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The success of messenger (m)RNA-based vaccines against SARS-CoV-2 during the COVID-19 pandemic has led to rapid growth and innovation in the field of mRNA-based therapeutics. However, mRNA production, whether in small amounts for research or large-scale GMP-grade for biopharmaceutics, is still based on the In Vitro Transcription (IVT) reaction developed in the early 1980s. The IVT reaction exploits phage RNA polymerase to catalyze the formation of an engineered mRNA that depends on a linearized DNA template, nucleotide building blocks, as well as pH, temperature, and reaction time. But depending on the IVT conditions and subsequent purification steps, diverse byproducts such as dsRNA, abortive RNAs and RNA:DNA hybrids might form. Unwanted byproducts, if not removed, could be formulated together with the full-length mRNA and cause an immune response in cells by activating host pattern recognition receptors. In this review, we summarize the potential types of IVT byproducts, their known biological activity, and how they can impact the efficacy and safety of mRNA therapeutics. In addition, we briefly overview non-nucleotide-based contaminants such as RNases, endotoxin and metal ions that, when present in the IVT reaction, can also influence the activity of mRNA-based drugs. We further discuss current approaches aimed at adjusting the IVT reaction conditions or improving mRNA purification to achieve optimal performance for medical applications.
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Coronary artery bypass surgery can result in endothelial dysfunction due to ischemia/reperfusion (IR) injury. Previous studies have demonstrated that DuraGraft helps maintain endothelial integrity of saphenous vein grafts during ischemic conditions. In this study, we investigated the potential of DuraGraft to mitigate endothelial dysfunction in arterial grafts after IR injury using an aortic transplantation model. Lewis rats (n = 7-9/group) were divided in three groups. Aortic arches from the control group were prepared and rings were immediately placed in organ baths, while the aortic arches of IR and IR + DuraGraft rats were preserved in saline or DuraGraft, respectively, for 1 h before being transplanted heterotopically. After 1 h after reperfusion, the grafts were explanted, rings were prepared, and mounted in organ baths. Our results demonstrated that the maximum endothelium-dependent vasorelaxation to acetylcholine was significantly impaired in the IR group compared to the control group, but DuraGraft improved it (control: 89 ± 2%; IR: 24 ± 1%; IR + DuraGraft: 48 ± 1%, p < 0.05). Immunohistochemical analysis revealed decreased intercellular adhesion molecule-1, 4-hydroxy-2-nonenal, caspase-3 and caspase-8 expression, while endothelial cell adhesion molecule-1 immunoreactivity was increased in the IR + DuraGraft grafts compared to the IR-group. DuraGraft mitigates endothelial dysfunction following IR injury in a rat bypass model. Its protective effect may be attributed, at least in part, to its ability to reduce the inflammatory response, oxidative stress, and apoptosis.
Subject(s)
Endothelium, Vascular , Rats, Inbred Lew , Reperfusion Injury , Animals , Rats , Endothelium, Vascular/drug effects , Endothelium, Vascular/metabolism , Reperfusion Injury/metabolism , Male , Coronary Artery Bypass/methods , Coronary Artery Bypass/adverse effects , Oxidative Stress/drug effects , Intercellular Adhesion Molecule-1/metabolism , Disease Models, Animal , Aldehydes/metabolism , Aldehydes/pharmacology , Caspase 3/metabolism , Vasodilation/drug effects , Apoptosis/drug effects , Acetylcholine/pharmacologyABSTRACT
The determination of age-related transcriptional changes may contribute to the understanding of health and life expectancy. The broad application of results from age cohorts may have limitations. Altering sample sizes per time point or sex, using a single mouse strain or tissue, a limited number of replicates, or omitting the middle of life can bias the surveys. To achieve higher general validity and to identify less distinctive players, bulk RNA sequencing of a mouse cohort, including seven organs of two strains from both sexes of 5 ages, was performed. Machine learning by bootstrapped variable importance and selection methodology (Boruta) was used to identify common aging features where the circadian rhythms (CiR) transcripts appear as promising age markers in an unsupervised analysis. Pathways of 11 numerically analyzed local network clusters were affected and classified into four major gene expression profiles, whereby CiR and proteostasis candidates were particularly conspicuous with partially opposing changes. In a data-based interaction association network, the CiR-proteostasis axis occupies an exposed central position, highlighting its relevance. The computation of 11,830 individual transcript associations provides potential superordinate contributors, such as hormones, to age-related changes, as in CiR. In hormone-sensitive LNCaP cells, short-term supraphysiologic levels of the sex hormones dihydrotestosterone or estradiol increase the expression of the CiR transcript Bhlhe40 and the associated senescence regulator Cdkn2b (p15). According to these findings, the bilateral dysregulation of CiR appears as a fundamental protagonist of aging, whose transcripts could serve as a biological marker and its restoration as a therapeutic opportunity.
