Diagnostic Potential of Exosomal HypoxamiRs in the Context of Hypoxia–Sumoylation–HypoxamiRs in Early Onset Preeclampsia at the Preclinical Stage

As the search for non-invasive preclinical markers of preeclampsia (PE) expands, the number of studies on the diagnostic potential of exosomes is growing. Changes in the partial pressure of oxygen caused by impaired uteroplacental perfusion in PE are a powerful inducer of increased production and release of exosomes from cells, which also determine their cargo. At the same time, the expression pattern of oxygen-dependent microRNAs (miRNAs), called “hypoxamiRs”, is modulated, and their packing into exosomes is strictly regulated by sumoylation. In connection therewith, we emphasize the evaluation of exosomal hypoxamiR expression (miR-27b-3p, miR-92b-3p, miR-181a-5p, and miR-186-5p) using quantitative RT-PCR, as well as SUMO 1–4 and UBC9 (by Western blotting), in pregnant women with early-onset PE. The findings show that miR-27b-3p and miR-92b-3p expression was significantly changed at 11–14 and 24–26 weeks of gestation in the blood plasma of pregnant women with early-onset PE, which subsequently manifested. High sensitivity and specificity (AUC = 1) were demonstrated for these miRNAs in the first trimester, and significant correlations with a decrease in hemoglobin (r = 0.71, p = 0.002; r = −0.71, p = 0.002) were established. In mid-pregnancy, the miR-27b-3p expression was found to correlate with an increase in platelets (r = −0.95, p = 0.003), and miR-92b-3p was associated with a decrease in the prothrombin index (r = 0.95, p = 0.003). Specific exomotifs of studied miRNAs were also identified, to which the sumoylated ribonucleoprotein hnRNPA2/B1 binds, carrying out their packaging into exosomes. The expression of conjugated SUMO 1 (p = 0.05), SUMO 2/3/4 (p = 0.03), and UBC9 (p = 0.1) was increased in exosomes at early-onset PE, and the expression of free SUMO 1 (p = 0.03) and SUMO 2/3/4 (p = 0.01) was significantly increased in the placenta, as an adaptive response to hypoxia. Moreover, SUMO 2/3/4 was negatively correlated with miR-27b-3p expression in the placenta. In conclusion, the diagnostic potential of exosomal hypoxamiRs mediated by sumoylation may form the basis for the development of combined specific targets for the treatment of early-onset PE, as hnRNPA2/B1 is a target of miR-27b-3p, and its sumoylation creates miR-27b-3p–hnRNPA2/B1–SUMO 1–4 cross-talk.

Effects of pulsed inhaled nitric oxide delivery on the distribution of pulmonary perfusion in spontaneously breathing and mechanically ventilated anesthetized ponies

OBJECTIVE To measure changes in pulmonary perfusion during pulsed inhaled nitric oxide (PiNO) delivery in anesthetized, spontaneously breathing and mechanically ventilated ponies positioned in dorsal recumbency. ANIMALS 6 adult ponies. PROCEDURES Ponies were anesthetized, positioned in dorsal recumbency in a CT gantry, and allowed to breathe spontaneously. Pulmonary artery, right atrial, and facial artery catheters were placed. Analysis time points were baseline, after 30 minutes of PiNO, and 30 minutes after discontinuation of PiNO. At each time point, iodinated contrast medium was injected, and CT angiography was used to measure pulmonary perfusion. Thermodilution was used to measure cardiac output, and arterial and mixed venous blood samples were collected simultaneously and analyzed. Analyses were repeated while ponies were mechanically ventilated. RESULTS During PiNO delivery, perfusion to aerated lung regions increased, perfusion to atelectatic lung regions decreased, arterial partial pressure of oxygen increased, and venous admixture and the alveolar-arterial difference in partial pressure of oxygen decreased. Changes in regional perfusion during PiNO delivery were more pronounced when ponies were spontaneously breathing than when they were mechanically ventilated. CLINICAL RELEVANCE In anesthetized, dorsally recumbent ponies, PiNO delivery resulted in redistribution of pulmonary perfusion from dependent, atelectatic lung regions to nondependent aerated lung regions, leading to improvements in oxygenation. PiNO may offer a treatment option for impaired oxygenation induced by recumbency.

