Analysis of cytokines in the aqueous humor during intravitreal Ranibizumab treatment of diabetic macular edema

This study aimed to analyze the concentrations of VEGF, b-FGF, TNF, interleukin (IL)-1, IL-6, IL-8, IL-10, and IL-12 in the aqueous humor of patients with diabetic macular edema with and without peripheral retinal ischemia and to ascertain the changes in the levels of these molecules during treatment with ranibizumab. A therapeutic, prospective, randomized interventional study was carried out. Twenty-four eyes from 24 patients were studied and divided into 3 groups. Group 1 (9 eyes) included patients with diabetic macular edema without peripheral ischemia. Group 2 (10 eyes) included patients with diabetic macular edema with peripheral ischemia. Group 3 (5 eyes), the control group, included patients without systemic and/or eye diseases. Patients in Groups 1 and 2 received 3 intravitreal injections of 2 mg/0.05 ml ranibizumab at an interval of approximately 30 days. Before administering the injections, the aqueous humor was collected. In the control group, aqueous humor was collected before facetectomy. During treatment, the median IL-6 concentration significantly increased in Group 1 but showed a slight but not significant decrease in Group 2. Interleukin 8 levels were significantly different at the end of treatment compared to the beginning in Groups 1 and 2. TNF, IL-1, IL-10, and IL-12 levels were practically unchanged in both groups. VEGF was significantly reduced at the end of the study in Groups 1 and 2. B-FGF was not detected in most of the studied patients, and in those with detectable levels, there was no significant variation. There was a significant increase in the median level of interleukin 6 in the group without ischemia and a significant decrease in VEGF in both groups. The cytokines TNF, IL-1, IL-10, and IL-12 did not show significant variation.

Effects of Bone Marrow Mesenchymal Stem Cells on Neurological Function, Transforming Growth Factor Beta 1 and Nogo-A Expression in Stroke Rats

To investigate BMSCs’ effect on neurological function, TGF-β1 and Nogo-A expression in stroke rats. Rats were assigned into sham operation group, ischemia group (MACO rat model) and BMSCs group (BMSCs transplantation) followed by analysis of neurological function, brain pathological changes, cerebral infarction volume, TGF-β1 and Nogo-A level by Western blot. Compared with sham operation group, the score of rats was significantly elevated in ischemic group and decreased in BMSCs group (P <0.05). Compared with sham-operated group, ischemic group showed significantly increased cerebral infarction area (P <0.05) and BMSCs group had a significant decreased water level and brain infarct volume (P < 0.05). Compared with sham-operated group, ischemic group had more edema in the nerve cells with serious vacuole, uneven cytoplasm staining and reduced number of neurons, which were all significantly improved in BMSCs group. Compared to sham group, ischemic group showed significantly reduced TGF-β1 and increased Nogo-A level (P <0.05), which were all reversed in BMSCs group (P <0.05). BMSCs transplantation can significantly improve the nerve function of stroke rats, promote TGF-β1 secretion and inhibit Nogo-A expression.

Prevalence of Ischemia, Health-Related Quality of Life, Medical use and Expenses by Physical Activity and Ischemia Status in Korean Adults

PURPOSE: The purpose of this study is to analyze the different prevalence of ischemia of Korea adults, and to compare the HealthRelated Quality of Life (HRQoL), annual personal medical use and expenses according to physical activity and ischemia status.METHODS: The 2018 Korea Medical Panel data was used (13,791 adults and 604 ischemia). Physical activity was measured with IPAQ and converted to MET-minutes per week. The physical activity group was classified as less than 600 MET-min per week in the inactive group, 600-3,000 MET-min per week in the minimally active group, and 3,000 MET-min more per week in the active group.RESULTS: The prevalence of ischemia was low in the inactive group compared to the minimally active group and the active group (OR=0.75, p<.01) and the active group (OR=0.36, p<.001). In both ischemic and non-ischemic groups, HRQoL was the lowest in the inactive group (p<.05). Inpatient days and emergency days showed no significant difference in according to the physical activity level and the ischemia status. However, within the group with ischemia, the outpatient days of inactive group were 42.8% higher (p<.05) and minimally active group was 4.3% higher (p>.05) compared to the active group (32.5±32.1 days) respectively. Within the group with ischemia, the medical expenses of inactive group were 5.2% lower (p>.05) and minimally active group was 33.9% lower (p<.05) compared to the active group ($1,738±2,457) respectively.CONCLUSIONS: Higher physical activity results in a lower prevalence of ischemia, and higher physical activity results in positive HRQoL and outpatient days in ischemia group. However Annual personal medical expenses showed a significant difference according to the level of physical activity in ischemia group.