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Background: Off-pump coronary artery bypass grafting (OPCAB) is an alternative to on-pump coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB). During OPCAB, the temporary use of an intracoronary shunt and inotropic medication or catecholamines should keep the central hemodynamics constant. Nevertheless, the need for conversion to on-pump CABG often occurs unexpectedly, most likely due to circulation instability. Circulation instability can appear first in peripheral body parts; therefore, peripheral microcirculation might serve as a predictor for the upcoming conversion to on-pump CABG. We investigated the impact of coronary artery ligation and shunt insertion during OPCAB on cutaneous microcirculation (cLDP) with Laser Doppler Perfusion Technology and transcutaneous oxygen partial pressure ( tcpO 2 ). Methods: In a pig model of OPCAB, peripheral circulation was evaluated after cLDP (N = 17) and tcpO 2 (N = 6) monitoring. Systolic, diastolic, and mean arterial pressure were also observed to prove the independence of perfusion measurement results from hemodynamic parameters. Results: Ligation time during cLDP and tcpO 2 monitoring were 101 ± 49 s and 83 ± 33 s, respectively. Shunt time was 11 ± 3 min during cLDP and 13 ± 2 min during tcpO 2 measurement. Ligation of the left anterior descending coronary artery (LAD) reduced cLDP significantly to 88 ± 14% (p = 0.007) and tcpO 2 to 71 ± 25% (p = 0.038). Inserting a temporary shunt into the LAD significantly improved cLDP (p = 0.006) and tcpO 2 (p = 0.015) compared to ligation. cLDP was restored to 99%, and tcpO 2 was restored to 91% of the baseline level before ligation. All hemodynamic parameters remained stable and did not change significantly during OPCAB. Conclusions: Although hemodynamic parameters stayed constant, peripheral microcirculation was influenced markedly during OPCAB. Inserting a temporary shut into the LAD leads to a complete normalization of peripheral microcirculation, regarding evaluation by cLDP and tcpO 2 .
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Stroke can have a range of physical, psychological, cognitive, and social impacts that are challenging for survivors. This study aimed to evaluate the efficacy of a group-based mindfulness intervention integrated into an inpatient rehabilitation program compared to standard care. A single-center, randomized, controlled trial was conducted in 93 poststroke patients. The intervention group received 6-weeks of mindfulness-based cognitive therapy (MBCT) and standard care; the control group received standard care. Primary outcomes were depression and trait anxiety; secondary outcomes were trait mindfulness and attention. Participants completed questionnaires at baseline, and postintervention (6â weeks). Mixed-effect model repeated measures analysis of variance was conducted between groups and across time. A total of 80 participants (intervention n â =â 43; standard care n â =â 37) were included in the postintervention analysis. There were no statistically significant differences in the primary outcomes between the groups over time. An improvement was found, however, on the trait mindfulness observing subscale in favor of the intervention group. Eight sessions of MBCT integrated into an inpatient stroke rehabilitation program over 6â weeks was not effective in improving depression and anxiety compared to standard care. Lack of follow-up and low to moderate pathological symptoms at baseline may have limited the effectiveness of this intervention.
