Insulin and Metformin Administration: Unravelling the Multifaceted Association with Mortality across Various Clinical Settings Considering Type 2 Diabetes Mellitus and COVID-19.

Due to the molecular mechanisms of action of antidiabetic drugs, they are considered to be effective in the treatment of both COVID-19 and the post-COVID-19 syndromes. The aim of this study was to determine the effect of administering insulin and metformin on the mortality of patients with type 2 diabetes (T2DM) with symptomatic COVID-19 with the use of logistic regression models. The association between death and insulin and metformin was weak and could not be included in the multivariate model. However, the interaction of both drugs with other factors, including remdesivir and low-molecular-weight heparin (metformin), age and hsCRP (insulin), modulated the odds of death. These interactions hint at multifaceted (anti-/pro-) associations of both insulin and metformin with the odds of death, depending on the patient's characteristics. In the multivariate model, RDW-SD, adjusted with low-molecular-weight heparin treatment, age, sex and K+, was associated with mortality among patients with COVID-19 and T2DM. With a 15% increase in RDW-SD, the risk of death increased by 87.7%. This preliminary study provides the foundations for developing further, more personalized models to assess the risk of death in T2DM patients, as well as for identifying patients at an increased risk of death due to COVID-19.

Apigenin Modulates AnxA6- and TNAP-Mediated Osteoblast Mineralization.

Mineralization-competent cells like osteoblasts and chondrocytes release matrix vesicles (MVs) which accumulate Ca2+ and Pi, creating an optimal environment for apatite formation. The mineralization process requires the involvement of proteins, such as annexins (Anx) and tissue-nonspecific alkaline phosphatase (TNAP), as well as low molecular-weight compounds. Apigenin, a flavonoid compound, has been reported to affect bone metabolism, but there are doubts about its mechanism of action under physiological and pathological conditions. In this report, apigenin potency to modulate annexin A6 (AnxA6)- and TNAP-mediated osteoblast mineralization was explored using three cell lines: human fetal osteoblastic hFOB 1.19, human osteosarcoma Saos-2, and human coronary artery smooth muscle cells HCASMC. We compared the mineralization competence, the morphology and composition of minerals, and the protein distribution in control and apigenin-treated cells and vesicles. The mineralization ability was monitored by AR-S/CPC analysis, and TNAP activity was determined by ELISA assay. Apigenin affected the mineral structure and modulated TNAP activity depending on the concentration. We also observed increased mineralization in Saos-2 cells. Based on TEM-EDX, we found that apigenin influenced the mineral composition. This flavonoid also disturbed the intracellular distribution of AnxA6 and TNAP, especially blocking AnxA6 aggregation and TNAP attachment to the membrane, as examined by FM analysis of cells and TEM-gold analysis of vesicles. In summary, apigenin modulates the mineralization process by regulating AnxA6 and TNAP, as well as through various effects on normal and cancer bone tissues or atherosclerotic soft tissue.

27-gauge sutureless vitrectomy under topical anesthesia: A pilot study.

BACKGROUND: The implementation of the 27-gauge (G) sutureless vitrectomy technique is associated with a marked shortening of surgery time, faster healing of scleral and conjunctival wounds, less severe conjunctival scarring, limited postoperative corneal astigmatism, and marked improvement in the postoperative comfort of patients. The traditional methods of anesthesia for vitrectomy surgery are quite varied and each has its own potential for complications. OBJECTIVES: To assess the feasibility and safety of 27G pars plana vitrectomy (PPV) performed under local topical anesthesia for diabetic maculopathy, asteroid hyalosis and vitreomacular traction syndrome associated with high myopia. MATERIAL AND METHODS: Three carefully selected patients with various vitreoretinal disorders underwent primary 27G PPV performed by a single surgeon under local topical anesthesia. Patients were analyzed in regard to best corrected visual acuity, intraocular pressure, intraoperative/postoperative complications, intraoperative/postoperative pain, and surgery time. RESULTS: All patients showed postoperative improvement in visual acuity. No decrease in intraocular pressure below 10 mm Hg was documented on postoperative day 1. Furthermore, no postoperative complications were recorded during the six-month follow-up, and evident improvement in the anatomical status was confirmed using ophthalmic coherence tomography in all cases. CONCLUSION: Our findings support that 27G PPV performed solely under local topical anesthesia is safe and effective for treating selected vitreoretinal disorders.