Positronium as a biomarker of hypoxia

In this review article, we present arguments demonstrating that the advent of high sensitivity total-body PET systems and the invention of the method of positronium imaging, open realistic perspectives for the application of positronium as a biomarker for in-vivo assessment of the degree of hypoxia. Hypoxia is a state or condition, in which the availability of oxygen is not sufficient to support physiological processes in tissue and organs. Positronium is a metastable atom formed from electron and positron which is copiously produced in the intramolecular spaces in the living organisms undergoing positron emission tomography (PET). Properties of positronium, such as e.g., lifetime, depend on the size of intramolecular spaces and the concentration in them of oxygen molecules. Therefore, information on the partial pressure of oxygen (pO2) in the tissue may be derived from the positronium lifetime measurement. The partial pressure of oxygen differs between healthy and cancer tissues in the range from 10 to 50 mmHg. Such differences of pO2 result in the change of ortho-positronium lifetime e.g., in water by about 2–7 ps. Thus, the application of positronium as a biomarker of hypoxia requires the determination of the mean positronium lifetime with the resolution in the order of 2 ps. We argue that such resolution is in principle achievable for organ-wise positronium imaging with the total-body PET systems.

Impact of the small bowel impassability on expression of the hypoxia-induced factor-1α

Objective. Studying of the hypoxia-induced factor-1α expression and peritoneal oxygenation in experimental small bowel intestinal impassability. Materials and methods. The investigation was done on 18 laboratory animals, in which 62 metrics of direct oxymetry performed with the objective to study the impact of the small bowel impassability on velocity of the mass transduction and partial pressure of oxygen and the hypoxia-induced factor-1α expression, influenced by hypoxia. Results. In experimental ileus, complete or partial one, partial pressure and velocity of the oxygen mass-transduction in peritoneum were statistically significantly lower, than such in a control, indicating on inhibition of cellular structures, utilizing the oxygen, what promotes the adhesive disease occurrence. Experimental ileus have led to lowering of the oxygen partial pressure in peritoneum by 88% - from 28.7 (in a control) to 3.5 mm Hg (p<0.01). The partial (by 277.8%) and the complete (by 248.2%) experimental ileus was characterized by enhancement of the hypoxia-induced factor-1α expression. Conclusion. Ileus, accompanied by change in the parietal and visceral peritoneum oxygenation, stimulates the abdominal cavity adhesive process development.

Oxygen: A Stimulus, Not “Only” a Drug

Depending on the oxygen partial pressure in a tissue, the therapeutic effect of oxygenation can vary from simple substance substitution up to hyperbaric oxygenation when breathing hyperbaric oxygen at 2.5–3.0 ATA. Surprisingly, new data showed that it is not only the oxygen supply that matters as even a minimal increase in the partial pressure of oxygen is efficient in triggering cellular reactions by eliciting the production of hypoxia-inducible factors and heat-shock proteins. Moreover, it was shown that extreme environments could also interact with the genome; in fact, epigenetics appears to play a major role in extreme environments and exercise, especially when changes in oxygen partial pressure are involved. Hyperbaric oxygen therapy is, essentially, “intermittent oxygen” exposure. We must investigate hyperbaric oxygen with a new paradigm of treating oxygen as a potent stimulus of the molecular network of reactions.

Clinical observation of high-flow nasal cannula (HFNC) with non-rebreather mask (NRM) use on severe or critically ill COVID-19 diabetic patients

Objective: Diabetes prevalence is a vital factor in COVID-19's clinical prognosis. This study aimed to investigate and compare the efficacy of High-flow Nasal Cannula (HFNC) with/without non-rebreather mask (NRM) on critical COVID-19 patients with/without diabetes. Materials and methods: For analysis and comparison, epidemiological, biochemical, and clinical data were collected from 240 HFNC±NRM treated severe and critical COVID-19 ICU patients (diabetic = 136; non-diabetic = 104) of five hospitals in Chattogram, Bangladesh. Results and Discussion: 59.1% patients with fever had diabetes (p=0.012). ICU stay was longer for diabetic patients (9.06±5.70) than non-diabetic ones (7.41±5.11) (p=0.020). Majority of hypertensive patients were diabetic (68.3%; p<0.001). Most of the diabetic patients (70.4%; p<0.005) had elevated creatinine levels. The partial pressure of oxygen after HFNC (only) was significantly (p=0.031) higher in non-diabetic patients (69.30±23.56) than diabetic ones (61.50±14.49). Diabetic (62.64±13.05) and non-diabetic patients (59.40±13.22) had similar partial pressure of oxygen from HFNC+NRM. Majority of the diabetic patients who required HFNC+NRM had elevated RBS (73.8%; p=0.001) and creatinine (75.7%; p=0.009). Factors affecting the HFNC only treated patients were fever and impaired glucose tolerance. Besides, increased plasma glucose level, age, and hypertension affected the HFNC + NRM treated diabetic patients. Conclusion: The results of this study imply that oxygen supply with HFNC+NRM may be beneficial for the elderly/hypertensive diabetic patients with COVID-19 associated AHRF; and that IGT and increased blood glucose levels could be determinants for COVID-19 severity. However, further experiments to substantiate these claims are required on a larger sample and among different clinical cohorts.

