bluuebunny/crossref_metadata_2025 huggingface dataset:
Aspects of somatogenic asthenic syndrome in patients with high cardiovascular risk
Authors: Demikhov A , Demikhova N , Rudenko T , Orlovskiy A
Published: June 2022

Funding Acknowledgements

Type of funding sources: None.

Aim

To study frequency and nature of psychopathological symptoms in various forms of somatogenic asthenic syndrome in patients with high cardiovascular risk (CVR).

Methods

The quantitative anamnestic analysis of medical history, the variational statistics, the probabilistic allocation of clinical signs with estimation of reliability of the results. Among the 199 persons with high CVR and non-psychotic mental disorders: 31 patients had somatogenic asthenic syndrome (SAS), stratified by clinical variants: asthenic (1n2=14); asthenic-anxious (2n2=8); asthenic-subdepressive (3n2=6) and dyssomniac (4n2=3).

Results

The frequency and kind of pathopsychological symptoms in young people with increased CVR and SAS was studied. Each variant of SAS in patients with high CVR has its features of symptomological structure. More, than in half of cases in asthenic variant of SAS in patients with high CVR, registered a headache, a feeling of heaviness in the head (63.4±12.8%), intolerance to loud sounds and bright lights (57.1±13.2%) and low mood (50.0±13.4%). Patients with high CVR and asthenic-anxious variant of SAS on the first place by the frequency of diagnosing was also weakness (87.5±11.7%), lack of vigor after a night's sleep (87.5±11.7%) and almost with the same frequency were registered fatigue (75.0±15.3%), memory impairment (62.5±17.1%), which in 1.5-3 times exceeded the average in patients with SAS by the frequency; anxiety, absentmindedness were diagnosed in 50.0±17.7% of cases in this subgroup. Prevailing (most common) psychopathological symptoms, significantly more represented than on the average in patients with high CVR and dyssomniac variant of SAS were (at 65-100%): absentmindedness, irritability, fatigue, weakness, anxiety.

Most common symptom in patients with high CVR and asthenic variant of SAS was a weakness - in (92.9±6.9)%, and the prevalence was significantly higher, than on the average in group of patients with SAS. There were fatigue (85.7±9.4%), tearfulness (85.7±9.4%), irritability (63.4±12.8%), difficulty falling asleep (57.1±13.2%), the prevalence of which significantly exceeded the average in patients with SAS (p<0.05). In patients with high CVR and asthenic-anxious SAS on the first place by the frequency of diagnosis was also weakness (87.5±11.7%), lack of vigor after a night's sleep (87.5±11.7%) almost on the same frequency was registered fatigue (75.0±15.3%), memory impairment (62.5±17.1%), which in 1.5-3 times exceeded the average in patients with SAS by the frequency. Most common for patients with high CVR and asthenic-subdepressive variant of SAS were: dizziness (83.3±15.2), sleep disorders and restless sleep (66.7±19.2%), touchiness and anguish (66.7±19.2%).

Conclusions

Ranking of symptoms was made and the major syndromes, depending on the variant of SAS in patients with high CVR, were defined.
Endothelial CaSR is involved in the induction of atherosclerosis by promoting cell adhesion and local inflammation
Authors: Sundararaman S , Peters L , Bonnin Marquez A , Bouma J , Maas S , Jansen Y , Gencer S , Soehnlein O , Wagner U , Bidzhekov K , Weber C , Doering Y , Jankowski J , Biessen E , Van Der Vorst E
Published: June 2022

Funding Acknowledgements

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Humboldt foundation

Background

Calcium-Sensing Receptor (CaSR) is a cell surface G-protein coupled receptor that senses calcium in the extracellular environment. This receptor is widely studied in mineral homeostasis due to its presence in varied calcitropic tissues. However, CaSR is also present on the surface of vascular and hematopoietic cells and recent studies suggest that this receptor can also have pathological consequences related to cardiovascular diseases, like atherosclerosis. Since endothelial cells are crucial players in atherogenesis, we aimed to investigate which role endothelial CaSR plays in the development and progression of atherosclerosis.

Methods

We cross-bred CaSRflox/flox Apoe-/- mice with BmxCreERT2 Apoe-/- (endothelial cell specific Cre driver) mice to obtain tamoxifen-inducible mice which have an endothelial cell specific deletion of CaSR. The mice were then fed with a high fat diet (HFD) for 4 or 12 weeks, reflecting early and late atherosclerosis, respectively. We used histological and immuno-fluorescent stainings to analyse the atherosclerotic lesion size and its cellular and acellular composition. Systemic effects on leukocytes were evaluated using flow-cytometry, while intra-vital microscopy was used to study leukocyte adhesion to activated endothelium in-vivo. Further mechanistic studies were performed in human coronary artery endothelial cells (HCAECs) in-vitro.

Results

Endothelial CaSR deficiency in mice resulted in significantly smaller lesion size in early atherosclerotic stages (4 weeks HFD), whereas late atherosclerotic lesions (12 weeks HFD) were not affected by the lack of endothelial CaSR. Moreover, the phenotype of atherosclerotic plaques, characterized by macrophage, smooth muscle cell, collagen and necrotic core content remained unaltered between wild-type and endothelial cell specific CaSR knockout mice. Interestingly, leukocyte adhesion in-vivo, especially neutrophil adhesion, was significantly reduced in endothelial cell CaSR deficient mice. In line with this, overexpression of CaSR in HCAECs in-vitro increased the production of inflammatory cytokines and expression of adhesion molecules ICAM and VCAM.

