Sleep-disordered breathing in children and adults with intellectual disability: mind the gap!

BACKGROUND: In adults and children with intellectual disability (ID), sleep -disordered breathing (SDB) is thought to be common. However, large epidemiological studies are lacking, and there are few studies on optimal methods of investigation and even fewer randomised, controlled intervention trials of treatment. METHOD: Peer-reviewed publications from various databases were examined in line with search terms relevant to ID and SDB spanning the years 200-2024. RESULTS: Findings suggest that, due to comorbid conditions, children and adults with ID may experience both an increased risk of SDB, as well as lower frequency of diagnosis. SDB can compromise the emotional, physical and mental health of individuals with ID. Appropriate treatment when tolerated leads to an improvement in health and well-being and several studies emphasized the importance of consistent follow-up of people with ID - something that is not universally occurring during childhood, in the transition to adulthood and during adulthood itself. As the most frequently occurring form of ID worldwide, we use Down syndrome as a specific example of how diagnosing and treating SDB can lead to improved outcomes. CONCLUSIONS: This review highlights the importance of identifying SDB in this heterogenous population, recognising the multi-faceted, deleterious consequences of untreated SDB in people with ID, and presents some strategies that can be harnessed to improve diagnosis and management. Until further ID-specific research is available, we urge flexibility in the approach to people with ID and SDB based in guidelines and standard practice developed for the typically developing population.

The convexity condition of density-functional theory.

It has long been postulated that within density-functional theory (DFT), the total energy of a finite electronic system is convex with respect to electron count so that 2Ev[N0] ≤ Ev[N0 - 1] + Ev[N0 + 1]. Using the infinite-separation-limit technique, this Communication proves the convexity condition for any formulation of DFT that is (1) exact for all v-representable densities, (2) size-consistent, and (3) translationally invariant. An analogous result is also proven for one-body reduced density matrix functional theory. While there are known DFT formulations in which the ground state is not always accessible, indicating that convexity does not hold in such cases, this proof, nonetheless, confirms a stringent constraint on the exact exchange-correlation functional. We also provide sufficient conditions for convexity in approximate DFT, which could aid in the development of density-functional approximations. This result lifts a standing assumption in the proof of the piecewise linearity condition with respect to electron count, which has proven central to understanding the Kohn-Sham bandgap and the exchange-correlation derivative discontinuity of DFT.

Long-term Outcomes Are Poor in Intravenous Drug Users Following Infective Endocarditis, Even After Surgery.

BACKGROUND: Previous studies of outcomes in people who inject drugs (PWID) with infective endocarditis (IE) have often been retrospective, have had small sample sizes, and the duration of follow-up has been short and limited to patients who were operated on. METHODS: PWID treated for IE between 1 January 2006 and 31 December 2016 were identified from a prospectively collected database. PWID hospitalized with other infections acted as a novel comparison group. Outcomes were all-cause mortality, cause of death, relapse, recurrence, and reoperation. RESULTS: There were 105 episodes of IE in 92 PWID and 112 episodes of other infections in 107 PWID in whom IE was suspected but rejected. Survival at 30 days for the IE group was 85%, and 30-day survival following surgery was 96%. The most common pathogens were Staphylococcus species (60%) and Streptococcus species (30%). The surgical intervention rate was 47%. Survival for the IE group at 1, 3, 5, and 10 years was 74%, 63%, 58%, and 44%, respectively. This was significantly lower compared with the comparator group of other infections in PWID (P = .0002). Mortality was higher in patients who required surgery compared with those who did not (hazard ratio, 1.8 [95% confidence interval, .95-3.3]). The commonest cause of death was infection (66%), usually a further episode of IE (55%). CONCLUSIONS: Although early survival was good, long-term life expectancy was low. This was attributable to ongoing infection risk, rather than other factors known to affect prognosis in PWID. Surgery conferred no long-term survival advantage. More efforts are needed to reduce reinfection risk following an episode of IE in PWID.While early survival for people who inject drugs (PWID) with infective endocarditis is good, long-term survival is poor due to ongoing infection risk. Surgery conferred no long-term survival advantage, so more efforts are needed to reduce reinfection risks for PWID.