Mechanisms and triggers of adaptation to hypoxia

It is believed that hypoxia-induced factor (HIF1) is the key mediator of oxygen metabolism. It was first identified as a transcription factor activated in cells and tissues by lowering the partial pressure of oxygen (O2). The HIF1 activator spectrum includes both external factors hypoxia, psycho-emotional stress and in ternal factors and varies from hormones to iron chelators. This review is dedicated to the molecular mechanisms of HIF1 activation, some of its natural activators HIF1, the potential for which is due to the low level of toxicity and the reduced likelihood of undesirable side effects. In turn, this opens up new options to treat diseases associated with local and general ischemia and hypoxia, the possibilities of their prophylactic use for researchers and clinicians in order to reduce the degree of damage in the event of an unforeseen condition of acute injurious to organs and tissues by hypoxia and reperfusion after it.

Partial pressure of oxygen level at admission as a predictor of postoperative pneumonia after hip fracture surgery in a geriatric population: a retrospective cohort study

ObjectiveTo identify whether the partial pressure of oxygen in arterial blood (PaO2) level at admission is an independent risk factor as a prognostic biomarker to predict postoperative pneumonia (POP) in the geriatric population who have undergone hip fracture surgical repair at our hospital.DesignA retrospective cohort study.SettingThis is a retrospective chart review of POP after hip fracture surgery in China.ParticipantsIn training cohort, patients aged ≥65 years who had hip fracture surgery between 1 January 2018 and 30 November 2019. In the validation cohort, a series of patients who underwent hip fracture surgery between 1 January 2020 and 28 February 2020.InterventionsReceiver operating characteristic (ROC) analysis was used to obtain the area under the ROC curve (AUC) and cut-off values of PaO2 to predict POP. A binomial logistic regression model was used to identify potential risk factors for POP by analysing demographic distribution factors, laboratory results, preoperative comorbidities and surgical factors. Then the regression model was validated using an independent cohort.ResultsIn the training cohort, ROC curves were generated to compare the predictive performance of PaO2 for the occurrence of POP, and the area under the receiver operating characteristic curve (AUC) was 0.653 (95% CI 0.577 to 0.729, p<0.0001), with sensitivity and specificity values of 60.0% and 63.8%, respectively. The cut-off value of the PaO2 for POP was 72.5 mm Hg. Binary logistic regression analysis revealed that hypoxaemia (PaO2 <72.5 mm Hg) at hospital admission (OR=3.000, 95% CI 1.629 to 5.528; p<0.0001) was independent risk factors associated with POP after hip fracture surgery. In the validation cohort, PaO2 had a predictive effect for POP (AUC 0.71, 95% CI 0.541 to 0.891).ConclusionsThe current study revealed that the PaO2 level at hospital admission is a simple and widely available biomarker predictor of POP after hip fracture surgery in elderly patients.

Mathematical Modeling of Flow and Diffusion in the Lens of the Eye

The present work is concerned with the development of a simple transient mathematical model for the oxygen diffusion-consumption in the eye lens. The model takes into account the transport of oxygen by diffusion and consumption of oxygen is assumed to follow the Michaelis- Menten’s kinetics. The partial differential equation governing the partial pressure of oxygen has been solved by using implicit Crank-Nicholson’s iteration scheme. The prime objective of the present study is to investigate the effect of model parameters: the Michaelis- Menten’s kinetic constant and maximum rate of consumption on the partial pressure of oxygen in the mammalian lens. The computational results of the model have been presented by graphs and effects of model parameters also have been shown through the graphs and discussed. The present mathematical analysis of oxygen diffusion in the lens may contribute to the knowledge of regulation of tissue oxygen in the lens and quantitative understanding achieved through the analysis may facilitate the design of new therapeutic procedures. This analysis may help in regulating the partial pressure of oxygen in the lens.