Fatty acid-binding protein-4 as a biomarker predicting acromegaly-associated diabetes mellitus

Background/aimThe known pathogenesis of diabetes mellitus (DM) in acromegaly is mainly based on growth hormone (GH) and insulin-like growth factor-1 (IGF-1) excess. Fatty acid-binding protein 4 (FABP-4), a novel adipokine, is found to induce insulin resistance and type 2 DM. We aimed to investigate the possible effect of FABP-4 on glucose metabolism in patients with acromegaly.Materials and methodsThis case-control study included 28 patients newly diagnosed with acromegaly and 57 healthy volunteers. The patients with acromegaly were classified according to their glycemic status as with DM, prediabetes, and normal glucose tolerance. Anthropometric measurements, laboratory test results, and FABP-4 levels of the subjects were evaluated.ResultsAlthough no difference was observed in FABP-4 levels between acromegaly and control groups, the FABP-4 level was higher in the patients with acromegaly having DM compared to the patients with acromegaly having prediabetes and NGT, and the control group (p = 0.004, p = 0.001, p = 0.004, respectively). Logistic regression analysis suggested that the FABP-4 is an independent predictor of DM in acromegaly (β = 7.382, OR = 38.96, 95% CI: 1.52-5.76, p = 0.018).Conclusion The FABP-4 may be a helpful predictor of acromegaly-associated DM.     

Congenital middle-ear deafness: CT study

Computed tomography (CT) was used to study 25 patients with congenital conductive hearing loss and normal external auditory canals. Deformities were subdivided according to ossicular, fenestral, and cholesteatomatous origin. Isolated ossicular deformities were found in 14 patients (five bilateral), cholesteatoma in eight, oval-window nondevelopment (with ossicular deformity) in one, and normal studies in two (congenital stapes fixation at the level of the annular ligament). Ossicular deformities may be subdivided into incudostapedial disconnections into incudostapedial disconnections (most common), malleoincudal fixations, and stapes fixations. Most are due to developmental anomaly of the first or second branchial arch. The stapes has a dual origin (second arch and otic capsule). A cholesteatoma is defined as congenital only if there is no history of otitis and the tympanic membrane is intact. In this series, six were in the middle ear proper, and two were within the attic beyond otoscopic view. Their CT appearance, with one exception, was essentially identical to that of acquired lesions.     

Prenatal ultrasonographic detection and prenatal (prior to birth) management of hereditary retinoblastoma

Graefe's Archive for Clinical and Experimental Ophthalmology -     

Molecular requirements involving the human platelet protease-activated receptor-4 mechanism of activation by peptide analogues of its tethered-ligand

Thrombin is the most potent agonist of human platelets and its effects are primarily mediated through the protease-activated receptors (PARs)-1 and -4. Although PAR-1 has higher affinity for thrombin than PAR-4, both receptors contribute to thrombin-mediated actions on platelets. Recently, a potent and selective PAR-1 antagonist (vorapaxar) was approved for clinical use in selected patients. In contrast, despite the fact that several PAR-4 antagonists have been developed, few of them have been tested in clinical trials.

The aim of the present study was to elucidate the molecular requirements involving the PAR-4 mechanism of activation by peptide analogues of its tethered-ligand.

Eight synthetic PAR-4 tethered-ligand peptide analogues were synthesized and studied for their agonistic/antagonistic potency and selectivity toward human washed platelet aggregation, using light transmittance aggregometry. In addition, in silico studies were conducted to describe the receptor–peptide interactions that are developed following PAR-4 exposure to the above analogues. To provide a first structure-activity relationship rationale on the bioactivity profiles recorded for the studied analogues, molecular docking was applied in a homology model of PAR-4, derived using the crystal structure of PAR-1.

The following peptide analogues were synthesized: AYPGKF-NH₂ (1), GYPGKF-NH₂ (2), Ac-AYPGKF-NH₂ (3), trans-cinnamoyl-AYPGKF-NH₂ (4), YPGKF-NH₂ (5), Ac-YPGKF-NH₂ (6), trans-cinnamoyl-YPGKF-NH₂ (7), and caffeoyl-YPGKF-NH₂ (8). Peptide (1) is a selective PAR-4 agonist inducing platelet aggregation with an IC₅₀ value of 26.2 μM. Substitution of Ala-1 with Gly-1 resulted in peptide (2), which significantly reduces the agonistic potency of peptide (1) by 25-fold. Importantly, substitution of Ala-1 with trans-cinnamoyl-1 resulted in peptide (7), which completely abolishes the agonistic activity of peptide (1) and renders it with a potent antagonistic activity toward peptide (1)-induced platelet aggregation. All other peptides tested were inactive. Tyr-2, residue, along with its neighboring environment was a key determinant in the PAR-4 recognition mode. When the neighboring residues to Tyr-2 provided an optimum spatial ability for the ligand to enter into the binding site of the transmembrane receptor, a biological response was propagated. These results were compared with the predicted binding poses of small molecule antagonists of PAR-4, denoted as YD-3, ML-354, and BMS-986120. π–π stacking interaction with Tyr-183 appears to be critical and common for both small molecules antagonists and the peptide trans-cinnamoyl-YPGKF-NH₂.

Conclusively, the lipophilicity, size, and aromatic nature of the residue preceding Tyr-2 are determining factors on whether a human platelet PAR-4 tethered-ligand peptide analogue will exert an agonistic or antagonistic activity.