The ONETEP linear-scaling density functional theory program.

We present an overview of the onetep program for linear-scaling density functional theory (DFT) calculations with large basis set (plane-wave) accuracy on parallel computers. The DFT energy is computed from the density matrix, which is constructed from spatially localized orbitals we call Non-orthogonal Generalized Wannier Functions (NGWFs), expressed in terms of periodic sinc (psinc) functions. During the calculation, both the density matrix and the NGWFs are optimized with localization constraints. By taking advantage of localization, onetep is able to perform calculations including thousands of atoms with computational effort, which scales linearly with the number or atoms. The code has a large and diverse range of capabilities, explored in this paper, including different boundary conditions, various exchange-correlation functionals (with and without exact exchange), finite electronic temperature methods for metallic systems, methods for strongly correlated systems, molecular dynamics, vibrational calculations, time-dependent DFT, electronic transport, core loss spectroscopy, implicit solvation, quantum mechanical (QM)/molecular mechanical and QM-in-QM embedding, density of states calculations, distributed multipole analysis, and methods for partitioning charges and interactions between fragments. Calculations with onetep provide unique insights into large and complex systems that require an accurate atomic-level description, ranging from biomolecular to chemical, to materials, and to physical problems, as we show with a small selection of illustrative examples. onetep has always aimed to be at the cutting edge of method and software developments, and it serves as a platform for developing new methods of electronic structure simulation. We therefore conclude by describing some of the challenges and directions for its future developments and applications.

How to stich? 90 degrees: The perfect angle.

OBJECTIVE: This is a discussion about correct suturing techniques and implications that follow inappropriate suturing. We deconstruct the suturing needle angles and methods to be adopted to acquire the perfect needle angle to the tissue being sutured. A study of angles confirms that 90° is perceptible to the naked eye and easy to identify, making it an appropriate foundation to explain, communicate and teach the concepts in the wet-lab and the operating room. BACKGROUND: There is a lack of robust teaching regarding entry of the needle orthogonal to the tissue planes. In addition, objective methods of assessing angles of the needle relative to the tissue and consequences of inaccuracy are lacking. The authors aim to deconstruct the steps of suturing with the aim of demonstrating ninety degrees is the perfect suturing angle. STUDY DESIGN: We conducted a study to identify 90° (the perfect suturing angle) as an angle easy to identify with the naked eye. Angles from 86° to 94° and 41° to 49° were printed and presented to volunteers with the instruction to identify the angles of 90° and 45°. RESULTS: Fifty-one volunteers replied to the 90° angle study and sixty-five volunteers replied to the 45° study. 92% correctly identified at least one 90° angle and 72% identified both the 90° angles. 63% identified at least one 45° angle and only 27% identified both the 45° angles presented to them. This supported our hypothesis that 90° is an angle that is readily identifiable to the human eye. CONCLUSIONS: Objective assessment of surgical skills and training should focus on the basic needle skills with particular emphasis on suturing angles, progressing to higher skills using low and intermediate fidelity models and correlating practice alongside the trainees' operative progress.

Video polysomnographic findings in non-rapid eye movement parasomnia.