Conclusion

Our results indicate that while endothelial cell specific CaSR is involved in the induction of atherosclerosis, it does not play a major role in its progression. CaSR has a major influence on endothelium-leukocyte interaction and endothelial inflammation. The increased expression of ICAM/VCAM suggest that CaSR mainly mediates such adhesive effects by modulating integrin expression. Thereby this study highlights that CaSR plays a crucial role in atherosclerosis development, rendering it a novel, so far unexplored therapeutic target.
Aneurysmal cyclic circumferential stretch affects the expression of endothelial genes involved in vascular homeostasis
Authors: Diagbouga MR , Morel S , Lemeille S , Kwak BR
Published: June 2022

Funding Acknowledgements

Type of funding sources: None.

Background

Intracranial aneurysm (IA) rupture is a common cause of hemorrhagic stroke. IAs are present in 3 to 5% of the general population and the annual rupture rate of an IA has been estimated to 1%. Once formed, an IA can rupture immediately, grow before rupturing, or remain stable. Predicting the evolution of an unruptured IA is very difficult. Indeed, the biology of the IA wall is complex and the precise biomechanical processes leading to aneurysm wall rupture are not yet known. While the contribution of wall shear stress in IA disease has been demonstrated in several studies, the role of cyclic circumferential stretch (CCS) remains poorly understood.

Purpose

The levels of CCS in saccular IAs are unknown but are generally considered very low or even absent. The goal of our study was to investigate the transcriptional response of endothelial cells (ECs) to absence of CCS and the potential impact on the endothelium function.

Methods

Human umbilical veins ECs (HUVECs) from 6 different donors were exposed to physiological CCS levels for cerebral arteries (6% stretch) or to aneurysmal CCS (0%) for 48h using the Flexcell strain unit FX-5000T, and unbiased transcriptomics were performed. The expression of selected genes was confirmed by qPCR.

Results

As a validation of our methodology, we verified the induction of eNOS phosphorylation after exposure of the ECs to physiological CCS. Stretched EC samples display a high similarity between each other while EC samples under aneurysmal CCS were spread-out on a multidimensional scaling plot. The differential gene expression of ECs exposed to aneurysmal or physiological CCS revealed 51 up-regulated genes and 49 down-regulated genes in absence of CCS. The gene set enrichment analysis identified 70 up-regulated and 38 down-regulated pathways in HUVECs exposed to aneurysmal CCS. Up-regulated pathways were involved in oxidative stress, angiogenic and inflammatory pathways, and the down-regulated pathways in proliferation and extracellular matrix-receptor interactions. We confirmed by qPCR the down-regulation by aneurysmal CCS of Gja4 and Gja5, genes coding for the gap junction proteins Connexin37 (Cx37) and Connexin40 (Cx40), respectively. Connexins (Cxs) are crucial proteins for endothelial homeostasis, vascular function, endothelial cell cycle regulation and inflammation, and their role in the context of IA disease will be further studied.

Conclusion

Our results indicate that physiological CCS prevents large deviation in ECs and regulate the expression of genes essential for maintaining vascular homeostasis. The down-regulation of endothelial Cx37 and Cx40 under aneurysmal CSS may contribute to the endothelial dysfunction associated with IA progression. Further investigation may help to better define the role of Cxs in aneurysmal disease and to understand the significance of absence of CCS in IA disease progression.
Mitochondrial division inhibitor 1 (mdivi-1) as a potential pharmacological strategy to prevent vascular restenosis
Authors: Crespo-Avilan G , Hernandez-Resendiz S , Ramachandra C , Liehn E , Preissner K , Hausenloy D
Published: June 2022

Funding Acknowledgements

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Singapore National Medical Research Council

Background

New treatments are needed to prevent post-angioplasty and stent restenosis in coronary artery disease (CAD) and peripheral arterial disease (PAD) patients. Accumulated findings have shown that mitochondrial dysfunction is involved in the pathophysiology mechanisms underlying several cardiovascular conditions, however, in the scenario of vascular remodelling after injury, the role of mitochondrial dynamics is not completely understood.

Purpose

In this study, we investigate the effect of mdivi-1 on neointimal hyperplasia and plaque development in a wire-induced endothelial injury animal model.­

Methods

Using ApoE-/- mice on a background of hyperlipidaemia, we investigated weather in vivo administration of mdivi-1 (1.2mg/kg/d) could reduce atherosclerotic plaque volume, plaque complexity and inflammation in a carotid-wire injury model of neointimal hyperplasia. Also, THP-1 monocytes (T-M) and THP-1-derived Macrophages (T-DM) were stimulated in vitro with LPS + IFN-gamma to induce M1 polarization and then subjected to gene expression and protein analysis in the presence or absence of mdivi-1 (50µM). Transmigration and 3D chemotaxis assays were performed in T-M cells and Human peripheral blood monocytes, to evaluate the effect of mdivi-1 on cell migration in response to M-CSF and MCP-1. Finally, we investigated the effects of Mdivi-1 on mitochondrial respiration using Seahorse assay in T-M and T-DM.

Results

In vivo treatment with mdivi-1 reduced neointimal hyperplasia by 37% when compared to control, and was associated with a significant decrease of vascular smooth muscle cells and macrophages cell numbers, as well as reduction of the pro-inflammatory mediators TNF-α and ICAM-1 in the plaque. In vitro M1 polarization of T-M and T-DM induced both up-regulation and production of pro-inflammatory mediators and mdivi-1 significantly suppressed this effects. In addition, monocyte chemotaxis response to M-CSF and MCP-1 was significantly reduced in the presence of mdivi-1. Lastly, mdivi-1 reduced oxygen consumption rate in T-M and T-DM, and prevented M1-cell polarization.