Subject(s)
Mindfulness , Stroke Rehabilitation , Humans , Mindfulness/methods , Stroke Rehabilitation/methods , Male , Female , Middle Aged , Aged , Cognitive Behavioral Therapy/methods , Anxiety/rehabilitation , Anxiety/psychology , Depression/rehabilitation , Depression/psychology , Stroke/psychologyABSTRACT
BACKGROUND: New prosthetic valves and surgical approaches that shorten operation time and improve the outcome of patients with aortic valve (AV) infective endocarditis (IE) and AV insufficiency (AVI) are crucial. The aim of this study was to evaluate the outcome of patients with AV IE or AVI treated with the EDWARDS INTUITY Rapid-Deployment AV prosthesis for this off-label indication. METHODS: This single-centre retrospective study analyzed data from patients who underwent AV replacement with the EDWARDS INTUITY Rapid-Deployment AV prosthesis for AV IE or regurgitation. (n = 8 for IE and n = 6 for AVI). RESULTS: Heart-lung machine times were significantly shorter in the AVI group (111.3 ± 20.7 min) compared to the IE group (171.9 ± 52.4 min) (p = 0.02). Aortic cross-clamp followed a similar trend (73.7 ± 9.9 min for AVI vs. 113.4 ± 35.6 min for IE) (p = 0.02). The length of ICU stay was also shorter in the AVI group (3.8 ± 2.6 days) compared to the IE group (16.9 ± 8.9 days) (p = 0.005). Postoperative echocardiography revealed no paravalvular leakage or significant valvular dysfunction in any patient. One patient died postoperatively from aspiration pneumonia. CONCLUSION: The INTUITY valve demonstrates as a safe option for complex AV IE and AVI surgery. Further prospective studies with larger patient cohorts are necessary to confirm these findings and explore the long-term benefits of this approach.
Subject(s)
Aortic Valve Insufficiency , Aortic Valve , Endocarditis , Heart Valve Prosthesis Implantation , Heart Valve Prosthesis , Humans , Male , Retrospective Studies , Female , Middle Aged , Aortic Valve Insufficiency/surgery , Heart Valve Prosthesis Implantation/methods , Endocarditis/surgery , Endocarditis/complications , Aortic Valve/surgery , Aged , Treatment Outcome , AdultABSTRACT
Background: Microvascular resistance reserve (MRR) is a recently introduced specific index of coronary microcirculation. MRR calculation can utilize parameters deriving from coronary flow reserve (CFR) assessment, provided that intracoronary pressure data are also available. The previously proposed pressure-bounded CFR (CFRpb) defines the possible CFR interval on the basis of resting and hyperemic pressure gradients in the epicardial vessel, however, its correlation to the Doppler wire measurement was reported to be rather poor without the correction for hydrostatic pressure. Purpose: We aimed to determine the pressure-bounded coronary MRR interval with hydrostatic pressure correction according to the previously established equations of CFRpb adapted for the MRR concept. Furthermore, we also aimed to design a prediction model using the actual MRR value within the pressure-bounded interval and validate the results against the gold-standard Doppler wire technique. Methods: Hydrostatic pressure between the tip of the catheter and the sensor of the pressure wire was calculated by height difference measurement from a lateral angiographic view. In the derivation cohort the pressure-bounded MRR interval (between MRRpbmin and MRRpbmax) was determined solely from hydrostatic pressure-corrected intracoronary pressure data. The actual MRR was calculated by simple hemodynamic equations incorporating the anatomical data of the three-dimensionally reconstructed coronary artery (MRRp-3D). These results were analyzed by regression analyses to find relations between the MRRpb bounds and the actual MRRp-3D. Results: In the derivation cohort of 23 measurements, linear regression analysis showed a tight relation between MRRpbmax and MRRp-3D (r 2 = 0.74, p < 0.0001). Using this relation (MRRp-3D = 1.04 + 0.51 × MRRpbmax), the linear prediction of the MRR was tested in the validation cohort of 19 measurements against the gold standard Doppler wire technique. A significant correlation was found between the linearly predicted and the measured values (r = 0.54, p = 0.01). If the area stenosis (AS%) was included to a quadratic prediction model, the correlation was improved (r = 0.63, p = 0.004). Conclusions: The MRR can be predicted reliably to assess microvascular function by our simple model. After the correction for hydrostatic pressure error, the pressure data during routine FFR measurement provides a simultaneous physiological assessment of the macro- and microvasculature.
