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.

     

Proximal femoral nailing without a fracture table

The treatment of unstable trochanteric femoral fractures is still challenging, and the proximal femoral nails are becoming more commonly used. The proximal femoral nailing is usually performed on a fracture table under traction which is associated with some possible complications. In our study, we tried to present the results of proximal nailing surgery performed in the lateral decubitus position and manual traction on a radiolucent table without the fracture table traction.     

TNF-α receptor 1 deficiency reduces antigen-presenting capacity of Schwann cells and ameliorates experimental autoimmune neuritis in mice

Tumor necrosis factor-α (TNF-α) is a pleiotropic pro-inflammatory cytokine with potentially neurodestructive effects and plays a pivotal role in autoimmune demyelinating disease. To address the role of TNF-α in the pathogenesis of experimental autoimmune neuritis (EAN), the current study investigated the antigen-presenting capacity of Schwann cells (SCs) in EAN induced by P0 protein peptide 106–125 in TNF-α recepter 1 deficient (TNFR1^−/−) mice. The antigen-presenting capacity of SCs was assessed by the expression of MHC class II (MHCII), CD40, CD80 and CD86 molecules on activated SCs as well as by induction of T cell proliferation in co-cultures of P0 protein peptide 106–125 specific T cells with activated SCs. In addition, the expression of inducible nitric oxide synthase (iNOS) was measured in activated SCs by flow cytometry. TNFR1^−/− EAN mice developed significantly delayed and reduced clinical signs of EAN compared to wild type EAN mice. In parallel, the expression of MHCII, CD80 and iNOS on SCs were decreased in TNFR1^−/− mice compared to wild type mice. Likewise, proliferation of P0 protein peptide 106–125 specific T cells simulated by activated SCs of TNFR1^−/− EAN mice was lower than that of wild type EAN mice. Our data suggest that TNF-α may exert pro-inflammatory effects in EAN via TNFR1 by up-regulating the antigen-presenting function and iNOS production of SCs.     

The superior vena cava syndrome caused by malignant disease. Imaging with multi-detector row CT

OBJECTIVE: The superior vena cava (SVC) obstruction by malignant diseases is either by direct invasion and compression or by tumour thrombus of the SVC. Whatever is its cause, obstruction of the SVC causes elevated pressure in the veins draining into the SVC and increased or reversed blood flow through collateral vessels. Severity of the syndrome depends on the collateral vascular system development. Therefore, imaging of the collateral veins with variable location and connection is important in determining the extension and management of the disease. Our aims are to describe collateral vessels of the superior vena cava syndrome (SVCS) related with the malignant diseases and to assess the ability of multi-detector row CT with multiplanar and 3D volume rendering techniques in determining and describing collateral circulations. MATERIALS AND METHODS: We present CT angiography findings of seven patients with small cell carcinoma of the lung (n = 2), squamous cell carcinoma of the lung (n = 3), Hodgkin disease of the thorax (n = 1), and squamous cell carcinoma of the oesophagus (n = 1). The patients received contrast-enhanced CT scans of the chest and abdomen on a multi-detector row CT during breath holding at suspended inspiration. RESULTS: CT images revealed the cause and level of the SVC obstruction in all patients with axial and multiplanar reconstructed images. The SVC showed total obstruction in five patients and partial obstruction in two patients. The most common experienced collateral vessels were azygos vein (6), intercostal veins (6), mediastinal veins (6), paravertebral veins (5), hemiazygos vein (5), thoracoepigastric vein (5), internal mammary vein (5), thoracoacromioclavicular venous plexus (5), and anterior chest wall veins (5). While one case showed the portal-systemic shunt, V. cordis media and sinus coronarius with phrenic veins were enlarged in two cases, and the left adrenal vein was enlarged in a patient. In one case, the azygos vein with reversed blood flow was drained into both inferior vena cava and hemiazygos vein with the left renal vein. CONCLUSION: Multi-detector row CT with multiplanar and 3D imaging is an effective tool in evaluation of the SVCS and has a greater advantage than the other imaging techniques. 3D volume rendering is a useful technique in determining and describing collateral circulations in addition to the primary disease process.     

Anatomical and surgical study of the sphenopalatine artery branches

The sphenopalatine artery gives off two main branches: the posterior lateral nasal branch and the posterior septal branch. From 2007 to 2012 17 patients were treated with cauterization and/or ligature of the sphenopalatine artery with endonasal endoscopic approach. 90 nasal dissections were performed in 45 adult cadaveric heads. We evaluated the number of branches emerging from the sphenopalatine foramen and the presence of an accessory foramen. In the surgery group, we observed a single trunk in 76 % of the patients (13/17) and a double trunk in 24 % (4/17). We found an accessory foramen in four cases. We obtained a successful result in bleeding control in 88 % of the cases. In the cadaver dissection group, 55 nasal cavities had a single arterial trunk (61 %), 30 had 2 arterial trunks (33 %) and in only 5 nasal fossae we observed 3 arterial trunks (6 %). We were able to dissect four accessory foramina. We suggest that in most cases only one or two branches are found in the sphenopalatine foramen.