Although video polysomnography (vPSG) is not routinely recommended for the evaluation of typical cases of non-rapid eye movement (NREM) parasomnias, it can aid diagnosis of unusual cases, other sleep disorders and complicated cases with REM behaviour disorder (RBD), and in differentiating parasomnias from epilepsy. In this study, we aimed to assess vPSG findings in consecutive patients with a clinical diagnosis of NREM-parasomnia covering the whole phenotypic spectrum. Five hundred and twelve patients with a final diagnosis of NREM parasomnia who had undergone vPSG were retrospectively identified. vPSGs were analysed for features of NREM parasomnia and for the presence of other sleep disorders. Two hundred and six (40.0%) patients were clinically diagnosed with sleepwalking, 72 (14.1%) with sleep terrors, 39 (7.6%) with confusional arousals, 15 (2.9%) with sexsomnia, seven (1.4%) with sleep-related eating disorder, 122 (23.8%) with mixed phenotype, and 51 (10.0%) with parasomnia overlap disorder (POD). The vPSG supported the diagnosis of NREM parasomnia in 64.4% of the patients and of POD in 98%. In 28.9% of the patients, obstructive sleep apnea (OSA) or/and periodic limb movements during sleep (PLMS) were identified, most commonly in older, male, sleepy and obese patients. vPSG has a high diagnostic yield in patients with NREM parasomnia and should be routinely performed when there is diagnostic doubt, or in patients where there is a suspicion of OSA and PLMS.

MicroRNA-21 drives the switch to a synthetic phenotype in human saphenous vein smooth muscle cells.

Cardiovascular disease is a leading cause of morbidity and mortality. Smooth muscle cells (SMC) comprising the vascular wall can switch phenotypes from contractile to synthetic, which can promote the development of aberrant remodelling and intimal hyperplasia (IH). MicroRNA-21 (miR-21) is a short, non-coding RNA that has been implicated in cardiovascular diseases including proliferative vascular disease and ischaemic heart disease. However, its involvement in the complex development of atherosclerosis has yet to be ascertained. Smooth muscle cells (SMC) were isolated from human saphenous veins (SV). miR-21 was over-expressed and the impact of this on morphology, proliferation, gene and protein expression related to synthetic SMC phenotypes monitored. Over-expression of miR-21 increased the spread cell area and proliferative capacity of SV-SMC and expression of MMP-1, whilst reducing RECK protein, indicating a switch to the synthetic phenotype. Furthermore, platelet-derived growth factor BB (PDGF-BB; a growth factor implicated in vasculoproliferative conditions) was able to induce miR-21 expression via the PI3K and ERK signalling pathways. This study has revealed a mechanism whereby PDGF-BB induces expression of miR-21 in SV-SMC, subsequently driving conversion to a synthetic SMC phenotype, propagating the development of IH. Thus, these signaling pathways may be attractive therapeutic targets to minimise progression of the disease. © 2018 IUBMB Life, 70(7):649-657, 2018.

Renormalization of myoglobin-ligand binding energetics by quantum many-body effects.

We carry out a first-principles atomistic study of the electronic mechanisms of ligand binding and discrimination in the myoglobin protein. Electronic correlation effects are taken into account using one of the most advanced methods currently available, namely a linear-scaling density functional theory (DFT) approach wherein the treatment of localized iron 3d electrons is further refined using dynamical mean-field theory. This combination of methods explicitly accounts for dynamical and multireference quantum physics, such as valence and spin fluctuations, of the 3d electrons, while treating a significant proportion of the protein (more than 1,000 atoms) with DFT. The computed electronic structure of the myoglobin complexes and the nature of the Fe-O2 bonding are validated against experimental spectroscopic observables. We elucidate and solve a long-standing problem related to the quantum-mechanical description of the respiration process, namely that DFT calculations predict a strong imbalance between O2 and CO binding, favoring the latter to an unphysically large extent. We show that the explicit inclusion of the many-body effects induced by the Hund's coupling mechanism results in the correct prediction of similar binding energies for oxy- and carbonmonoxymyoglobin.

Orai3 Surface Accumulation and Calcium Entry Evoked by Vascular Endothelial Growth Factor.