Antixenosis in Glycine max (L.) Merr against Acyrthosiphon pisum (Harris).

To reveal the antixenosis potential against the pea aphid Acyrthosiphon pisum (Harris) (Hemiptera: Aphididae) we analyzed the pea aphid survival and probing behavior, and the quantitative and qualitative variation of flavonoids in the leaves of selected soybean Glycine max (L.) Merr (Fabaceae) cultivars 'Aldana', 'Annushka', 'Augusta', 'Madlen', 'Mavka', 'Simona', 'Violetta', and 'Viorica'. Aphid survival was drastically impeded on all cultivars. The electronic monitoring of aphid probing using the Electrical Penetration Graph (EPG) technique revealed that on all soybean cultivars, A. pisum readily probed into leaf tissues but the probes were usually terminated before reaching vascular tissues, which demonstrates the activity of antixenosis mechanisms in peripheral tissues epidermis and/or mesophyll in soybean leaves. The potency of antixenosis factors differed among soybean cultivars, which was reflected in differences in aphid survival and frequency and duration of phloem sap ingestion. Seven flavonoids were found: apigenin, daidzein, genistein, glycitein, isorhamnetin, kaempferol, and rutin, which occurred in different amount and proportion in individual cultivars. The content of apigenin and genistein in all soybean cultivars studied probably made them relatively unacceptable to A. pisum. Kaempferol in 'Aldana' might be responsible for the observed strong antixenosis resistance of this cultivar to A. pisum. The results of our survey provide the first detailed data that can be used for future studies.

Annexins A2, A6 and Fetuin-A Affect the Process of Mineralization in Vesicles Derived from Human Osteoblastic hFOB 1.19 and Osteosarcoma Saos-2 Cells.

The mineralization process is initiated by osteoblasts and chondrocytes during intramembranous and endochondral ossifications, respectively. Both types of cells release matrix vesicles (MVs), which accumulate Pi and Ca2+ and form apatites in their lumen. Tissue non-specific alkaline phosphatase (TNAP), a mineralization marker, is highly enriched in MVs, in which it removes inorganic pyrophosphate (PPi), an inhibitor of apatite formation. MVs then bud from the microvilli of mature osteoblasts or hypertrophic chondrocytes and, thanks to the action of the acto-myosin cortex, become released to the extracellular matrix (ECM), where they bind to collagen fibers and propagate mineral growth. In this report, we compared the mineralization ability of human fetal osteoblastic cell line (hFOB 1.19 cells) with that of osteosarcoma cell line (Saos-2 cells). Both types of cells were able to mineralize in an osteogenic medium containing ascorbic acid and beta glycerophosphate. The composition of calcium and phosphate compounds in cytoplasmic vesicles was distinct from that in extracellular vesicles (mostly MVs) released after collagenase-digestion. Apatites were identified only in MVs derived from Saos-2 cells, while MVs from hFOB 1.19 cells contained amorphous calcium phosphate complexes. In addition, AnxA6 and AnxA2 (nucleators of mineralization) increased mineralization in the sub-membrane region in strongly mineralizing Saos-2 osteosarcoma, where they co-localized with TNAP, whereas in less mineralizing hFOB 1.19 osteoblasts, AnxA6, and AnxA2 co-localizations with TNAP were less visible in the membrane. We also observed a reduction in the level of fetuin-A (FetuA), an inhibitor of mineralization in ECM, following treatment with TNAP and Ca channels inhibitors, especially in osteosarcoma cells. Moreover, a fraction of FetuA was translocated from the cytoplasm towards the plasma membrane during the stimulation of Saos-2 cells, while this displacement was less pronounced in stimulated hFOB 19 cells. In summary, osteosarcoma Saos-2 cells had a better ability to mineralize than osteoblastic hFOB 1.19 cells. The formation of apatites was observed in Saos-2 cells, while only complexes of calcium and phosphate were identified in hFOB 1.19 cells. This was also evidenced by a more pronounced accumulation of AnxA2, AnxA6, FetuA in the plasma membrane, where they were partly co-localized with TNAP in Saos-2 cells, in comparison to hFOB 1.19 cells. This suggests that both activators (AnxA2, AnxA6) and inhibitors (FetuA) of mineralization were recruited to the membrane and co-localized with TNAP to take part in the process of mineralization.

One-year outcomes of the Polish treatment program for the wet form of age-related macular degeneration using intravitreal therapy.