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Recent genome-wide analyses identified chromatin modifiers as one of the most frequently mutated classes of genes across all cancers. However, chemotherapies developed for cancers involving DNA damage remain the standard of care for chromatin-deranged malignancies. In this review we address this conundrum by establishing the concept of 'chromatin damage': the non-genetic damage to protein-DNA interactions induced by certain small molecules. We highlight anthracyclines, a class of chemotherapeutic agents ubiquitously applied in oncology, as an example of overlooked chromatin-targeting agents. We discuss our current understanding of this phenomenon and explore emerging chromatin-damaging agents as a basis for further studies to maximize their impact in modern cancer treatment.
Subject(s)
Antineoplastic Agents , Chromatin , DNA Damage , Neoplasms , Humans , Chromatin/metabolism , Chromatin/drug effects , Neoplasms/drug therapy , Neoplasms/genetics , Neoplasms/pathology , DNA Damage/drug effects , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Molecular Targeted Therapy/methods , Anthracyclines/therapeutic use , Anthracyclines/pharmacology , AnimalsABSTRACT
We compare multiple temporal pulse characterization techniques in three different pulse duration regimes from 15 fs to sub-5 fs, as there are no available standards yet for measuring such ultrashort pulses. To accomplish this, a versatile post-compression platform was developed, where the 100 fs near infrared pulses were post-compressed to the sub-two-cycle regime in a hybrid, three-stage configuration. After each stage, the duration of the compressed pulse was measured with the d-scan, TIPTOE and SRSI techniques and the retrieved temporal intensity profiles, spectrum and spectral phases were compared. Spectral homogeneity was also measured with an imaging spectrometer to understand the input coupling conditions of the temporal measurements. Our findings suggest that the different devices give similar results in terms of temporal intensity profile, however they are extremely sensitive to alignment and to beam quality, especially in the case of the shortest pulses. We address specific steps of measurement procedures, which paves the way towards the standardization of pulse characterization in the near future.
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BACKGROUND: Although the FDA Accelerated Approval Program (AAP) has come under scrutiny, the population-level health benefit of the program has not been quantified. Therefore, the objective of this study was to estimate the number of life years gained among patients with cancer that can be attributable to the therapies receiving FDA accelerated approvals in oncology between 2006 and 2022 in the United States. METHODS: The data sources used were FDA listings, FDA approval letters and labels, published clinical trial data and other publications including relative effectiveness estimates, and the Ipsos Oncology Uptake Tool for product uptake. Data for 130 oncology treatments approved by the FDA under the AAP were extracted and validated. We developed a decision analytic model to estimate the survival gain for each indication and to accumulate life years gained for consecutive cohorts of patients receiving the therapies. Life year gains were estimated with and without the AAP, and the incremental life years gained were attributed to the program. RESULTS: The analysis estimated that through December 2022 in the United States, the program gained approximately 263,000 life years across 69 products for which overall survival data were available, for approximately 911,000 patients with cancer. CONCLUSIONS: Policy discussions about the evaluation of AAP cannot be complete without assessing its impact on its most important target outcome: patient survival. To date, there has been no estimation of the life year gain delivered by the AAP. Our research shows that substantial number of life years were gained for patients with high unmet need by the cancer therapies approved through the program.
Subject(s)
Drug Approval , Medical Oncology , Neoplasms , United States Food and Drug Administration , Humans , United States , United States Food and Drug Administration/standards , Neoplasms/drug therapy , Neoplasms/mortality , Medical Oncology/standards , Medical Oncology/methods , Antineoplastic Agents/therapeutic useABSTRACT
Personalized medicine shows promise for the management of patients with coronary artery disease (CAD) [...].