OBJECTIVE: Vascular endothelial growth factor (VEGF) acts, in part, by triggering calcium ion (Ca(2+)) entry. Here, we sought understanding of a Synta66-resistant Ca(2+) entry pathway activated by VEGF. APPROACH AND RESULTS: Measurement of intracellular Ca(2+) in human umbilical vein endothelial cells detected a Synta66-resistant component of VEGF-activated Ca(2+) entry that occurred within 2 minutes after VEGF exposure. Knockdown of the channel-forming protein Orai3 suppressed this Ca(2+) entry. Similar effects occurred in 3 further types of human endothelial cell. Orai3 knockdown was inhibitory for VEGF-dependent endothelial tube formation in Matrigel in vitro and in vivo in the mouse. Unexpectedly, immunofluorescence and biotinylation experiments showed that Orai3 was not at the surface membrane unless VEGF was applied, after which it accumulated in the membrane within 2 minutes. The signaling pathway coupling VEGF to the effect on Orai3 involved activation of phospholipase Cγ1, Ca(2+) release, cytosolic group IV phospholipase A2α, arachidonic acid production, and, in part, microsomal glutathione S-transferase 2, an enzyme which catalyses the formation of leukotriene C4 from arachidonic acid. Shear stress reduced microsomal glutathione S-transferase 2 expression while inducing expression of leukotriene C4 synthase, suggesting reciprocal regulation of leukotriene C4-synthesizing enzymes and greater role of microsomal glutathione S-transferase 2 in low shear stress. CONCLUSIONS: VEGF signaling via arachidonic acid and arachidonic acid metabolism causes Orai3 to accumulate at the cell surface to mediate Ca(2+) entry and downstream endothelial cell remodeling.

Spontaneous Hemothorax Following Cardiac Surgery.

We report a case of spontaneous hemothorax after aortic valve replacement in a 72-year-old female resulting from rupture of a pleural adhesion leading to hemodynamic instability. doi: 10.1111/jocs.12729 (J Card Surg 2016;31:211-213).

Elevated expression levels of miR-143/5 in saphenous vein smooth muscle cells from patients with Type 2 diabetes drive persistent changes in phenotype and function.

Type 2 diabetes (T2DM) promotes premature atherosclerosis and inferior prognosis after arterial reconstruction. Vascular smooth muscle cells (SMC) respond to patho/physiological stimuli, switching between quiescent contractile and activated synthetic phenotypes under the control of microRNAs (miRs) that regulate multiple genes critical to SMC plasticity. The importance of miRs to SMC function specifically in T2DM is unknown. This study was performed to evaluate phenotype and function in SMC cultured from non-diabetic and T2DM patients, to explore any aberrancies and investigate underlying mechanisms. Saphenous vein SMC cultured from T2DM patients (T2DM-SMC) exhibited increased spread cell area, disorganised cytoskeleton and impaired proliferation relative to cells from non-diabetic patients (ND-SMC), accompanied by a persistent, selective up-regulation of miR-143 and miR-145. Transfection of premiR-143/145 into ND-SMC induced morphological and functional characteristics similar to native T2DM-SMC; modulating miR-143/145 targets Kruppel-like factor 4, alpha smooth muscle actin and myosin VI. Conversely, transfection of antimiR-143/145 into T2DM-SMC conferred characteristics of the ND phenotype. Exposure of ND-SMC to transforming growth factor beta (TGFß) induced a diabetes-like phenotype; elevated miR-143/145, increased cell area and reduced proliferation. Furthermore, these effects were dependent on miR-143/145. In conclusion, aberrant expression of miR-143/145 induces a distinct saphenous vein SMC phenotype that may contribute to vascular complications in patients with T2DM, and is potentially amenable to therapeutic manipulation.

Platelet-derived growth factor maintains stored calcium through a nonclustering Orai1 mechanism but evokes clustering if the endoplasmic reticulum is stressed by store depletion.