PURPOSE: To report 12-month outcomes of a Polish National Treatment Program using aflibercept and ranibizumab in eyes with wet, age-related macular degeneration in routine clinical practice. MATERIAL AND METHODS: This was a non-randomized, retrospective, observational multicenter study. Anonymous data contained in the electronic Therapeutic Program Monitoring System were utilized in this study. RESULTS: The study population consisted of 2828 eyes from 2718 patients. The median age was 76.0 [70.0, 81.0] years; 61.7% were female. Best corrected visual acuity increased from 58.86 [50.05, 69.95] letters to 65.1 [50.1, 73.9] letters (p < 0.001). The median change in best corrected visual acuity was 0.0 [-4.0, 12.2] letters: 2.9 [-2.9, 15.1] letters for treatment-naïve eyes and 0.0 [-4.0, 8.8] letters for those continuing treatment (p < 0.001). The median central retinal thickness was significantly reduced from 341.0 [281.0, 422.0] to 275.0 [221.0, 344.0] µm (p < 0.001). The median number of visits was 9.0 [8.0, 9.0]. The median number of injections was 7.0 [6.0, 8.0]: 8.0 [7.0, 8.0] for treatment-naïve eyes and 6.0 [5.0, 7.0] for those continuing treatment (p < 0.001). CONCLUSION: Eyes treated as part of the Polish therapeutic program gained functional stability and morphological improvement. Treatment-naïve eyes showed the greatest functional benefit.

Coronary artery disease: New Insights into revascularization treatment of diabetic patients.

Diabetes mellitus is an independent cardiovascular risk factor, considered an equivalent of coronary artery disease in terms of prognosis. A history of acute coronary syndrome is a strong predictor of another coronary episode, and cardiovascular complications are the leading cause of mortality in diabetic patients. Many patients with coronary artery disease suffer from concomitant diabetes or pre-diabetes. There are 3 strategies of coronary artery disease treatment: conservative management, coronary artery bypass graft (CABG) and percutaneous coronary intervention (PCI). Since drug-eluting stents (DES) were developed, PCI has become one of the most widespread interventional cardiology procedures performed in Europe and worldwide. Among all coronary risk factors, diabetes mellitus remains the most important predictor of unfavorable outcomes of revascularization therapy. This paper reviews the current evidence regarding revascularization in diabetic patients, with particular emphasis on PCI. A systematic analysis of clinical trials of CABG and PCI, especially with DES, was conducted.

Intravitreal ocriplasmin: A breakthrough in the treatment of vitreomacular traction?

Vitreoretinal interface pathologies, such as vitreomacular traction syndrome, epiretinal membranes and macular holes are sight-threatening conditions and one of the important causes of vision defects and vision loss. To this date, vigilance with observation of how the vitreomacular traction resolves, or vitreoretinal surgery in more severe cases, were the only treatment options. Recent rapid progress in ophthalmology, especially in diagnostic and visualization techniques, provided better insight into the mechanisms taking place on the vitreoretinal surface, which enabled a more accurate selection of treatment options. Development of ophthalmic pharmacological procedures, such as treatment of vitreomacular traction syndrome with ocriplasmin, constitutes an innovative breakthrough in ophthalmology. The enzyme is a genetically engineered form of human plasmin, a component of blood coagulation cascade that has been envisioned for human therapy since 1950s. It has never been used for vitreolysis in ophthalmology before. The aim of this review is to analyze and compare therapeutic options for symptomatic vitreomacular adhesion and vitreoretinal traction, with particular emphasis on microplasmin. We reviewed the results of recent studies comparing ocriplasmin to other widespread treatment options, such as pars plana vitrectomy.

Glucocorticoid receptor polymorphism in obesity and glucose homeostasis.

Glucocorticoid receptor (GR) activity plays a significant role in the etiology of obesity and is essential for glucose homeostasis, the development of hyperinsulinaemia and subsequent increased fat deposition. Several polymorphisms in the GR gene have been described, and at least three of them seem to be associated with altered glucocorticoid sensitivity and changes in glucose homeostasis, and other metabolic parameters. The N363S polymorphism has been associated with increased sensitivity to glucocorticoides, increased insulin response to dexamethasone and increased plasma glucose level. BclI polymorphism is associated with increased abdominal obesity, hyperinsulinaemia and increased insulin resistance. Another polymorphism, ER22/23EK, in contrast to the others, is associated with relative resistance to glucocoricides actions and more beneficial metabolic profile-lower insulin resistance level, decreased lower cardiovascular risk and subseuent prolongation of life time. More research is still needed to understand the mechanisms behind these associations at the molecular level.