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In endometrial cancer (EC), deep myometrial invasion (DMI) is a prognostic factor that can be evaluated by various imaging methods; however, the best method of choice is uncertain. We aimed to compare the diagnostic performance of two-dimensional transvaginal ultrasound (TVS) and magnetic resonance imaging (MRI) in the preoperative detection of DMI in patients with EC. Pubmed, Embase and Cochrane Library were systematically searched in May 2023. We included original articles that compared TVS to MRI on the same cohort of patients, with final histopathological confirmation of DMI as reference standard. Several subgroup analyses were performed. Eighteen studies comprising 1548 patients were included. Pooled sensitivity and specificity were 76.6% (95% confidence interval (CI), 70.9-81.4%) and 87.4% (95% CI, 80.6-92%) for TVS. The corresponding values for MRI were 81.1% (95% CI, 74.9-85.9%) and 83.8% (95% CI, 79.2-87.5%). No significant difference was observed (sensitivity: p = 0.116, specificity: p = 0.707). A non-significant difference between TVS and MRI was observed when no-myometrium infiltration vs. myometrium infiltration was considered. However, when only low-grade EC patients were evaluated, the specificity of MRI was significantly better (p = 0.044). Both TVS and MRI demonstrated comparable sensitivity and specificity. Further studies are needed to assess the presence of myometrium infiltration in patients with fertility-sparing wishes.
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Protection of the coronary arteries during donor heart maintenance is pivotal to improve results and prevent the development of coronary allograft vasculopathy. The effect of hypothermic, oxygenated perfusion (HOP) with the traditional HTK and the novel HTK-N solution on the coronary microvasculature of donation-after-circulatory-death (DCD) hearts is known. However, the effect on the coronary macrovasculature is unknown. Thus, we maintained porcine DCD hearts by HOP with HTK or HTK-N for 4 h, followed by transplantation-equivalent reperfusion with blood for 2 h. Then, we removed the left anterior descending coronary artery (LAD) and compared the endothelial-dependent and -independent vasomotor function of both groups using bradykinin and sodium-nitroprusside (SNP). We also determined the transcriptome of LAD samples using microarrays. The endothelial-dependent relaxation was significantly better after HOP with HTK-N. The endothelial-independent relaxation was comparable between both groups. In total, 257 genes were expressed higher, and 668 genes were expressed lower in the HTK-N group. Upregulated genes/pathways were involved in endothelial and vascular smooth muscle cell preservation and heart development. Downregulated genes were related to ischemia/reperfusion injury, oxidative stress, mitochondrion organization, and immune reaction. The novel HTK-N solution preserves the endothelial function of DCD heart coronary arteries more effectively than traditional HTK.
Subject(s)
Heart Transplantation , Swine , Animals , Humans , Heart Transplantation/methods , Tissue Donors , Heart , Perfusion , Coronary Vessels/physiology , Organ Preservation/methodsABSTRACT
The parallel measurements of wavelength dependent optical absorption, particle number size distribution have made by a multi wavelength photoacoustic spectrometer (4λ-PAS) and scanning mobility particle sizer (SMPS) respectively at different modes of a diesel engine using two different types of fuel. The thermal evolution of the emission was also investigated using posterior temperature treatment of emission. The bimodal size distribution of emitted particles at a set reference temperature has been observed regardless of the applied fuel at idle. However, the emitted particulate assembly had lognormal size distribution falls into the accumulation mode at all other defined engine modes and both fuel types. The total number- and volume concentration (TNC and TVC) showed retrograde tendency with the increasing torque and rpm independently of the applied fuel types. The TNC values decreased up to 50% for both fuels with engine operation changes from idle engine mode(em#1) to low engine mode(em#2). With further increase in torque and rpm of engine, the change in TNC is negligible. On the other hand, the TVC remains more or less the same for idle to low engine mode transition and increased more than 60% for high mode (em#3) transition. The Optical Absorption Coefficient (OAC) values measured at the operational wavelengths of the 4λ-PAS instrument decreased at all wavelengths with increasing rpm and torque. The wavelength dependency quantified by Aerosol Ängström Exponent (AAE) was applied here for qualitative analysis of the carbonaceous emission and showed decreased values towards the higher engine speed and torque output of the engine. The proposed technique can be used as real-time, precise and accurate measurement of light absorption by DPM aerosols, which opens up novel possibilities for the volatility and thermal evolution investigation of diesel emissions.