Conclusions

We show that mdivi-1 significantly reduces vessel wall thickness, neointimal hyperplasia, monocyte recruitment, and inflammation after vascular endothelial injury, positioning Mdivi-1 as a potential pharmacological strategy to reduce restenosis following angioplasty and stenting in CAD and PAD patients.
Comparative secretome analysis of obese perivascular adipose tissue reveals impaired adipose-neuronal crosstalk
Authors: Duregotti E , Reumiller C , Mayr U , Hasman M , Schmidt L , Burnap S A , Theofilatos K , Barallobre-Barreiro J , Viviano A , Jahangiri M , Mayr M
Published: June 2022

Funding Acknowledgements

Type of funding sources: Foundation. Main funding source(s): BHF Programme Grant (RG/16/14/32397)

VASCage-Research Center on Vascular Ageing and Stroke (No. 868624)

Background

While canonical adipose tissue (AT) depots have been extensively characterised in health and disease, comparatively little is known about the pathological changes affecting the perivascular AT’s (PVAT) physiology during obesity.

Purpose

The aim of this study was to study the impact of obesity on the secretory activity of the murine PVAT.

Methods

We exploited proteomics to profile the secretome of peri-aortic and canonical AT depots in wild-type (wt) and obese (ob/ob) mice. In parallel, fat tissues were processed for biochemical and histological analysis and mechanistical experiments were performed in vitro on primary neuronal cultures.

Results

Proteomics on ATs conditioned media from wt mice revealed that each fat depot displays a unique secretory profile. The enrichment of neuronal cell-adhesion molecules detected in PVAT secretomes reflected a higher content of intra-parenchymal sympathetic projections compared to non-perivascular ATs. A significant decrease of the same neuronal proteins in PVAT conditioned media from ob/ob mice was found to be associated with a substantial reduction of the perivascular sympathetic innervation. Intriguingly, a similar decrease of sympathetic markers was detected in the epicardial AT from obese patients. Mechanistically, the conditioned media from ob/ob AT explants was found to exert a deleterious effect on the axons of primary sympathetic neurons in vitro, indicating that this neuropathy is due to local alterations of the PVAT secretome that detrimentally impact on the embedded sympathetic neurites. Among proteins significantly down-regulated in the secretomes of ob/ob PVAT samples, neuronal growth regulator 1 (Negr1) was found to promote axonal elongation and branching on sympathetic neurons in vitro. Administration of recombinant Negr1 also partially restored the neurotrophic effect of ob/ob AT secretomes on sympathetic axons both in vitro and in vivo.

Conclusions

Obesity-related alterations in the secretome of PVAT severely affect the homeostasis of the perivascular environment, leading to a loss of perivascular sympathetic innervation. A novel neurotrophic role is unveiled for Negr1, whose locus has been associated with human obesity.
MicroRNAs in circulating microvesicles and plasma as biomarkers that complement the clinical diagnosis of diabetic dyslipidemia and its complications
Authors: Nemecz M , Stefan DS , Constantin A , Procopciuc A , Comarita K , Tanko G , Georgescu A
Published: June 2022

Funding Acknowledgements

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Research funded by grants of the Romanian Ministry of Education and Research, CNCS-UEFISCDI, project no. PN-III-P1-1.2-PCCDI-2017–0527 (Contract no. 83PCCDI/2018), project no. PN-III-P1-1.1-TE-2019–0811, within PNCDI III” (Contract no. TE 97/2020)

Background

Dislypidemia is a major risk factor for cardiovascular diseases as well as for diabetes where often leads to severe microvascular complications. Reportedly, microRNAs (miRNAs) associated with microvesicles (MVs) regulate cellular mechanisms in the progression of diabetic dyslipidemia. We hypothesised that detection of the changes in plasma MV components could be used as early biomarkers to prevent the irreversible effects of diabetic dyslipidemia. Purpose: of this study was to search whether in diabetic dyslipidemia with/without microvascular complications there are modifications of the circulating MVs and plasma miRNAs and whether these changes could be predictive of the disease evolution.

Methods

Plasma/sera was collected from diabetic patients with dyslipidemia with/without microvascular complications and the main parameters and the inflammatory markers were assessed. Results showed that, compared to either diabetes or dyslipidemia alone, in the diabetic dyslipidemic patients, significant increases in plasma glucose, cholesterol, LDL-cholesterol, triglyceride concentrations, systolic blood pressure were present. In addition, high levels of circulating IL-6 and MVs-derived from endothelial cells (CD144+), platelets (CD41+), macrophages (CD14+), and leucocytes (CD18+) were detected. Significant changes were found in plasma miRNAs and MV-associated miRNAs: 122,-132,-143,-200b,-212, decreased miR-34a,-155,-218 expressions in MVs, and reduced miR-21,-34a,-132,-143 expressions in plasma. Notably, when microvascular complications were associated to diabetic dyslipidemia, we found significant changes such as increased expression of miR-21,-34a,-122,-126,-143,-218,-223 in MV and plasma miR-143,-132 and decreased miR-200b,-212 in MVs and plasma miR-223.

Conclusion

In patients with diabetic dyslipidemia and, in particular, with diabetic dyslipidemia associated with microvascular complications, a significant modification in the plasma MV content and miRNAs occur suggesting that they could turn into biomarkers and potential diagnostic tool for diabetic dyslipidemia and its complications.
Alterations in coronary resistance artery network geometry in diabetes and the role of Tenascin C
Authors: Aykac I
Published: June 2022

Funding Acknowledgements

Type of funding sources: None.

