Aspirin, protein transacetylation and inhibition of prostaglandin synthetase in the kidney

1 The effect of aspirin on the kidney has been investigated in mice and rabbits. [Acetyl-¹⁴C]-aspirin was administered intraperitoneally in doses ranging from subtherapeutic to toxic. The degree of acetylation of protein was determined by the radioactivity remaining on protein precipitates of renal cortex and medulla after sequential washing designed to remove non-covalently bound material. Controls were established, by the use of [carboxyl-¹⁴C]-aspirin.

2 The acetyl-¹⁴C residue was bound to renal proteins in a linear manner in increasing amounts with increasing dosage up to 100 mg/kg. The [carboxyl-¹⁴C]-aspirin was not bound and thus the salicylate portion of the molecule was not bound covalently to the renal protein. The time course of the acetylation was rapid, consistent with the rate of aspirin absorption. The disappearance of acetylated protein was slow, with a T_1/2 of 112.5 h in the renal cortex, and 129.5 h in the renal medulla.

3 Differential centrifugation, Sephadex chromatography and gel electrophoresis were carried out on tissue homogenates to determine the site of acetylation. The acetylation was greatest in the microsomal fraction, although all protein fractions showed some degree of acetylation.

4 The prostaglandin synthetase activity of a particulate preparation from rabbit kidney was determined by a spectrophotometric assay of malondialdehyde formation. Aspirin (10 mg/kg, i.v.) significantly inhibited prostaglandin synthetase in the renal cortex and medulla.

5 Aspirin and renal proteins undergo a transacetylation reaction resulting in stable acetylated protein, with acetylation being greatest in the microsomal fraction. Aspirin has been shown to inhibit prostaglandin synthetase and this could lead to functional impairment of the tissue.

     

Testicular function after renal transplantation: comparison of Cyclosporin A with azathioprine and prednisone combination regimes

Testicular function was assessed in 24 men after renal transplantation who were on either Cyclosporin A (CSA) (8 men) or a combination of azathioprine and prednisone (AZP) (16 men) as immunosuppressive therapy. The different regimes were not associated with any differences in clinical or hormonal (LH, FSH, prolactin, testosterone, estradiol) indices of testicular function although adrenal androgen (dehydroepiandrosterone sulphate) was suppressed in prednisone-treated men. Overall, however, poor graft function was associated with abnormal testicular function. Renal allograft function rather than immunosuppressive regime was the major determinant of gonadal function.     

Meta-analysis of two genome-wide association studies identifies four genetic loci associated with thyroid function

Thyroid hormones play key roles in cellular growth, development and metabolism. Although there is a strong genetic influence on thyroid hormone levels, the genes involved are widely unknown. The levels of circulating thyroid hormones are tightly regulated by thyrotropin (TSH), which also represents the most important diagnostic marker for thyroid function. Therefore, in order to identify genetic loci associated with TSH levels, we performed a discovery meta-analysis of two genome-wide association studies including two cohorts from Germany, KORA (n = 1287) and SHIP (n = 2449), resulting in a total sample size of 3736. Four genetic loci at 5q13.3, 1p36, 16q23 and 4q31 were associated with serum TSH levels. The lead single-nucleotide polymorphisms of these four loci were located within PDE8B encoding phosphodiesterase 8B, upstream of CAPZB that encodes the β-subunit of the barbed-end F-actin-binding protein, in a former 'gene desert' that was recently demonstrated to encode a functional gene (LOC440389) associated with thyroid volume, and upstream of NR3C2 encoding the mineralocorticoid receptor. The latter association for the first time suggests the modulation of thyroid function by mineral corticoids. All four loci were replicated in three additional cohorts: the HUNT study from Norway (n = 1487) and the two German studies CARLA (CARLA, n = 1357) and SHIP-TREND (n = 883). Together, these four quantitative trait loci accounted for ～3.3% of the variance in TSH serum levels. These results contribute to our understanding of genetic factors and physiological mechanisms mediating thyroid function.     

Assessment of left atrial appendage by live three-dimensional echocardiography: early experience and comparison with transesophageal echocardiography

BACKGROUND: Live Three-Dimensional Echocardiography (L3D, Sonos 7500, Philips) has the potential to visualize all cardiac structures including left atrial appendage (LAA). We tested the feasibility of evaluating LAA by L3D and compared the findings to transthoracic echocardiography (2D) and in a subset of patients with transesophageal echocardiography (TEE). METHODS: L3D images were obtained in 204 consecutive patients referred for routine 2D or TEE. We performed wide-angled acquisitions from parasternal and apical views. TomTec system (4D Cardio-view, RT 1.2) was used to visualize LAA from multiple vantage points. RESULTS: LAA was adequately visualized by L3D in 139 of 204 (68.1%) patients. L3D visualization was dependent on image quality, suboptimal in 100 and diagnostic in 104 patients. Overall, LAA was visualized in 93 (45.5%) patients by 2D compared to 139 (68.1%) by L3D (P < 0.0001). In 100 patients with suboptimal image quality by L3D, LAA visualization was 16% by 2D and 35% by L3D, whereas in 104 patients with diagnostic images, LAA was visualized in 77 (74%) by 2D and in all 104 (100%) patients by L3D (P < 0.0001). In 37 patients referred for transesophageal echocardiography (TEE), live three-dimensional echocardiography (L3D) visualized left atrial appendage (LAA) in 34 patients with diagnostic image quality. Eight patients with LAA thrombi on TEE had thrombi detected by L3D as well. All patients with LAA thrombus had enlarged LA by both 2D and TEE. CONCLUSIONS: L3D is a promising technique in evaluation of LAA with and without thrombi. In patients with good quality transthoracic images L3D may be used as a screening tool in assessment of LAA.