Microvascular Structure Changes After Intravitreal Ranibizumab Injection in Retinal Vein Occlusion Patients With and Without Macular Ischemia

Purpose: To investigate the changes in the macular microvascular structure after anti-vascular endothelial growth factor (anti-VEGF) treatment in retinal vein occlusion (RVO) patients with and without macular ischemia.Methods: A total of 39 patients were divided into the macular ischemia group (n = 22) and the nonischemia group (n = 17) at baseline. All the patients received an intravitreal injection of ranibizumab with a 3+ pro re nata (PRN) regimen. The foveal avascular zone (FAZ) areas, macular vessel density (VD), and macular ischemic index (ISI) were evaluated at baseline and 3 and 6 months after treatment.Results: After treatment, some patients in the macular ischemia group achieved obvious reperfusion in macular nonperfusion areas. The VD and macular ISI improved in RVO patients, but the changes in VD and macular ISI were different in the two groups. The improvement of best corrected visual acuity (BCVA) was positively correlated with the improvement of macular perfusion status. Macular perfusion remained stable in most patients in RVO and only one patient had macular ischemia aggravation.Conclusion: The macular microvascular structures were stable in most RVO patients after anti-VEGF treatment. At the same time, some patients with macular ischemia presented reperfusion in macular nonperfusion areas, and still a few patients presented aggravated macular ischemia. Macular ISI is a good way to evaluate macular perfusion status in RVO compared to VD.

Dynamic Observation of the Effect of L-Theanine on Cerebral Ischemia-Reperfusion Injury Using Magnetic Resonance Imaging under Mathematical Model Analysis

This study was to use the partial differential mathematical model to analyze the magnetic resonance imaging (MRI) images of cerebral ischemia-reperfusion injury (CIRI) and to dynamically observe the role of L-theanine in CIRI based on this. 30 patients with cerebral ischemia in a hospital in a certain area were selected and divided into a cerebral ischemia group and a L-theanine treatment group. The two groups of patients were examined by MRI within 48 hours, and the relative apparent diffusion coefficient (rADC) of the cerebral ischemic part of the patients was determined. The partial differential mathematical model was used for data processing to obtain the function of cerebral ischemia time and infarct area, and the data of patients in the cerebral ischemia group and L-theanine treatment group were compared and analyzed. The results showed that the partial differential mathematical model could effectively analyze the linear relationship between the rADC value and time in the treatment of CIRI using L-theanine. The rADC values of the four points of interest in the L-theanine treatment group all increased with time, and there was a positive correlation between the variables X and Y. In observing the efficacy indicators of L-theanine, the L-theanine treatment group showed a significant advantage in the neurospecific enolase (NSE) content compared with the cerebral ischemia group ( P < 0.01 ), and the neurological function score of the L-theanine treatment group gradually decreased and showed a statistically obvious difference on the 7th day of treatment ( P < 0.05 ). In summary, it was verified in this study that the role of L-theanine in the treatment of CIRI was of a great and positive significance for the subsequent treatment of patients with cerebral ischemia, providing reliable theoretical basis and data basis for clinical treatment of CIRI.

Diagnostic Efficacy of CCTA And CT-FFR Based On Risk Factors For Myocardial Ischemia