Caspase-Dependent Apoptosis of Retinal Ganglion Cells During the Development of Diabetic Retinopathy.

Diabetic retinopathy constitutes the most frequent cause of vision loss in professionally active individuals. Progressive impairment of visual acuity results from massive fibrovascular proliferation involving the fundus of the eye, as well as from the apoptosis of the neuronal structures of the retina. The results of many clinical studies, both on experimental models and on human material, confirmed evident enhancement of this process in the course of diabetes. The programmed cell death of retinal ganglion cells predominantly occurs secondarily to caspase-dependent intracellular processes. This paper presents evidence for the considerable involvement of the caspase-dependent mechanism of apoptosis of retinal ganglion cells in the early stages of retinal changes associated with progressive impairment of visual acuity. The authors emphasize the necessity of comprehensive understanding of mechanisms that underlie the programmed death of neural cells in the eyes of patients with diabetes. This clinical problem becomes of vital importance in view of the constantly increasing incidence of diabetes and severe impairment associated with the disorders of carbohydrate metabolism. Identification of a key component involved in this process would enable attempts oriented at pharmacological blockade of apoptosis in the retinal ganglion cells of patients with diabetes.

The Dry Form of Age-Related Macular Degeneration (AMD): The Current Concepts of Pathogenesis and Prospects for Treatment.

Age-related macular degeneration (AMD) is a disease that causes varying degrees of blindness, which afflicts millions of adults in their later years. Preliminary changes occur during normal aging, but in some individuals the pathology leads to the development of AMD. The pathology seems to be a mixture of biochemical, cellular, and molecular events. Lipofuscinogenesis and early drusen genesis are in the early stages of AMD and their inhibition or reversal would dramatically increase the quality of vision in elderly people. The disease is characterized by abnormal extracellular deposits, known as drusen, which accumulate along the basal surface of the retinal pigmented epithelium RPE. Widespread drusen deposition is associated with retinal pigmented epithelial cell dysfunction and degeneration of the photoreceptors. Recent studies have shown that drusen contain a variety of immunomodulatory molecules, suggesting that the process of drusen formation involves local inflammatory events, including activation of the complement cascade. Molecular pathways involved in the etiology of this disease and the potential prospects of its treatment will be presented on the basis of the results of the current studies.

Expression of the PAR-1 protein on the surface of platelets in patients with chronic peripheral arterial insufficiency - preliminary report.

BACKGROUND: The activation of pro-coagulation mechanisms associated with the vascular wall's immune and inflammatory responses wall to injury plays a crucial role in the mechanisms of the induction and progression of atherosclerosis. OBJECTIVES: The aim of this study was to determine the role of protease activated receptors (PAR-1) expressed on the surface of blood platelets in the pathogenesis of chronic peripheral arterial obliterative disease (PAOD) in patients with obliterative atherosclerosis (n = 24) and diabetic macroangiopathy (n = 16), as well as in the controls (n = 12). MATERIAL AND METHODS: In addition to the expression of PAR-1, serum/plasma concentrations of thrombin-antithrombin complex (TAT), the von Willebrand factor (vWF), the platelet-derived growth factor, monocyte chemotactic protein, the soluble form of the platelet endothelial cell adhesion molecule, thrombin activatable fibrinolysis inhibitor and interleukin 6 (IL-6) were determined. RESULTS: Compared to the controls, PAOD patients were characterized by significantly higher levels of PAR-1 expression, vWF, TAT and IL-6. Individuals with diabetic macroangiopathy did not differ significantly from individuals with obliterative atherosclerosis in terms of PAR-1 expression. Upon activation with thrombin receptor antagonist peptide (TRAP), the levels of PAR-1 were comparable in all analyzed groups. In patients with diabetic macroangiopathy, a significant association was observed between the expression of PAR-1 on the surface of the platelet and the serum TAT concentration, as well as between TAT and serum IL-6 concentration. CONCLUSIONS: Enhanced expression of PAR-1 on the thrombocyte surface in chronic PAOD patients occurs equally in cases of diabetic macroangiopathy and in individuals free from this endocrine pathology.