RATIONALE: Calcium entry through Orai1 channels drives vascular smooth muscle cell migration and neointimal hyperplasia. The channels are activated by the important growth factor platelet-derived growth factor (PDGF). Channel activation is suggested to depend on store depletion, which redistributes and clusters stromal interaction molecule 1 (STIM1), which then coclusters and activates Orai1. OBJECTIVE: To determine the relevance of STIM1 and Orai1 redistribution in PDGF responses. METHODS AND RESULTS: Vascular smooth muscle cells were cultured from human saphenous vein. STIM1 and Orai1 were tagged with green and red fluorescent proteins to track them in live cells. Under basal conditions, the proteins were mobile but mostly independent of each other. Inhibition of sarco-endoplasmic reticulum calcium ATPase led to store depletion and dramatic redistribution of STIM1 and Orai1 into coclusters. PDGF did not evoke redistribution, even though it caused calcium release and Orai1-mediated calcium entry in the same time period. After chemical blockade of Orai1-mediated calcium entry, however, PDGF caused redistribution. Similarly, mutagenic disruption of calcium flux through Orai1 caused PDGF to evoke redistribution, showing that calcium flux through the wild-type channels had been filling the stores. Acidification of the extracellular medium to pH 6.4 caused inhibition of Orai1-mediated calcium entry and conferred capability for PDGF to evoke complete redistribution and coclustering. CONCLUSIONS: The data suggest that PDGF has a nonclustering mechanism by which to activate Orai1 channels and maintain calcium stores replete. Redistribution and clustering become important, however, when the endoplasmic reticulum stress signal of store depletion arises, for example when acidosis inhibits Orai1 channels.

Constitutively active TRPC channels of adipocytes confer a mechanism for sensing dietary fatty acids and regulating adiponectin.

RATIONALE: Calcium entry is pivotal in the heart and blood vessels, but its significance and mechanisms in adipose tissue are largely unknown. An important factor produced by adipocytes is adiponectin, which confers myocardial protection, insulin-sensitization, and antiatherosclerotic effects. OBJECTIVE: To investigate the relevance of calcium channels to adipocytes and the production of adiponectin. METHODS AND RESULTS: Microarray analysis led to identification of transient receptor potential canonical (TRPC)1 and TRPC5 as channel subunits that are induced when adipocytes mature. Both subunits were found in perivascular fat of patients with atherosclerosis. Intracellular calcium and patch-clamp measurements showed that adipocytes exhibit constitutively active calcium-permeable nonselective cationic channels that depend on TRPC1 and TRPC5. The activity could be enhanced by lanthanum or rosiglitazone, known stimulators of TRPC5 and TRPC5-containing channels. Screening identified lipid modulators of the channels that are relevant to adipose biology. Dietary ω-3 fatty acids (eg, α-linolenic acid) were inhibitory at concentrations that are achieved by ingestion. The adipocyte TRPC1/TRPC5-containing channel was functionally negative for the generation of adiponectin because channel blockade by antibodies, knock-down of TRPC1-TRPC5 in vitro, or conditional disruption of calcium permeability in TRPC5-incorporating channels in vivo increased the generation of adiponectin. The previously recognized capability of α-linolenic acid to stimulate the generation of adiponectin was lost when calcium permeability in the channels was disrupted. CONCLUSIONS: The data suggest that TRPC1 and TRPC5 contribute a constitutively active heteromultimeric channel of adipocytes that negatively regulates adiponectin and through which ω-3 fatty acids enhance the anti-inflammatory adipokine, adiponectin.

Making a Stand.

OBJECTIVE: This is a review of the advertisements for basic surgical training course on social media and a comment on the ergonomics of the training. DESIGN: The author examined social media advertisements (Twitter and Instagram) over 4 months with a focus on stitching courses. No computer algorithm was available or could be made to ensure a comprehensive inclusion of all courses. RESULTS: One hundred nine basic surgical skills courses were identified, and 102 out of 109 (94%) courses are conducted sitting down. Courses were run in regular rooms or lecture theatres at regular table and using ordinary chairs. CONCLUSION: The practice and acquisition of basic surgical skills needs to address correctness of the technique and ergonomics especially with regards to posture. This influences not only muscle memory and musculoskeletal health but also the position of the needle and potential trauma to the tissues.

Assessment and management of chronic insomnia disorder: an algorithm for primary care physicians.