Background: Coronary artery CCTA can observe the degree of coronary artery stenosis and FFR can evaluate the physiological function of coronary artery. However, noninvasive imaging examination that can both observe the above two methods at the same time has not yet been elucidated.Objective: To investigate the diagnostic efficacy of coronary computed tomography angiography (CCTA) and computed tomography-derived fractional flow reserve (CT-FFR) based on different risk factors for myocardial ischemia.Methods: Patients undergoing CCTA in our hospital from August 18, 2020 to April 28, 2021 were randomly selected, and the data were subjected to CT-FFR analysis. Vascular characteristics were measured, including total plaque volume, calcified plaque volume, non-calcified plaque volume, plaque length, and lumen stenosis, and the patients were categorized into a non-ischemia group (FFR>0.8) and an ischemia group (FFR≤0.8). Plaque characteristics were compared between the two groups, and logistic regression analysis was employed to explore the correlations between plaque characteristics and ischemic lesions.Results: From a total of 122 patients enrolled in the study, there were 218 vascular branches with FFR>0.8 and 174 vascular branches with FFR≤0.8. There were significant group differences in total plaque volume, calcified plaque volume, plaque length, and lumen stenosis >50% (n). The obtained data were as follows: non-ischemic group 10.57 (4.80, 259.65), ischemic group 14.87 (3.39, 424.45), Z=9.772, p=0.002, non-ischemic group 10.57 (0, 168.77), ischemic group 14.87 (0, 191.00), Z=2.503，p≤0.001), non-ischemic group 8.17 (37.05, 40.53), ischemic group 8.38 (56.66, 86.47), Z=5.923, p=0.016, and lumen stenosis >50%, non-ischemic group 46, ischemic group 90, x2=14.77，p≤0.001. The regression analysis results indicated that total plaque volume, calcified plaque volume, plaque length and lumen stenosis >50% were risk factors for myocardial ischemia, with ORs and p values of (2.311, p=0.002), (1.021, p=0.004), (2.159, p<0.001), and (0.181, p<0.001), respectively.Conclusion: Total plaque volume, calcified plaque volume, plaque length and lumen stenosis >50% are predictors for myocardial ischemia. Coronary artery CCTA combined with CT-FFR could simultaneously observe the anatomical stenosis and evaluate myocardial blood supply at the functional level. Thus, myocardial ischemia could be better diagnosed.

Relationship of Laser-Doppler-Flow and coronary perfusion and a concise update on the importance of coronary microcirculation in donor heart machine perfusion

BACKGROUND: Machine perfusion (MP) is a novel method for donor heart preservation. The coronary microvascular function is important for the transplantation outcome. However, current research on MP in heart transplantation focuses mainly on contractile function. OBJECTIVE: We aim to present the application of Laser-Doppler-Flowmetry to investigate coronary microvascular function during MP. Furthermore, we will discuss the importance of microcirculation monitoring for perfusion-associated studies in HTx research. METHODS: Porcine hearts were cardioplegically arrested and harvested (Control group, N = 4). In an ischemia group (N = 5), we induced global ischemia of the animal by the termination of mechanical ventilation before harvesting. All hearts were mounted on an MP system for blood perfusion. After 90 minutes, we evaluated the effect of coronary perfusion pressures from 20 to 100 mmHg while coronary laser-doppler-flow (LDF) was measured. RESULTS: Ischemic hearts showed a significantly decreased relative LDF compared to control hearts (1.07±0.06 vs. 1.47±0.15; p = 0.034). In the control group, the coronary flow was significantly lower at 100 mmHg of perfusion pressure than in the ischemia group (895±66 ml vs. 1112±32 ml; p = 0.016). CONCLUSIONS: Laser-Doppler-Flowmetry is able to reveal coronary microvascular dysfunction during machine perfusion of hearts and is therefore of substantial interest for perfusion-associated research in heart transplantation.

Changes in Cyclin D1, cdk4, and Their Associated Molecules in Ischemic Pyramidal Neurons in Gerbil Hippocampus after Transient Ischemia and Neuroprotective Effects of Ischemic Preconditioning by Keeping the Molecules in the Ischemic Neurons

Inadequate activation of cell cycle proteins including cyclin D1 and cdk4 is involved in neuronal cell death induced by diverse pathological stresses, including transient global brain ischemia. The neuroprotective effect of ischemic preconditioning is well-established, but the underlying mechanism is still unknown. In this study, we examined changes in cyclin D1, cdk4, and related molecules in cells or neurons located in Cornu Ammonis 1 (CA1) of gerbil hippocampus after transient ischemia for 5 min (ischemia and reperfusion) and investigated the effects of IPC on these molecules after ischemia. Four groups were used in this study as follows: sham group, ischemia group, IPC plus (+) sham group, and IPC+ischemia group. IPC was developed by inducing 2-min ischemia at 24 h before 5-min ischemia (real ischemia). Most pyramidal cells located in CA1 of the ischemia group died five days after ischemia. CA1 pyramidal cells in the IPC+ischemia group were protected. In the ischemia group, the expressions of cyclin D1, cdk4, phosphorylated retinoblastoma (p-Rb), and E2F1 (a transcription factor regulated by p-Rb) were significantly altered in the pyramidal cells with time after ischemia; in the IPC+ischemia group, they were controlled at the level shown in the sham group. In particular, the expression of p16INK4a (an endogenous cdk inhibitor) in the ischemia group was reversely altered in the pyramidal cells; in the IPC+TI group, the expression of p16INK4a was not different from that shown in the sham group. Our current results indicate that cyclin D1/cdk4-related signals may have important roles in events in neurons related to damage/death following ischemia and reperfusion. In particular, the preservation of p16INK4a by IPC may be crucial in attenuating neuronal death/damage or protecting neurons after brain ischemic insults.