Background and Aims: Geometrical alterations in the coronary resistance artery network and potential involvement of the Tenascin C (TNC) protein were examined in diabetic mice.

Methods

Diabetes was induced by streptozotocin injections (n=7-11 animals in each group) in Wild type (A/J) and Tenascin C KO (TNC KO) mice, and 16-18 weeks later the heart was removed and the whole subsurface network of the left coronary artery was microprepared (down to branches of 40 µm outer diameter), in situ pressure-perfused and studied using video-microscopy. Outer and inner diameters, wall thicknesses and bifurcation angles were measured on whole network pictures reconstructed into collages at 1.7 µm pixel resolutions.

Results

Diabetic networks featured abnormal morphological alterations including trifurcations, sharp bends of larger branches, and branches directed in the retrograde direction (p<0.001 by the χ2 test). Networks of TNC KO mice tended to form early divisions producing parallel running larger branches (p<0.001 by the χ2 probe). Diabetic networks were substantially more abundant in 100-180 µm components, appearing in 2-5 mm flow distance from orifice. This was accompanied by thickening of the wall of larger arterioles (>220 µm) and thinning of the wall of a population of smaller (100-140 µm) arterioles (p<0.001). Interestingly, diabetes model by STZ-injection did not induce further geometrical changes in TNC KO mice. Blood flow should cover larger distances in diabetic networks.

Conclusion

In diabetic mice, a combined network remodelling of the coronary vasculature was observed with hypertrophic and hypotrophic remodelling and vasculogenesis at well defined, specific positions of the network. TNC plays an important role in the formation of network geometry, and TNC knockout induces parallel fragmentation preventing diabetes-induced abnormal vascular morphologies
Transition for transduction: how to make cardiac endothelial cells more permissive to AAV
Authors: Volf N , Ring N , Colliva A , Vuerich R , Braga L , Zentilin L , Zacchigna S
Published: June 2022

Funding Acknowledgements

Type of funding sources: None.

Introduction

Despite major attempts aiming to revascularize an ischemic heart, prognosis of cardiac ischemia remains poor. A major obstacle for the induction of new blood vessels, referred as therapeutic angiogenesis, is inefficient gene transfer in cardiac endothelial cells (ECs). This poor permissiveness to genetic modification is a limiting step in studies of pathological conditions with inadequate, but also with increased vascularization. To study the function of a specific gene and its potential implications in angiogenesis, the most straightforward approach would be to either overexpress or silence it in ECs. We and others have tested multiple protocols for either transfection and transduction of primary ECs in vitro and in vivo, with no success. Vectors based on Adeno-associated virus (AAV) and Lentivirus (LV) stand as ideal tools for gene delivery, however they do not work in cardiac ECs.

Purpose

To enhance the permissiveness of EC, we optimized and performed high-throughput screening on adult cardiac ECs using a library of FDA approved drugs, to search for compounds increasing transduction by AAV6 and LV, with the final aim to identify the major determinants inhibiting genetic modification of ECs.

Methods

Cardiac ECs were isolated from 2 months old C57BL/6 mice and plated on 384-well plates. After 48 hours, the FDA drug library (> 1500 compounds)  was added  together with  AAV6-dsRed and LV-GFP. Cells were fixed with 4% PFA 72 hours post-transduction, and subsequently stained for the EC marker ERG. The levels of AAV6-dsRed, LV-GFP and ERG expression were assessed by automated, high-content microscopy.

Results

After two rounds of screening at different drug concentrations, we obtained a list of candidate compounds able to increase adult cardiac EC transduction by either AAV6 or LV over two folds. Among these, our best hit increasing AAV6-mediated transduction was Vatalanib, a tyrosine kinase inhibitor acting on VEGFRs, PDGFR, and c-Kit. Valatanib not only increased permissiveness to AAV6, but it also changed the morphology of the cells, which became elongated and similar to mesenchymal cells. This suggested ongoing endothelial mesenchymal transition (EndMT), which was verified by decreased CD31 and increased α-SMA expression. Interestingly, AAV mostly transduced cells with the lowest CD31 expression.

Conclusions

Our high-throughput screening identified Vatalanib as the most potent drug in increasing permissiveness of cardiac ECs to AAV transduction. Because the drug induced loss of CD31 and gain in α-SMA, we hypothesized that the reason for increased permissiveness was EndMT. This hypothesis is consistent with the known mechanism of action of Valatanib, which inhibits VEGFR2 and thus interferes with VEGF signalling, that in turn is essential to maintain EC identity.
Correction of myocardial changes on an animal experimental model with meldonim
Authors: Yarmolenko O , Bumeister V , Prykhodko O , Gordienko O , Demikhova N
Published: June 2022

Funding Acknowledgements

Type of funding sources: None.

Prolonged hypoosmolar overhydration causes a volume overload necessitating cardioprotectors together with a complex of measures aimed at stabilizing the water and electrolyte balance. The content of water and electrolytes in the human body changes throughout life, so the body's response to the disorder of water and salt balance may be different depending on age. The fluid overload positively correlates with adverse outcomes in critically ill patients. One of the main tasks of modern cardiology is to find the means of leveling the influence of adverse factors on myocardium in different aged patients.

The aim of our study was the determination of morphological changes in the myocardium of old laboratory animals under the influence of severe hypoosmolar hyperhydration and attempt to correct the identified changes by means of meldonium.

