The role of globins in cardiovascular physiology.

Globin proteins exist in every cell type of the vasculature, from erythrocytes to endothelial cells, vascular smooth muscle cells, and peripheral nerve cells. Many globin subtypes are also expressed in muscle tissues (including cardiac and skeletal muscle), in other organ-specific cell types, and in cells of the central nervous system (CNS). The ability of each of these globins to interact with molecular oxygen (O2) and nitric oxide (NO) is preserved across these contexts. Endothelial α-globin is an example of extraerythrocytic globin expression. Other globins, including myoglobin, cytoglobin, and neuroglobin, are observed in other vascular tissues. Myoglobin is observed primarily in skeletal muscle and smooth muscle cells surrounding the aorta or other large arteries. Cytoglobin is found in vascular smooth muscle but can also be expressed in nonvascular cell types, especially in oxidative stress conditions after ischemic insult. Neuroglobin was first observed in neuronal cells, and its expression appears to be restricted mainly to the CNS and the peripheral nervous system. Brain and CNS neurons expressing neuroglobin are positioned close to many arteries within the brain parenchyma and can control smooth muscle contraction and thus tissue perfusion and vascular reactivity. Overall, reactions between NO and globin heme iron contribute to vascular homeostasis by regulating vasodilatory NO signals and scavenging reactive species in cells of the mammalian vascular system. Here, we discuss how globin proteins affect vascular physiology, with a focus on NO biology, and offer perspectives for future study of these functions.

Heterocellular Contact Can Dictate Arterial Function.

RATIONALE: Resistance arteries and conduit arteries rely on different relative contributions of endothelial-derived hyperpolarization versus nitric oxide to achieve dilatory heterocellular signaling. Anatomically, resistance arteries use myoendothelial junctions (MEJs), endothelial cell projections that make contact with smooth muscle cells. Conduit arteries have very few to no MEJs. OBJECTIVE: Determine if the presence of MEJs in conduit arteries can alter heterocellular signaling. METHODS AND RESULTS: We previously demonstrated that PAI-1 (plasminogen activator inhibitor-1) can regulate formation of MEJs. Thus, we applied pluronic gel containing PAI-1 directly to conduit arteries (carotid arteries) to determine if this could induce formation of MEJs. We found a significant increase in endothelial cell projections resembling MEJs that correlated with increased biocytin dye transfer from endothelial cells to smooth muscle cells. Next, we used pressure myography to investigate whether these structural changes were accompanied by a functional change in vasodilatory signaling. Interestingly, PAI-1-treated carotids underwent a switch from a conduit to resistance artery vasodilatory profile via diminished nitric oxide signaling and increased endothelial-derived hyperpolarization signaling in response to the endothelium-dependent agonists acetylcholine and NS309. After PAI-1 application, we also found a significant increase in carotid expression of endothelial alpha globin, a protein predominantly expressed in resistance arteries. Carotids from mice with PAI-1, but lacking alpha globin (Hba1-/-), demonstrated that l-nitro-arginine methyl ester, an inhibitor of nitric oxide signaling, was able to prevent arterial relaxation. CONCLUSIONS: The presence or absence of MEJs is an important determinant for influencing heterocellular communication in the arterial wall. In particular, alpha globin expression, induced within newly formed endothelial cell projections, may influence the balance between endothelial-derived hyperpolarization and nitric oxide-mediated vasodilation.

Treatment of intraoperative hypotension with cafedrine/theodrenaline versus ephedrine : A prospective, national, multicenter, non-interventional study-the HYPOTENS trial.

BACKGROUND: Sympathomimetic drugs are a therapeutic cornerstone for the management of hypotensive states like intraoperative hypotension (IOH). While cafedrine/theodrenaline (C/T) is widely used in Germany to restore blood pressure in patients with IOH, more research is required to compare its effectiveness with alternatives such as ephedrine (E) that are more commonly available internationally. METHODS: HYPOTENS (NCT02893241, DRKS00010740) was a prospective, national, multicenter, open-label, two-armed, non-interventional study that compared C/T with E for treatment of IOH. We describe a prospectively defined cohort of patients ≥50 years old with comorbidities undergoing general anesthesia induced with propofol and fentanyl. Primary objectives were to examine treatment precision, rapidity of onset and the ability to restore blood pressure without relevant increases in heart rate. Secondary endpoints were treatment satisfaction and the number of required additional boluses or other accompanying measures. RESULTS: A total of 1496 patients were included in the per protocol analysis. Overall, effective stabilization of blood pressure was achieved with both C/T and E. Post-hoc analysis showed that blood pressure increase from baseline was more pronounced with C/T. Fewer additional boluses or other accompanying measures were required in the C/T arm. The incidence of tachycardia was comparable between groups. Post-hoc analysis showed that E produced dose-dependent elevated heart rate values. By contrast, heart rate remained stable in patients treated with C/T. Physicians reported a higher level of treatment satisfaction with C/T, with a higher proportion of anesthetists rating treatment precision and rapidity of onset as good or very good when compared with E. CONCLUSION: Neither drug was superior in restoring blood pressure levels; however, post-hoc analyses suggested that treatment is more goal-orientated and easier to control with C/T. Heart rate was shown to be more stable with C/T and fewer additional interventions were required to restore blood pressure, which could have contributed to the increased treatment satisfaction reported by anesthetists using C/T.