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Donation after circulatory death (DCD) hearts are predominantly maintained by normothermic blood perfusion (NBP). Nevertheless, it was shown that hypothermic crystalloid perfusion (HCP) is superior to blood perfusion to recondition left ventricular (LV) contractility. However, transcriptomic changes in the myocardium and coronary artery in DCD hearts after HCP and NBP have not been investigated yet. In a pig model, DCD hearts were harvested and maintained for 4 h by NBP (DCD-BP group, N = 8) or HCP with oxygenated histidine-tryptophane-ketoglutarate (HTK) solution (DCD-HTK, N = 8) followed by reperfusion with fresh blood for 2 h. In the DCD group (N = 8), hearts underwent reperfusion immediately after procurement. In the control group (N = 7), no circulatory death was induced. We performed transcriptomics from LV myocardial and left anterior descending (LAD) samples using microarrays (25,470 genes). We applied the Boruta algorithm for variable selection to identify relevant genes. In the DCD-BP group, compared to DCD, six genes were regulated in the myocardium and 1915 genes were regulated in the LAD. In the DCD-HTK group, 259 genes were downregulated in the myocardium and 27 in the LAD; and 52 genes were upregulated in the myocardium and 765 in the LAD, compared to the DCD group. We identified seven genes of relevance for group identification: ITPRIP, G3BP1, ARRDC3, XPO6, NOP2, SPTSSA, and IL-6. NBP resulted in the upregulation of genes involved in mitochondrial calcium accumulation and ROS production, the reduction in microvascular endothelial sprouting, and inflammation. HCP resulted in the downregulation of genes involved in NF-κB-, STAT3-, and SASP-activation and inflammation.
Subject(s)
Heart Transplantation , Swine , Animals , Humans , Heart Transplantation/methods , Coronary Vessels , Transcriptome , DNA Helicases , Tissue Donors , Poly-ADP-Ribose Binding Proteins , RNA Helicases , RNA Recognition Motif Proteins , Myocardium , Perfusion/methods , Gene Expression Profiling , Inflammation , Organ Preservation/methods , DeathABSTRACT
OBJECTIVES: To test the accuracy of TVS applying the IDEA approach for suspected rectosigmoid DE and to determine the frequency of other pelvic diseases mimicking DE in patients undergoing surgery. MATERIALS UND METHODS: Prospective single center observational study including consecutive women undergoing TVS for clinically suspected rectosigmoid DE followed by conservative or surgical therapy. TVS findings were compared with those obtained by laparoscopy and confirmed histologically. RESULTS: Of the 671 included patients, 128 women opted for medical therapy, and 6 patients decided for surgery but did not give consent to participate in the study. 537 women were enrolled in the final analysis. 279 (52â%) exhibited surgically confirmed rectosigmoid DE. The sensitivity and specificity, positive and negative predictive value (PPV, NPV), positive and negative likelihood ratio (LR+/-) and accuracy of TVS for diagnosing DE in the rectosigmoid were 93.5â%, 94.6â%, 94.9â%, 93.1â%, 17.24, 0.07, 94.04â%. 12 women who were clinically suspected for DE and mimicked sonographic signs fulfilling the IDEA criteria did exhibit other pathologies. Diagnoses were as follows: vaginal Gartner duct cyst (3/291;1.0â%), anorectal abscess (3/291; 1.0â%), rectal cancer (2/291;0.7â%), hydrosalpinx (2/291;0.7â%), metastatic endometrial cancer (1/291;0.35â%) and Crohn's disease (1/291;0.35â%). CONCLUSION: TVS for diagnosing colorectal DE applying the IDEA criteria is highly accurate for presurgical diagnosis. However, additional pelvic pathologies are encountered in 4-5â% of women attending for suspected rectosigmoid DE. These need to be taken into account when investigating patients for suspected DE.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Endometriosis , Female , Humans , Cytarabine , Dexamethasone , Endometriosis/diagnostic imaging , Endometriosis/surgery , Etoposide , Ifosfamide , Prospective Studies , Sensitivity and Specificity , Ultrasonography/methods , Vagina/diagnostic imagingABSTRACT