BACKGROUND: Primary care physicians often lack resources and training to correctly diagnose and manage chronic insomnia disorder. Tools supporting chronic insomnia diagnosis and management could fill this critical gap. A survey was conducted to understand insomnia disorder diagnosis and treatment practices among primary care physicians, and to evaluate a diagnosis and treatment algorithm on its use, to identify ways to optimize it specifically for these providers. METHODS: A panel of experts developed an algorithm for diagnosing and treating chronic insomnia disorder, based on current guidelines and experience in clinical practice. An online survey was conducted with primary care physicians from France, Germany, Italy, Spain, and the United Kingdom, who treat chronic insomnia patients, between January and February 2023. A sub-sample of participants provided open-ended feedback on the algorithm and gave suggestions for improvements. RESULTS: Overall, 106 primary care physicians completed the survey. Half (52%, 55/106) reported they did not regularly screen for insomnia and half (51%, 54/106) felt they did not have enough time to address patients' needs in relation to insomnia or trouble sleeping. The majority (87%,92/106) agreed the algorithm would help diagnose chronic insomnia patients and 82% (87/106) agreed the algorithm would help improve their clinical practice in relation to managing chronic insomnia. Suggestions for improvements were making the algorithm easier to read and use. CONCLUSION: The algorithm developed for, and tested by, primary care physicians to diagnose and treat chronic insomnia disorder may offer significant benefits to providers and their patients through ensuring standardization of insomnia diagnosis and management.

Dreaming Characteristics in Non-Rapid Eye Movement Parasomnia and Idiopathic Rapid Eye Movement Sleep Behaviour Disorder: Similarities and Differences.

Background: Speech graph analysis (SGA) of dreams has recently shown promise as an objective and language-invariant diagnostic tool that can aid neuropsychiatric diagnosis. Whilst the notion that dreaming mentations reflect distinct physiologic processes is not new, such studies in patients with sleep disorders remain exceptionally scarce. Here, using SGA and other dream content analyses, we set to investigate structural and thematic differences in morning dream recalls of patients diagnosed with Non-Rapid Eye Movement Parasomnia (NREMP) and Idiopathic REM Sleep Behavior Disorder (iRBD). Methods: A retrospective cross-sectional study of morning dream recalls of iRBD and NREMP patients was undertaken. Traditional dream content analyses, such as Orlinsky and Hall and Van de Castle analyses, were initially conducted. Subsequently, SGA was performed in order to objectively quantify structural speech differences between the dream recalls of the two patient groups. Results: Comparable rate of morning recall of dreams in the sleep laboratory was recorded; 25% of iRBD and 18.35% of NREMP patients. Aggression in dreams was recorded by 28.57% iRBD versus 20.00% in NREMP group. iRBD patients were more likely to recall dreams (iRBD vs NREMP; P = 0.007), but they also had more white dreams, ie having a feeling of having dreamt, but with no memory of it. Visual and quantitative graph speech analyses of iRBD dreams suggested stable sequential structure, reflecting the linearity of the chronological narrative. Conversely, NREMP dream reports displayed more recursive, less stable systems, with significantly higher scores of graph connectivity measures. Conclusion: The findings of our exploratory study suggest that iRBD and NREMP patients may not only differ on what is recalled in their dreams but also, perhaps more strikingly, on how dreams are recalled. It is hoped that future SGA-led dream investigations of larger groups of patients will help discern distinct mechanistic underpinnings and any associated clinical implications.

p38 MAPK alpha mediates cytokine-induced IL-6 and MMP-3 expression in human cardiac fibroblasts.