Materials and methods

The experiment was conducted in accordance with the "European Convention of the Protection of Vertebrate Animals used for Experimental and other Scientific Purposes" (Strasbourg, 1986). 18 rats at the age of 22 months were divided into 3 series: 2 experimental and 1 control (6 in each). Animals of the first experimental series were modeling severe hypoosmolar hyperhydration by introduction of 10 ml distilled water three times a day through a tube during 25 days. Animals ate boiled unsalted food and were injected a synthetic analogue of antidiuretic hormone "Minirin" (Ferring) with drinking water 2 times a day at a dose 0.01 mg. In addition, the rats of the second experimental series were injected with meldonium intraperitoneally at a dose of 50 mg/kg once a day throughout the entire experiment. The animals of control series received normal drinking water and food and were injected the "Mynyrin"(Ferring) twice a day at a dose of 0.01 mg, considering the potential effects of vasopressin on the cardiovascular system. We measured the diameter of cardiomyocytes (DCMC) of both ventricles, the relative amount of cardiomyocytes (RACMC), connective tissue (RACT), and vessels (RAV), stromal-parenchymal ratio in the ventricles by the formula (RACT+RAV)/RACMC.

Results

In myocardium of rats administered meldonium, only isolated stromal hemorrhage are noted, while in myocardial samples of the first experimental series there are numerous hemorrhages. DCMC of left ventricle and DCMC of right ventricle are greater than control at 13.18% (p<0.0001) and 12.27% (p<0.0001) respectively. RAV does not change. RACT of left ventricle and RACT of right ventricle increase respectively by 3.72% (p=0.0060) and 5.23% (p <0.0001). RACMC of right ventricle is smaller than the control parameter by 0.63% (p = 0.0015).

Conclusion

In old animals, meldonium improves the vascular component of the myocardium. However, we have not found the positive effect of the drug on other studied parameters.
Vascular graft storage solution preserves endothelial function
Authors: Winkler B , Szabo PL , Dostal C , Arnold Z , Geisler D , Crailsheim I , Folkmann S , Grabenwoeger M , Podesser BK , Kiss A
Published: June 2022

Funding Acknowledgements

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Karl Landsteiner Institute Cardiovascular Research

Background

Saline is still the most widely used storage and flushing solution in cardiovascular procedures despite knowing evidence of its influence on the human endothelial cell function. Aim of this study was to assess the effect of DuraGraft©, an intraoperative graft treatment solution, on human saphenous vein segments, rat aortic segments and human umbilical vein endothelial cells (HUVECs) in comparison to saline.

Methods

Within 12 patients undergoing aortocoronary bypass surgery, saphenous vein graft segments were randomized to DuraGraft© (n=12/6) or saline (n=12/6) solution before intraoperative storage. These segments as well as rat aortic segments underwent assessment of vascular function in a multichamber isometric myograph system in comparison to Krebs-Henseleit solution (KHS), a physiologic organ buffer solution. Additionally, human umbilical vein endothelial cells (HUVECs) were used for cell viability tests.

Results

KCl-induced contraction showed a tendency toward increase when treated with DuraGraft© compared to normal saline preservation of human vein segments (24.73±16.22 vs. 15.59±9.53 N/m2, P

Conclusion

DuraGraft© demonstrated a favorable effect on graft relaxation and contraction indicating preservation of vascular endothelial function. Saline is clearly not only inferior to this specialized solution but may show additional harmful effects to viability.
Tip detection-antegrade dissection and reentry using intravascular ultrasound in chronic total occlusion intervention: first human case report
Authors: Suzuki Satoshi , Okamura Atsunori , Nagai Hiroyuki , Iwakura Katsuomi
Published: June 2022

Background

It has been considered impossible to perform antegrade dissection and reentry (ADR) by simply puncturing with a guidewire using the intravascular ultrasound (IVUS) observation without the support of the Stingray system.

Case summary

A 78-year-old man suffered from effort angina pectoris due to a chronic total occlusion (CTO) lesion in the left circumflex coronary artery. A retry percutaneous coronary intervention for the CTO lesion was attempted at our hospital. The J-CTO score was 3. The first guidewire entered the subintimal space. We moved onto Stingray-ADR using the angiographic observation, but the guidewire could not be led into the true lumen. AnteOwl WR-IVUS (AO-IVUS) observation revealed a distal true lumen in which the inner lumen was maintained 5 mm beyond the CTO exit. We decided to perform the tip detection-ADR using the AO-IVUS observation. The tip detection method allowed the tip of the penetration wire to puncture the wall between the subintima and the true lumen in an exactly vertical direction, resulting in the successful creation of a reentry point. The CTO lesion was dilated with one drug-eluting stent, and normal antegrade blood flow was achieved.

Discussion

Since the tip detection method enables accurate punctures, it may allow for ADR by simply puncturing using a guidewire. Due to this method being performed using the IVUS observation, it is likely more reliable than Stingray-ADR using the angiographic observation.
Percutaneous extraction of a malpositioned subclavian arterial pacing lead using the retained wire technique and a vascular closure device: a case report
Authors: Ng Primero , Paul Vince , Shetty Sharad , Lambert James
Published: June 2022

Background

Inadvertent lead malposition (ILM) in the left ventricle (LV) via the subclavian artery is a rare complication during the insertion of cardiac implantable electronic devices (CIED). If not identified, there is a risk of systemic thromboembolism. Transarterial pacing lead extraction often requires surgical removal and carries high risks of bleeding and thromboembolism, but percutaneous extraction has also been previously described.