INTRODUCTION: Extracorporeal membrane oxygenation (ECMO) is increasingly used for circulatory or pulmonary support not only in-hospital but also out-of-hospital. Small dimensions and a lightweight design are important, especially for out-of-hospital use but also for intra-hospital transportation of patients who require ECMO support. We share our first experience with the new Colibrì ECMO system. PATIENTS AND METHODS: From December 2022 to January 2023, we used the new Colibrì extracorporeal circulation (ECC) system in six patients with cardiac or pulmonary failure. RESULTS: The Colibrì system was used in-hospital in six patients with post-cardiac surgery low output syndrome, respiratory failure due to influenza or acute respiratory distress syndrome, cardiogenic shock, pulmonary embolism, and failed weaning from cardiopulmonary bypass. The system was implanted in venovenous (VV) and venoarterial (VA) fashion in 3 patients, respectively. In one patient, the configuration was switched from VA to VV after cardiac recovery. One patient received left-ventricular unloading using the IMPELLA®5.5. ECMO run time was 1 to 13 days. We did not notice any ECC system-associated complications. No ECMO system changes were required. CONCLUSION: Our case series concludes that the new Colibrì system is safe and effective for in-hospital ECMO indications. The small dimensions and lightweight design are very beneficial for the transportation of patients. It might be especially helpful for out-of-hospital situations.
Subject(s)
Extracorporeal Membrane Oxygenation , Respiratory Distress Syndrome , Respiratory Insufficiency , Humans , Extracorporeal Membrane Oxygenation/adverse effects , Extracorporeal Membrane Oxygenation/methods , Shock, Cardiogenic/therapy , Respiratory Distress Syndrome/therapy , Respiratory Insufficiency/therapy , Heart , Retrospective StudiesABSTRACT
Epidemiological studies have indicated that the consumption of whole-grain products is associated with a reduced risk of cardiovascular diseases, type II diabetes, and cancer. In the case of bread, high amounts of antioxidants and advanced glycation end products (AGEs) are formed during baking by the Maillard reaction in the bread crust; however, the formation of potentially harmful compounds such as acrylamide also occurs. This study investigated the antioxidant responses of different soluble extracts from whole-grain wheat bread crust extracts (WBCEs) in the context of the asparagine, AGE, and acrylamide content. For that, we analyzed nine bread wheat cultivars grown at three different locations in Germany (Hohenheim, Eckartsweier, and Oberer Lindenhof). We determined the asparagine content in the flour of the 27 wheat cultivars and the acrylamide content in the crust, and measured the antioxidant potential using the induced expression of the antioxidant genes GCLM and HMOX1 in HeLa cells. Our study uncovered, for the first time, that the wheat crust's antioxidant potential correlates with the AGE content, but not with the acrylamide content. Mass spectrometric analyses of WBCEs for identifying AGE-modified proteins relevant to the antioxidant potential were unsuccessful. However, we did identify the wheat cultivars with a high antioxidant potential while forming less acrylamide, such as Glaucus and Lear. Our findings indicate that the security of BCEs with antioxidative and cardioprotective potential can be improved by choosing the right wheat variety.