Determination of Dynamic Plasma Thiol -disulfide Homeostasis with a Novel Technique in Intestinal Ischemia Reperfusion Injury

Introduction: Intestinal ischemia/reperfusion (I/R) is a serious life-threatening clinical case. Overproduction of reactive oxygen species (ROS) associated with oxidative stress plays a key role in I/R pathophysiology. Objective: The aim of this study is to evaluate dynamic thiol / disulfide hemostasis in intestinal I/R in rats. Materials and Methods: 24 Winstar albino rats were divided into 3 groups (8 animals in each group: (1) sham (operation without ischemia), (2) ischemia (90 minutes ischemia), (3) ischemia/reperfusion (after ischemia for 30 minutes reperfusion for 60 minutes). At the end of the process, liver samples were evaluated pathologically. Also, in plasma samples, native thiol, disulphide and total thiol levels were measured. Results: Native thiol levels in ischemia and I/R group were found to be significantly lower compared to the sham group (P<0.001). Disulfide levels in Ischemia group were found to be significantly higher compared to the sham group (P< 0.05). Disulfide / native thiol levels in ischemia and I/R group were found to be significantly higher compared to the sham group (P < 0.05). Disulfide / total thiol levels in both ischemia and I/R group were found to be significantly higher compared to the sham group (P< 0.05). Conclusion: Balance of dynamic thiol/disulfide is a quite suitable indicator for evaluating oxidative stress which occurs as a result of intestinal I/R. As a result, measurement of dynamic thiol/disulfide balance with Erel method is fully automated and practical for evaluating oxidative environment which is formed with ischemia reperfusion.

Ischemia-Reperfusion under Hyperthermia Increases Heme Oxygenase-1 in Pyramidal Neurons and Astrocytes with Accelerating Neuronal Loss in Gerbil Hippocampus

It has been studied that the damage or death of neurons in the hippocampus is different according to hippocampal subregions, cornu ammonis 1–3 (CA1–3), after transient ischemia in the forebrain, showing that pyramidal neurons located in the subfield CA1 (CA1) are most vulnerable to this ischemia. Hyperthermia is a proven risk factor for brain ischemia and can develop more severe and extensive brain damage related with mortality rate. It is well known that heme oxygenase-1 (HO-1) activity and expression is increased by various stimuli in the brain, including hyperthermia. HO-1 can be either protective or deleterious in the central nervous system, and its roles depend on the expression levels of enzymes. In this study, we investigated the effects of hyperthermia during ischemia on HO-1 expression and neuronal damage/death in the hippocampus to examine the relationship between HO-1 and neuronal damage/death following 5-min transient ischemia in the forebrain using gerbils. Gerbils were assigned to four groups: (1) sham-operated gerbils with normothermia (Normo + sham group); (2) ischemia-operated gerbils with normothermia (Normo + ischemia group); (3) sham-operated gerbils with hyperthermia (39.5 ± 0.2 °C) during ischemia (Hyper + sham group); and (4) ischemia-operated gerbils with hyperthermia during ischemia (Hyper + ischemia group). HO-1 expression levels in CA1–3 of the Hyper + ischemia group were significantly higher than those in the Normo + ischemia group. HO-1 immunoreactivity in the Hyper + ischemia group was significantly increased in pyramidal neurons and astrocytes with time after ischemia, and the immunoreactivity was significantly higher than that in the Normo + ischemia group. In the Normo + Ischemia group, neuronal death was shown in pyramidal neurons located only in CA1 at 5 days after ischemia. However, in the Hyper + ischemia group, pyramidal neuronal death occurred in CA1–3 at 2 days after ischemia. Taken together, our findings showed that brain ischemic insult during hyperthermic condition brings up earlier and severer neuronal damage/death in the hippocampus, showing that HO-1 expression in neurons and astrocytes is different according to brain subregions and temperature condition. Based on these findings, we suggest that hyperthermia in patients with ischemic stroke must be taken into the consideration in the therapy.