Case summary

A 71-year-old female presented with left homonymous hemianopia on Day 1 post-insertion of a dual-chamber permanent pacemaker (PPM). A computed tomography (CT) angiogram of the brain and aortic arch revealed an acute occlusion of a branch of the right posterior circulating artery (PCA) and a malpositioned pacing lead in the left subclavian artery. Urgent percutaneous removal of the transarterial lead using the retained wire technique was successfully performed.

Discussion

Inadvertent lead malposition in the arterial system is rare and often requires lead extraction due to systemic thromboembolic complications. The retained wire technique has been previously described for percutaneous transvenous lead extraction and exchange, but to our knowledge, we are the first to report utilizing this technique for transarterial lead extraction. Using a case report, we highlight the utility, safety, and effectiveness of the retained wire technique in extracting a malposition lead in the subclavian artery and LV.
Empagliflozin and serum potassium in heart failure: an analysis from EMPEROR-Pooled
Authors: Ferreira João Pedro , Zannad Faiez , Butler Javed , Filipattos Gerasimos , Ritter Ivana , Schüler Elke , Kraus Bettina J , Pocock Stuart J , Anker Stefan D , Packer Milton
Published: June 2022

Aims

Hyperkalaemia frequently leads to interruption and discontinuation of neurohormonal antagonists, which may worsen heart failure prognosis. Some studies suggested that sodium-glucose cotransporter 2 inhibitors reduce hyperkalaemia, an effect that may have important clinical implications. This analysis evaluates the effect of empagliflozin on the occurrence of hyper- and hypokalaemia in HF.

Methods and results

EMPEROR-Pooled (i.e. EMPEROR-Reduced and EMPEROR-Preserved combined) included 9583 patients with available serum potassium levels at baseline (98.6% of the total EMPEROR-Pooled population, n = 9718). Hyperkalaemia was identified by investigators’ reports of adverse events, and by a laboratory serum potassium value above 5.5 mmol/L and 6.0 mmol/L. The main outcome was a composite of investigator-reported hyperkalaemia or initiation of potassium binders. Patients with high potassium at baseline were more frequently diagnosed with diabetes and ischaemic HF aetiology and had lower left ventricular ejection fraction and estimated glomerular filtration rate but were more frequently treated with sacubitril/valsartan or mineralocorticoid receptor antagonists. Empagliflozin (compared with placebo) reduced the composite of investigator-reported hyperkalaemia or initiation of potassium binders [6.5% vs. 7.7%, hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.71–0.95, P = 0.01]. Empagliflozin reduced hyperkalaemia rates regardless of the definition used (serum potassium >5.5 mmol/l: 8.6% vs. 9.9%, HR 0.85, 95% CI 0.74–0.97, P = 0.017; serum potassium >6.0 mmol/l: 1.9% vs. 2.9%, HR 0.62, 95% CI 0.48–0.81, P < 0.001). The incidence of hypokalaemia (investigator-reported or serum potassium <3.0 mmol/l) was not significantly increased with empagliflozin.

Conclusions

Empagliflozin reduced the incidence of hyperkalaemia without significant increase in hypokalaemia.
Assembly of complete diploid-phased chromosomes from draft genome sequences
Authors: Minio Andrea , Cochetel Noé , Vondras Amanda M , Massonnet Mélanie , Cantu Dario
Published: June 2022

De novo genome assembly is essential for genomic research. High-quality genomes assembled into phased pseudomolecules are challenging to produce and often contain assembly errors because of repeats, heterozygosity, or the chosen assembly strategy. Although algorithms that produce partially phased assemblies exist, haploid draft assemblies that may lack biological information remain favored because they are easier to generate and use. We developed HaploSync, a suite of tools that produces fully phased, chromosome-scale diploid genome assemblies, and performs extensive quality control to limit assembly artifacts. HaploSync scaffolds sequences from a draft diploid assembly into phased pseudomolecules guided by a genetic map and/or the genome of a closely related species. HaploSync generates a report that visualizes the relationships between current and legacy sequences, for both haplotypes, and displays their gene and marker content. This quality control helps the user identify misassemblies and guides Haplosync’s correction of scaffolding errors. Finally, HaploSync fills assembly gaps with unplaced sequences and resolves collapsed homozygous regions. In a series of plant, fungal, and animal kingdom case studies, we demonstrate that HaploSync efficiently increases the assembly contiguity of phased chromosomes, improves completeness by filling gaps, corrects scaffolding, and correctly phases highly heterozygous, complex regions.
Impact of social determinants of health on improving the LACE index for 30-day unplanned readmission prediction
Authors: Belouali Anas , Bai Haibin , Raja Kanimozhi , Liu Star , Ding Xiyu , Kharrazi Hadi
Published: June 2022

Objective

Early and accurate prediction of patients at risk of readmission is key to reducing costs and improving outcomes. LACE is a widely used score to predict 30-day readmissions. We examine whether adding social determinants of health (SDOH) to LACE can improve its predictive performance.

Methods

This is a retrospective study that included all inpatient encounters in the state of Maryland in 2019. We constructed predictive models by fitting Logistic Regression (LR) on LACE and different sets of SDOH predictors. We used the area under the curve (AUC) to evaluate discrimination and SHapley Additive exPlanations values to assess feature importance.

Results

Our study population included 316 558 patients of whom 35 431 (11.19%) patients were readmitted after 30 days. Readmitted patients had more challenges with individual-level SDOH and were more likely to reside in communities with poor SDOH conditions. Adding a combination of individual and community-level SDOH improved LACE performance from AUC = 0.698 (95% CI [0.695–0.7]; ref) to AUC = 0.708 (95% CI [0.705–0.71]; P < .001). The increase in AUC was highest in black patients (+1.6), patients aged 65 years or older (+1.4), and male patients (+1.4).