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BACKGROUND: In recent years, several indices have been proposed for quantifying coronary microvascular resistance. We intended to conduct a comprehensive review that systematically evaluates indices of microvascular resistance derived from angiography. OBJECTIVE: The objective of this study was to identify and analyze angiography-derived indices of microvascular resistance that have been validated against an invasive reference method. We aimed to compare their limits of agreement with their reference methods and explore their advantages and inherent limitations. METHODS AND RESULTS: We searched PubMed from inception until 2022 for studies on different techniques for quantifying microvascular resistance. Seven studies met the inclusion criteria. Five studies included techniques that applied calculations based solely on invasive angiography, and were validated against invasively measured thermodilution-derived index of microvascular resistance. The remaining two studies combined angiography with invasively measured intracoronary pressure data, and were validated against invasive Doppler measurements. We converted the ± 1.96 standard deviation limits of agreement with the reference method from the seven studies into percentages relative to the cut-off value of the reference method. The lower limits of agreement for angiography-based methods ranged from - 122 to - 60%, while the upper limits ranged from 74 to 135%. The range of the limits of agreement was considerably lower for the two combined angiography- and pressure-based methods, standing at - 52 to 60% and - 25 to 27%. CONCLUSION: Our findings suggest that combined angiography- and pressure-based methods provide a more reliable assessment of microvascular resistance compared to methods relying solely on angiography. Central illustration. Comparative assessment of image-based methods quantifying microvascular resistance with and without intracoronary pressure measurements. Angiography-based methods rely on angiography alone to calculate the microvascular resistance by utilizing angiographic frame counting to extrapolate coronary flow (Q) and subsequently deriving distal coronary pressure using fluid dynamic equations. Combined angiography- and pressure-based methods utilize invasive intracoronary pressure gradients measured during rest and maximal vasodilation to determine coronary flow in their calculation of microvascular resistance. The combined methods showed more acceptable levels of agreement with their reference methods compared to angiography-based methods alone.
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BACKGROUND: Heart transplantation (HTX) is the standard treatment for end-stage heart failure. However, reperfusion following an ischemic period can contribute to myocardial injury. Neutrophil infiltration, along with the subsequent release of tissue-degrading neutrophil elastase (NE)-related serine proteases and oxygen-derived radicals, is associated with adverse graft outcomes. The inhibition of cathepsin C (CatC) has been shown to block NE-related protease activation. We hypothesized that the CatC inhibitor BI-9740 improves graft function after HTX. METHODS: In a rat model of HTX, the recipient Lewis rats were orally administered with either a placebo (n = 12) or BI-9740 (n = 11, 20 mg/kg) once daily for 12 days. Donor hearts from untreated Lewis rats were explanted, preserved in a cardioplegic solution, and subsequently heterotopically implanted. In vivo left-ventricular (LV) graft function was assessed after 1 h of reperfusion. The proteolytic activity of neutrophil serine proteases was determined in bone marrow lysates from BI-9740-treated and control rats. Additionally, myocardial morphological changes were examined, and heart samples underwent immunohistochemistry and western blot analysis. RESULTS: The NE-related proteolytic activity in bone marrow cell lysates was markedly decreased in the BI-9740-treated rats compared to those of the placebo group. Histopathological lesions, elevated CatC and myeloperoxidase-positive cell infiltration, and nitrotyrosine immunoreactivity with an increased number of poly(ADP-ribose) polymerase (PARP)-1-positive cells were lowered in the hearts of animals treated with BI-9740 compared to placebo groups. Regarding the functional parameters of the implanted graft, improvements were observed in both systolic function (LV systolic pressure 110 ± 6 vs 74 ± 6 mmHg; dP/dtmax 2782 ± 149 vs 2076 ± 167 mmHg/s, LV developed pressure, at an intraventricular volume of 200 µl, p < 0.05) and diastolic function in the hearts of BI-9740 treated animals compared with those receiving the only placebo. Furthermore, the administration of BI-9740 resulted in a shorter graft re-beating time compared to the placebo group. However, this study did not provide evidence of DNA fragmentation, the generation of both superoxide anions and hydrogen peroxide, correlating with the absence of protein alterations related to apoptosis, as evidenced by western blot in grafts after HTX. CONCLUSIONS: We provided experimental evidence that pharmacological inhibition of CatC improves graft function following HTX in rats.