Constitutive SRC-mediated phosphorylation of pannexin 1 at tyrosine 198 occurs at the plasma membrane.

Pannexin 1 (PANX1)-mediated ATP release in vascular smooth muscle coordinates α1-adrenergic receptor (α1-AR) vasoconstriction and blood pressure homeostasis. We recently identified amino acids 198-200 (YLK) on the PANX1 intracellular loop that are critical for α1-AR-mediated vasoconstriction and PANX1 channel function. We report herein that the YLK motif is contained within an SRC homology 2 domain and is directly phosphorylated by SRC proto-oncogene, nonreceptor tyrosine kinase (SRC) at Tyr198 We demonstrate that PANX1-mediated ATP release occurs independently of intracellular calcium but is sensitive to SRC family kinase (SFK) inhibition, suggestive of channel regulation by tyrosine phosphorylation. Using a PANX1 Tyr198-specific antibody, SFK inhibitors, SRC knockdown, temperature-dependent SRC cells, and kinase assays, we found that PANX1-mediated ATP release and vasoconstriction involves constitutive phosphorylation of PANX1 Tyr198 by SRC. We specifically detected SRC-mediated Tyr198 phosphorylation at the plasma membrane and observed that it is not enhanced or induced by α1-AR activation. Last, we show that PANX1 immunostaining is enriched in the smooth muscle layer of arteries from hypertensive humans and that Tyr198 phosphorylation is detectable in these samples, indicative of a role for membrane-associated PANX1 in small arteries of hypertensive humans. Our discovery adds insight into the regulation of PANX1 by post-translational modifications and connects a significant purinergic vasoconstriction pathway with a previously identified, yet unexplored, tyrosine kinase-based α1-AR constriction mechanism. This work implicates SRC-mediated PANX1 function in normal vascular hemodynamics and suggests that Tyr198-phosphorylated PANX1 is involved in hypertensive vascular pathology.

Pannexin 1 channels in renin-expressing cells influence renin secretion and blood pressure homeostasis.

Kidney function and blood pressure homeostasis are regulated by purinergic signaling mechanisms. These autocrine/paracrine signaling pathways are initiated by the release of cellular ATP, which influences kidney hemodynamics and steady-state renin secretion from juxtaglomerular cells. However, the mechanism responsible for ATP release that supports tonic inputs to juxtaglomerular cells and regulates renin secretion remains unclear. Pannexin 1 (Panx1) channels localize to both afferent arterioles and juxtaglomerular cells and provide a transmembrane conduit for ATP release and ion permeability in the kidney and the vasculature. We hypothesized that Panx1 channels in renin-expressing cells regulate renin secretion in vivo. Using a renin cell-specific Panx1 knockout model, we found that male Panx1 deficient mice exhibiting a heightened activation of the renin-angiotensin-aldosterone system have markedly increased plasma renin and aldosterone concentrations, and elevated mean arterial pressure with altered peripheral hemodynamics. Following ovariectomy, female mice mirrored the male phenotype. Furthermore, constitutive Panx1 channel activity was observed in As4.1 renin-secreting cells, whereby Panx1 knockdown reduced extracellular ATP accumulation, lowered basal intracellular calcium concentrations and recapitulated a hyper-secretory renin phenotype. Moreover, in response to stress stimuli that lower blood pressure, Panx1-deficient mice exhibited aberrant "renin recruitment" as evidenced by reactivation of renin expression in pre-glomerular arteriolar smooth muscle cells. Thus, renin-cell Panx1 channels suppress renin secretion and influence adaptive renin responses when blood pressure homeostasis is threatened.

Interaction Between Pannexin 1 and Caveolin-1 in Smooth Muscle Can Regulate Blood Pressure.