Discussion

We demonstrated the value of SDOH in improving the LACE index. Further, the additional predictive value of SDOH on readmission risk varies by subpopulations. Vulnerable populations like black patients and the elderly are likely to benefit more from the inclusion of SDOH in readmission prediction.

Conclusion

These findings provide potential SDOH factors that health systems and policymakers can target to reduce overall readmissions.
Mechanical and fluid characteristics of triply periodic minimal surface bone scaffolds under various functionally graded strategies
Authors: Karuna Chatchai , Poltue Teerapong , Khrueaduangkham Suppakrit , Promoppatum Patcharapit
Published: June 2022

A laser powder bed fusion additive manufacturing has enabled the fabrication of triply periodic minimal surface (TPMS). These structures are widely acknowledged for their suitability in bone implant applications. Nevertheless, although it is essential for TPMS-based implants to exhibit graded features to mimic those of natural bones for desirable functionality, the effect of graded features on mechanical properties, flow behavior, and geometrical morphologies requires further clarification. As a result, this study carried out a comprehensive numerical and experimental assessment on the impact of graded IWP structures on the effective elastic modulus, Gaussian curvature, permeability, and fluid-induced wall shear stress. Among various TPMS architectures, the IWP structure was chosen to be explored in this work owing to its favorable physical responses for bone tissue ingrowth as reported in the literature. Overall, we found that the grading features had a considerable impact on the global response such as the effective modulus and fluid permeability. However, the local response such as Gaussian curvatures and fluid-induced wall shear stress was significantly less affected.
The intrinsic reddening of the Magellanic Clouds as traced by background galaxies – III. The Large Magellanic Cloud
Authors: Bell Cameron P M , Cioni Maria-Rosa L , Wright Angus H , Nidever David L , Chiang I-Da , Choudhury Samyaday , Groenewegen Martin A T , Pennock Clara M , Choi Yumi , de Grijs Richard , Ivanov Valentin D , Massana Pol , Nanni Ambra , Noël Noelia E D , Olsen Knut , van Loon Jacco Th , Vivas A Katherina , Zaritsky Dennis
Published: June 2022

We present a map of the total intrinsic reddening across ≃ 90 deg2 of the Large Magellanic Cloud (LMC) derived using optical (ugriz) and near-infrared (IR; YJKs) spectral energy distributions (SEDs) of background galaxies. The reddening map is created from a sample of 222 752 early-type galaxies based on the lephareχ2 minimization SED-fitting routine. We find excellent agreement between the regions of enhanced intrinsic reddening across the central (4 × 4 deg2) region of the LMC and the morphology of the low-level pervasive dust emission as traced by far-IR emission. In addition, we are able to distinguish smaller, isolated enhancements that are coincident with known star-forming regions and the clustering of young stars observed in morphology maps. The level of reddening associated with the molecular ridge south of 30 Doradus is, however, smaller than in the literature reddening maps. The reduced number of galaxies detected in this region, due to high extinction and crowding, may bias our results towards lower reddening values. Our map is consistent with maps derived from red clump stars and from the analysis of the star formation history across the LMC. This study represents one of the first large-scale categorizations of extragalactic sources behind the LMC and as such we provide the lephare outputs for our full sample of ∼ 2.5 million sources.
Recombination Landscape Divergence Between Populations is Marked by Larger Low-Recombining Regions in Domesticated Rye
Authors: Schreiber Mona , Gao Yixuan , Koch Natalie , Fuchs Joerg , Heckmann Stefan , Himmelbach Axel , Börner Andreas , Özkan Hakan , Maurer Andreas , Stein Nils , Mascher Martin , Dreissig Steven
Published: June 2022

The genomic landscape of recombination plays an essential role in evolution. Patterns of recombination are highly variable along chromosomes, between sexes, individuals, populations, and species. In many eukaryotes, recombination rates are elevated in sub-telomeric regions and drastically reduced near centromeres, resulting in large low-recombining (LR) regions. The processes of recombination are influenced by genetic factors, such as different alleles of genes involved in meiosis and chromatin structure, as well as external environmental stimuli like temperature and overall stress. In this work, we focused on the genomic landscapes of recombination in a collection of 916 rye (Secale cereale) individuals. By analyzing population structure among individuals of different domestication status and geographic origin, we detected high levels of admixture, reflecting the reproductive biology of a self-incompatible, wind-pollinating grass species. We then analyzed patterns of recombination in overlapping subpopulations, which revealed substantial variation in the physical size of LR regions, with a tendency for larger LR regions in domesticated subpopulations. Genome-wide association scans (GWAS) for LR region size revealed a major quantitative-trait-locus (QTL) at which, among 18 annotated genes, an ortholog of histone H4 acetyltransferase ESA1 was located. Rye individuals belonging to domesticated subpopulations showed increased synaptonemal complex length, but no difference in crossover frequency, indicating that only the recombination landscape is different. Furthermore, the genomic region harboring rye ScESA1 showed moderate patterns of selection in domesticated subpopulations, suggesting that larger LR regions were indirectly selected during domestication to achieve more homogeneous populations for agricultural use.
Successful treatment with tofacitinib for relapse of rapidly progressive interstitial lung disease in anti-melanoma differentiation-associated gene 5 antibody-positive clinically amyopathic dermatomyositis
Authors: Hama Satoshi , Akiyama Mitsuhiro , Higashida-Konishi Misako , Oshige Tatsuhiro , Takei Hiroshi , Izumi Keisuke , Oshima Hisaji , Okano Yutaka
Published: June 2022

