The main aim of this study was to evaluate the ability of serum biomarkers to predict the worsening of retinal neurodysfunction in subjects with type 2 diabetes. For this purpose, we measured selected molecules (N-epsilon-carboxy methyl lysine (CML), laminin P1 (Lam-P1), and asymmetric dimethylarginine (ADMA)) in the serum of 341 participants of the EUROCONDOR study at baseline, 24, and 48 weeks. Retinal neurodysfunction was assessed by measuring implicit time (IT) using multifocal electroretinography, and structural changes were examined by spectral domain–optical coherence tomography. The values of IT at baseline were directly correlated with baseline serum concentrations of CML (r = 0.135, p = 0.013). Furthermore, in the placebo group, increase in CML concentration throughout follow-up correlated with the IT (r = 0.20; p = 0.03). Baseline serum levels of CML also correlated with macular retinal thickness (RT) (r = 0.231; p < 0.001). Baseline Lam-P1 levels correlated with the increase of the RT at the end of follow-up in the placebo group (r = 0.22; p = 0.016). We provide evidence that CML may be a biomarker of both retinal neurodysfunction and RT, whereas Lam-P1 was associated with RT only. Therefore, circulating levels of these molecules could provide a complementary tool for monitoring the early changes of diabetic retinopathy (DR).

The non-natural amino acid mesitylalanine (2,4,6-trimethyl-L-phenylalanine; Msa) has an electron-richer and a more conformationally restricted side-chain than that of its natural phenylalanine counterpart. Taking these properties into account, we have synthesized ten somatostatin analogs containing Msa residues in different key positions to modify the intrinsic conformational flexibility of the natural hormone. We have measured the binding affinity of these analogs and correlated it with the main conformations they populate in solution. NMR and computational analysis revealed that analogs containing one Msa residue were conformationally more restricted than somatostatin under similar experimental conditions. Furthermore, we were able to characterize the presence of a hairpin at the pharmacophore region and a non-covalent interaction between aromatic residues 6 and 11. In all cases, the inclusion of a D-Trp in the eighth position further stabilized the main conformation. Some of these peptides bound selectively to one or two somatostatin receptors with similar or even higher affinity than the natural hormone. However, we also found that multiple incorporations of Msa residues increased the life span of the peptides in serum but with a loss of conformational rigidity and binding affinity.

Diabetic retinopathy (DR) is a neurodegenerative disease characterized by the presence of microcirculatory lesions. Among them, microaneurysms (MAs) are the first observable hallmark of early ophthalmological changes. The present work aims to study whether the quantification of MAs, hemorrhages (Hmas) and hard exudates (HEs) in the central retinal field could have a predictive value on DR severity. These retinal lesions were quantified in a single field NM-1 of 160 retinographies of diabetic patients from the IOBA’s reading center. Samples included different disease severity levels and excluded proliferating forms: no DR (n = 30), mild non-proliferative (n = 30), moderate (n = 50) and severe (n = 50). Quantification of MAs, Hmas, and HEs revealed an increasing trend as DR severity progresses. Differences between severity levels were statistically significant, suggesting that the analysis of the central field provides valuable information on severity level and could be used as a clinical tool to assess DR grading in the eyecare routine. Even though further validation is needed, counting microvascular lesions in a single retinal field can be proposed as a rapid screening system to classify DR patients with different stages of severity according to the international classification.

Teriparatide is an anabolic peptide drug indicated for the treatment of osteoporosis. Recombinant teriparatide was first approved in 2002 and has since been followed by patent-free alternatives under biosimilar or hybrid regulatory application. The aim of this study is to demonstrate the essential similarity between synthetic teriparatide BGW and the reference medicinal product (RMP), and thus to ensure the development of the first generic teriparatide drug. Hence, an extensive side-by-side comparative exercise, focusing on structural and biological activity, was performed using a wide range of state-of-the-art orthogonal methods. Nuclear magnetic resonance (NMR), ion mobility–mass spectrometry (IM–MS), UV, circular dichroism (CD) and Fourier transform infrared (FTIR) demonstrated the structural similarity between teriparatide BGW and the RMP. Comparative cell-based bioassays showed that the synthetic and recombinant peptides have identical behaviors. Teriparatide BGW, as a generic drug, provides an available treatment option for patients with osteoporosis and offers clinical benefits identical to those provided by the RMP.

Objective: Diabetic retinopathy (DR) is a neurodegenerative disease characterized by the presence of microcirculatory lesions. Among them, microaneurysms (MAs) are the first observable hallmark of early ophthalmological changes. The present work aims at studying whether the quantification of MA, haemorrhages (Hmas) and hard exudates (HEs) in the central retinal field (CRF) could have a predictive value on DR severity. Research Design and Methods: Retinal lesions (MAs, Hmas and HEs) were quantified in the CRF of 160 retinographies from diabetic patients from the IOBA’s reading center, previously classified by two expert readers with the 3 fields-Joslin system. Samples included different disease severity levels and excluded proliferating forms: no DR (n=30), mild non-proliferative (n=30), moderate (n=50) and severe (n=50). Results: Quantification of MAs, Hmas, and HEs revealed an increase trend of these lesions as DR severity progresses. Differences between severity levels were statistically significant, suggesting that the analysis of the CRF provides valuable information on severity level and could be used as a valuable tool to assess DR grading in the clinical practice. Conclusions: Even though further validation is needed, the counting of microvascular lesions in the central retinal field can be proposed as a rapid screening system to classify DR patients with different stages of severity according to the international classification.

Objective: To quantify microvascular lesions in a large real-world data (RWD) set, based on single central retinal fundus images of diabetic eyes from different origins, with the aim of validating its use as a precision tool for classifying diabetic retinopathy (DR) severity. Design: Retrospective meta-analysis across multiple fundus image datasets. Sample size: The study analyzed 2445 retinal fundus images from diabetic patients across four diverse RWD international datasets, including populations from Spain, India, China and the US. Intervention: The quantification of specific microvascular lesions: microaneurysms (MAs), hemorrhages (Hmas) and hard exudates (HEs) using advanced automated image analysis techniques on central retinal images to validate reliable metrics for DR severity assessment. The images were pre-classified in the DR severity levels as defined by the International Clinical Diabetic Retinopathy (ICDR) scale. Main Outcome Measures: The primary variables measured were the number of MAs, Hmas, red lesions (RLs) and HEs. These counts were related with DR severity levels using statistical methods to validate the relationship between lesion counts and disease severity. Results: The analysis revealed a robust and statistically significant increase (p < 0.001) in the number of microvascular lesions and the DR severity across all datasets. Tight data distributions were reported for MAs, Hmas and RLs, supporting the reliability of lesion quantification for accurately assessing DR severity. HEs also followed a similar pattern, but with a broader dispersion of data. Data used in this study are consistent with the definition of the DR severity levels established by the ICDR guidelines. Conclusions: The statistically significant increase in the number of microvascular lesions across DR severity validate the use of lesion quantification in a single central retinal field as a key biomarker for disease classification and assessment. This quantification method demonstrates an improvement over traditional assessment scales, providing a quantitative microvascular metric that enhances the precision of disease classification and patient monitoring. The inclusion of a numerical component allows for the detection of subtle variations within the same severity level, offering a deeper understanding of disease progression. The consistency of results across diverse datasets not only confirms the method’s reliability but also its applicability in a global healthcare setting.