The influence of incretin mimetics on cardiovascular risk factors in diabetes.

The authors discuss the strategy of use of incretin hormones in type 2 diabetes treatment in the context of cardiovascular complications. The results of the phase III study on human GLP-1 (Glucagon-like peptide-1) analogue-liraglutide have been presented under common acronym LEAD (Liraglutide-Effect and Action In Diabetes). The liraglutide therapy improved glycemic control with low hypoglycemia risk and decreased glycated hemoglobin by an average 1,13%. Decreases in systolic pressure and significant body weight loss were observed. Not only did the index describing beta cells function HOMA-B improve but also did the ratio of insulin to proinsulin. Summing up, incretin hormones beneficially influence blood glucose level, moreover, their use decreases blood pressure and body weight which might indicate their positive influence on cardiovascular system in diabetic patients.

Proliferative diabetic retinopathy-The influence of diabetes control on the activation of the intraocular molecule system.

AIMS: Demonstrate the influence of type 2 diabetes control on the degree of retinal endothelial damage (vWF, E-selectin) and local increases in the concentrations of selected adhesion molecules (ICAM-1, VCAM-1, E-selectin) in proliferative diabetic retinopathy (PDR). METHODS: Vitreous and serum samples were collected during vitrectomy from 19 patients with PDR and 15 patients who underwent vitrectomy for other reasons. Tests were performed using the ELISA method. RESULTS: Serum and intraocular concentrations of ICAM-1, VCAM-1, E-selectin, vWF were considerably higher in the subjects with PDR than in the controls. In the vitreous, the increase in vWF depended on the elevated levels of vWF in the serum (r=0.905, p<0.001). E-selectin correlated with diastolic blood pressure (r=0.506, p=0.045). The concentrations of vWF and E-selectin in both samples were related to the significant increases in intraocular ICAM-1, ICAM-1, VCAM-1 in the serum of PDR patients. Increased VCAM-1 level in the vitreous correlated with the concentration of HbA(1)c (r=0.59, p=0.007). CONCLUSIONS: Upon local and systemic damage to the endothelium there were significant increases in ICAM-1, VCAM-1, E-selectin. A significant positive correlation of VCAM-1 increase in the vitreous with HbA(1)c is an important argument for the influence of diabetes on immuno-inflammatory activation in the retinal microcirculation.

Assessment of selected adhesion molecule and proinflammatory cytokine levels in the vitreous body of patients with type 2 diabetes--role of the inflammatory-immune process in the pathogenesis of proliferative diabetic retinopathy.

BACKGROUND: The aim of the study is to demonstrate the participation of the inflammatory-immune process in the pathogenesis of proliferative diabetic retinopathy (PDR). METHODS: Twenty four women and 22 men with type 2 diabetes (mean age 63.97 +/- 9.00 years, mean duration of diabetes 12.56 +/- 6.87 years) were enrolled in the study. Serum concentrations of soluble forms of ICAM-1, VCAM-1 as well as IL-6 and TNF-alpha were evaluated in all study subjects. In 19 patients, simultaneous assessment of selected parameter levels in both serum and vitreous samples was performed. Vitrectomy was performed due to intravitreal hemorrhage, accompanied in some patients by traction retinal detachment. The control group consisted of 15 patients having undergone vitrectomy for reasons other than PDR. Tests were performed using the ELISA method. RESULTS: Serum and intraocular concentrations of sICAM-1, sVCAM-1, IL-6, TNF-alpha were considerably higher in study subjects with PDR than in controls. Simultaneously, a positive correlation was found between intraocular sVCAM-1 (r = 0.590, p = 0.007), TNF-alpha (r = 0.822, p < 0.001) concentrations and HbA(1)c levels. The above-mentioned dependence was not shown for sICAM-1 and IL-6 vitreous concentration. Local vitreous VCAM-1 level increase was also dependent on vitreous TNF-alpha concentration growth (r = 0.470, p = 0.043). No significant correlation was found between serum and vitreous levels of the selected parameters in the group of 19 patients with PDR. CONCLUSIONS: Increase in sICAM-1 and sVCAM-1 levels, as well as their correlation with high vitreous IL-6 and TNF-alpha concentrations in patients with PDR, seem to confirm the inflammatory-immune nature of this process. In diabetes, inadequate metabolic control remains an important risk factor in the development of PDR.