and 20 input parameters. Input parameters for the model consisted of concurrent use of drugs, blood levels, sampling time, age, gender, and dosing intervals. RESULTS: Fuzzy modeling produced eight rules. The developed ANFIS model exhibited a root mean square error (RMSE) of 0.045 with respect to the training data and an error of 0.057 with respect to the checking data in the MATLAB: environment. CONCLUSION: ANFIS can effectively assist physicians in choosing best therapeutic drug dose in the clinical setting.     

Do Anti-TNF Agents Increase the Risk of Inflammatory Bowel Disease Evolution in Patients with Ankylosing Spondylitis? Real Life Data

ObjectiveThe aim of this study was to determine whether there is any association with anti-tumor necrosis factor (TNF) agent administration and development of new-onset inflammatory bowel disease (IBD) in ankylosing spondylitis (AS) patients.MethodsRecords of the patients who met 1984 modified New York criteria for AS between 1998 and 2016 at Rheumatology Department were evaluated retrospectively and data about the patients, IBD properties and medication were obtained.ResultsAmong 420 patients, 310 were male, the average age was 42.9 ± 1.3 years, average disease duration was 16.7 ± 10.4 years. Anti-TNF agents were in use by 154 patients, 52 patients were receiving etanercept (ETN), infliximab (INF), adalimumab (ADA), and golimumab (GO) treatments were ongoing in 50, 41, and 11 patients, respectively. New-onset IBD developed in 10 patients; 3 from the group treated with non-anti-TNF drugs (1.1%) and 7 from the group treated with anti-TNF agents (4.5%) (p = 0.042). No significant difference was detected between three anti-TNF agent forms in relation with the risk of IBD onset. In AS patients, existence of familial AS (OR 4.69 (95%CI 1.28-17.19, p = 0.020) and anti-TNF agent treatment (OR 4.17 (95%CI 1.06-16.38, p = 0.041) were independent risk factors for new-onset IBD development.ConclusionDespite the increased risk of new-onset IBD development during the course of AS, paradoxical response to anti-TNF drugs must also be considered as a source that triggers onset of IBD.     

Fluoroscopic Anatomy of Right-Sided Heart Structures for Transcatheter Interventions

Performing transcatheter tricuspid valve interventions requires a thorough knowledge of right-heart imaging. Integration of chamber views across the spectrum of imaging modalities (i.e., multislice computed tomography, fluoroscopy, and echocardiography) can facilitate transcatheter interventions on the right heart. Optimal fluoroscopic viewing angles for guiding interventional procedures can be obtained using pre-procedural multislice computed tomography scans. The present paper describes fluoroscopic viewing angles necessary to appreciate right-heart chamber anatomy and their relationship to echocardiography using multislice computed tomography.     

Evidence-based prioritisation and enrichment of genes interacting with metformin in type 2 diabetes

Aims/hypothesis

There is an extensive body of literature suggesting the involvement of multiple loci in regulating the action of metformin; most findings lack replication, without which distinguishing true-positive from false-positive findings is difficult. To address this, we undertook evidence-based, multiple data integration to determine the validity of published evidence.

Methods

We (1) built a database of published data on gene–metformin interactions using an automated text-mining approach (n = 5963 publications), (2) generated evidence scores for each reported locus, (3) from which a rank-ordered gene set was generated, and (4) determined the extent to which this gene set was enriched for glycaemic response through replication analyses in a well-powered independent genome-wide association study (GWAS) dataset from the Genetics of Diabetes and Audit Research Tayside Study (GoDARTS).

Results

From the literature search, seven genes were identified that are related to the clinical outcomes of metformin. Fifteen genes were linked with either metformin pharmacokinetics or pharmacodynamics, and the expression profiles of a further 51 genes were found to be responsive to metformin. Gene-set enrichment analysis consisting of the three sets and two more composite sets derived from the above three showed no significant enrichment in four of the gene sets. However, we detected significant enrichment of genes in the least prioritised category (a gene set in which their expression is affected by metformin) with glycaemic response to metformin (p = 0.03). This gene set includes novel candidate genes such as SLC2A4 (p = 3.24 × 10^?04) and G6PC (p = 4.77 × 10^?04).

Conclusions/interpretation

We have described a semi-automated text-mining and evidence-scoring algorithm that facilitates the organisation and extraction of useful information about gene–drug interactions. We further validated the output of this algorithm in a drug-response GWAS dataset, providing novel candidate loci for gene–metformin interactions.