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody is associated with clinically amyopathic dermatomyositis (CADM) with rapidly progressive interstitial lung disease (RP-ILD). Recently, several studies have reported that tofacitinib (TOF), a Janus kinase inhibitor, might be effective for cases of new or refractory RP-ILD in anti-MDA5 antibody-positive CADM; however, it is unknown whether TOF can also be effective for relapsed cases. We herein report a relapsed case of RP-ILD in anti-MDA5 antibody-positive CADM, which was successfully treated by combination therapy with TOF (5 mg twice daily). Our case suggests that TOF may also be a potential treatment option for relapsed cases of this disease.
Schlafen 5 suppresses human immunodeficiency virus type 1 transcription by commandeering cellular epigenetic machinery
Authors: Ding Jiwei , Wang Shujie , Wang Zhen , Chen Shumin , Zhao Jianyuan , Solomon Magan , Liu Zhenlong , Guo Fei , Ma Ling , Wen Jiajia , Li Xiaoyu , Liang Chen , Cen Shan
Published: June 2022

Schlafen-5 (SLFN5) is an interferon-induced protein of the Schlafen family, which are involved in immune responses and oncogenesis. To date, little is known regarding its anti-HIV-1 function. Here, the authors report that overexpression of SLFN5 inhibits HIV-1 replication and reduces viral mRNA levels, whereas depletion of endogenous SLFN5 promotes HIV-1 replication. Moreover, they show that SLFN5 markedly decreases the transcriptional activity of HIV-1 long terminal repeat (LTR) via binding to two sequences in the U5-R region, which consequently represses the recruitment of RNA polymerase II to the transcription initiation site. Mutagenesis studies show the importance of nuclear localization and the N-terminal 1–570 amino acids fragment in the inhibition of HIV-1. Further mechanistic studies demonstrate that SLFN5 interacts with components of the PRC2 complex, G9a and Histone H3, thereby promoting H3K27me2 and H3K27me3 modification leading to silencing HIV-1 transcription. In concert with this, they find that SLFN5 blocks the activation of latent HIV-1. Altogether, their findings demonstrate that SLFN5 is a transcriptional repressor of HIV-1 through epigenetic modulation and a potential determinant of HIV-1 latency.
(NH4)3B11PO19F3: a deep-UV nonlinear optical crystal with unique [B5PO10F]∞ layers
Authors: Cheng Bingliang , Li Zijian , Chu Yu , Tudi Abudukadi , Mutailipu Miriding , Zhang Fangfang , Yang Zhihua , Pan Shilie
Published: June 2022

Deep-ultraviolet (DUV) nonlinear optical (NLO) crystals that can extend the output range of coherent light below 200 nm are pivotal materials for solid-state lasers. To date, KBe2BO3F2 (KBBF) is the only usable crystal that can generate DUV coherent light by direct second harmonic generation (SHG), but the layered growth habit and toxic ingredients limit its application. Herein, we report a new fluoroborophosphate, (NH4)3B11PO19F3 (ABPF), containing four different functional units: [BO3], [BO4], [BO3F] and [PO4]. ABPF exhibits a KBBF-like structure while eliminating the limitations of KBBF crystal. The unique [B5PO10F]∞ layers enhance ABPF’s performance; for example, it has a large SHG response (1.2 × KDP) and a sufficient birefringence (0.088 at 1064 nm) that enables the shortest phase-matching wavelength to reach the DUV region. Meanwhile, the introduction of strong B-O-P covalent bonds decreases the layered growth habit. These findings will enrich the structural chemistry of fluoroborophosphate and contribute to the discovery of more excellent DUV NLO crystals.
Pediatric Tularemia—A Case Series From a Single Center in Switzerland
Authors: Schöbi Nina , Agyeman Philipp K A , Duppenthaler Andrea , Bartenstein Andreas , Keller Peter M , Suter-Riniker Franziska , Schmidt Kristina M , Kopp Matthias V , Aebi Christoph
Published: June 2022

Background

The incidence of tularemia has recently increased throughout Europe. Pediatric tularemia typically presents with ulceroglandular or glandular disease and requires antimicrobial therapy not used in the empirical management of childhood acute lymphadenitis. We describe the clinical presentation and course in a case series comprising 20 patients.

Methods

This is a retrospective analysis of a single-center case series of microbiologically confirmed tularemia in patients <16 years of age diagnosed between 2010 and 2021.

Results

Nineteen patients (95%) presented with ulceroglandular (n = 14) or glandular disease (n = 5), respectively. A characteristic entry site lesion (eschar) was present in 14 (74%). Fever was present at illness onset in 15 patients (75%) and disappeared in all patients before targeted therapy was initiated. The diagnosis was confirmed by serology in 18 patients (90%). While immunochromatography was positive as early as on day 7, a microagglutination test titer 1:≥160 was found no earlier than on day 13. Sixteen patients (80%) were initially treated with an antimicrobial agent ineffective against F. tularensis. The median delay (range) from illness onset to initiation of targeted therapy was 12 (6–40) days. Surgical incision and drainage were ultimately performed in 12 patients (60%).

Conclusions

Pediatric tularemia in Switzerland usually presents with early, self-limiting fever and a characteristic entry site lesion with regional lymphadenopathy draining the scalp or legs. Particularly in association with a tick exposure history, this presentation may allow early first-line therapy with an agent specifically targeting F. tularensis, potentially obviating the need for surgical therapy.