Pre-clinical studies suggest that the p38 MAPK signaling pathway plays a detrimental role in cardiac remodeling, but its role in cardiac fibroblast (CF) function is not well defined. We aimed to identify the p38 MAPK subtypes expressed by human CF, study their activation in response to proinflammatory cytokines, and determine which subtypes were important for expression of specific cytokines and matrix metalloproteinases (MMPs). Quantitative real-time RT-PCR analysis of mRNA levels in human CF cultured from multiple patients revealed a consistent pattern of expression with p38α being most abundant, followed by p38γ, then p38δ and only low expression of p38ß (3% of p38α mRNA levels). Immunoblotting confirmed marked protein expression of p38α, γ and δ, with little or no expression of p38ß. Phospho-ELISA and combined immunoprecipitation/immunoblotting techniques demonstrated that the proinflammatory cytokines IL-1α and TNFα selectively activated p38α and p38γ, but not p38δ. Selective p38α siRNA gene silencing reduced IL-1α-induced IL-6 and MMP-3 mRNA expression and protein secretion, without affecting IL-1α-induced IL-1ß and MMP-9 mRNA expression. In conclusion, human CF express the α, γ and δ subtypes of p38 MAPK, and the α subtype is important for IL-1α-induced IL-6 and MMP-3 expression in this cell type.

Importance of many-body effects in the Kernel of hemoglobin for ligand binding.

We propose a mechanism for binding of diatomic ligands to heme based on a dynamical orbital selection process. This scenario may be described as bonding determined by local valence fluctuations. We support this model using linear-scaling first-principles calculations, in combination with dynamical mean-field theory, applied to heme, the kernel of the hemoglobin metalloprotein central to human respiration. We find that variations in Hund's exchange coupling induce a reduction of the iron 3d density, with a concomitant increase of valence fluctuations. We discuss the comparison between our computed optical absorption spectra and experimental data, our picture accounting for the observation of optical transitions in the infrared regime, and how the Hund's coupling reduces, by a factor of 5, the strong imbalance in the binding energies of heme with CO and O(2) ligands.

Orai1 and CRAC channel dependence of VEGF-activated Ca2+ entry and endothelial tube formation.

RATIONALE: Orai1 and the associated calcium release-activated calcium (CRAC) channel were discovered in the immune system. Existence also in endothelial cells has been suggested, but the relevance to endothelial biology is mostly unknown. OBJECTIVE: The aim of this study was to investigate the relevance of Orai1 and CRAC channels to vascular endothelial growth factor (VEGF) and endothelial tube formation. METHODS AND RESULTS: In human umbilical vein endothelial cells, Orai1 disruption by short-interfering RNA or dominant-negative mutant Orai1 inhibited calcium release-activated (store-operated) calcium entry, VEGF-evoked calcium entry, cell migration, and in vitro tube formation. Expression of exogenous wild-type Orai1 rescued the tube formation. VEGF receptor-2 and Orai1 partially colocalized. Orai1 disruption also inhibited calcium entry and tube formation in endothelial progenitor cells from human blood. A known blocker of the immune cell CRAC channel (3-fluoropyridine-4-carboxylic acid (2',5'-dimethoxybiphenyl-4-yl)amide) was a strong blocker of store-operated calcium entry in endothelial cells and inhibited calcium entry evoked by VEGF in 3 types of human endothelial cell. The compound lacked effect on VEGF-evoked calcium-release, STIM1 clustering, and 2 types of transient receptor potential channels, TRPC6 and TRPV4. Without effect on cell viability, the compound inhibited human endothelial cell migration and tube formation in vitro and suppressed angiogenesis in vivo in the chick chorioallantoic membrane. The compound showed 100-fold greater potency for endothelial compared with immune cell calcium entry. CONCLUSIONS: The data suggest positive roles for Orai1 and CRAC channels in VEGF-evoked calcium entry and new opportunity for chemical modulation of angiogenesis.

Early postoperative thrombosis of an aortic bioprosthetic valve: should anticoagulation be patient specific?

Optimal antithrombotic recommendations for patients following bioprosthetic aortic valve replacement have yet to be decided. Current guidelines present conflicting opinions and are based on historical studies, which are limited by their design. We review comparative studies investigating differing thromboprophylactic regimes and outcomes for bioprosthetic aortic valve replacement.