Objective- Sympathetic nerve innervation of vascular smooth muscle cells (VSMCs) is a major regulator of arteriolar vasoconstriction, vascular resistance, and blood pressure. Importantly, α-adrenergic receptor stimulation, which uniquely couples with Panx1 (pannexin 1) channel-mediated ATP release in resistance arteries, also requires localization to membrane caveolae. Here, we test whether localization of Panx1 to Cav1 (caveolin-1) promotes channel function (stimulus-dependent ATP release and adrenergic vasoconstriction) and is important for blood pressure homeostasis. Approach and Results- We use in vitro VSMC culture models, ex vivo resistance arteries, and a novel inducible VSMC-specific Cav1 knockout mouse to probe interactions between Panx1 and Cav1. We report that Panx1 and Cav1 colocalized on the VSMC plasma membrane of resistance arteries near sympathetic nerves in an adrenergic stimulus-dependent manner. Genetic deletion of Cav1 significantly blunts adrenergic-stimulated ATP release and vasoconstriction, with no direct influence on endothelium-dependent vasodilation or cardiac function. A significant reduction in mean arterial pressure (total=4 mm Hg; night=7 mm Hg) occurred in mice deficient for VSMC Cav1. These animals were resistant to further blood pressure lowering using a Panx1 peptide inhibitor Px1IL2P, which targets an intracellular loop region necessary for channel function. Conclusions- Translocalization of Panx1 to Cav1-enriched caveolae in VSMCs augments the release of purinergic stimuli necessary for proper adrenergic-mediated vasoconstriction and blood pressure homeostasis.

The sex-shift in single disease and multimorbid asthma and rhinitis during puberty - a study by MeDALL.

BACKGROUND: Cross-sectional studies suggested that allergy prevalence in childhood is higher in boys compared to girls, but it remains unclear whether this inequality changes after puberty. We examined the sex-specific prevalence of asthma and rhinitis as single and as multimorbid diseases before and after puberty onset in longitudinal cohort data. METHODS: In six European population-based birth cohorts of MeDALL, we assessed the outcomes: current rhinitis, current asthma, current allergic multimorbidity (ie, concurrent asthma and rhinitis), puberty status and allergic sensitization by specific serum antibodies (immunoglobulin E) against aero-allergens. With generalized estimating equations, we analysed the effects of sex, age, puberty (yes/no) and possible confounders on the prevalence of asthma and rhinitis, and allergic multimorbidity in each cohort separately and performed individual participant data meta-analysis. FINDINGS: We included data from 19 013 participants from birth to age 14-20 years. Current rhinitis only affected girls less often than boys before and after puberty onset: adjusted odds ratio for females vs males 0.79 (95%-confidence interval 0.73-0.86) and 0.86 (0.79-0.94), respectively (sex-puberty interaction P = .089). Similarly, for current asthma only, females were less often affected than boys both before and after puberty onset: 0.71, 0.63-0.81 and 0.81, 0.64-1.02, respectively (sex-puberty interaction P = .327). The prevalence of allergic multimorbidity showed the strongest sex effect before puberty onset (female-male-OR 0.55, 0.46-0.64) and a considerable shift towards a sex-balanced prevalence after puberty onset (0.89, 0.74-1.04); sex-puberty interaction: P < .001. INTERPRETATION: The male predominance in prevalence before puberty and the "sex-shift" towards females after puberty onset were strongest in multimorbid patients who had asthma and rhinitis concurrently.

Has Shouldice Repair in a Selected Group of Patients with Inguinal Hernia Comparable Results to Lichtenstein, TEP and TAPP Techniques?

BACKGROUND: In the new international guidelines only the mesh-based Lichtenstein, TEP and TAPP techniques are recommended. This present analysis of data from the Herniamed Registry compares the outcome for Shouldice versus Lichtenstein, TEP and TAPP. METHODS: Propensity score matching analyses were performed to obtain homogeneous comparison groups for Shouldice versus Lichtenstein (n = 2115/2608; 81.1%), Shouldice versus TEP (n = 2225/2608; 85.3%) and Shouldice versus TAPP (2400/2608; 92.0%). RESULTS: The most important characteristics of the Shouldice patient collective were younger patients with a mean age of 40 years, a large proportion of women of 30%, a mean BMI value of 24 and a proportion of defect sizes up to 3 cm of over 85%. For this selected patient collective, propensity score matched-pair analysis did not identify any difference in the perioperative and one-year follow-up outcome compared with TAPP, fewer intraoperative (0.5 vs. 1.3%; p = 0.009) but somewhat more postoperative complications (2.3 vs. 1.5%; p = 0.050) compared with TEP and advantages with regard to pain at rest (4.6 vs. 6.1%; p = 0.039) and on exertion (10.0 vs. 13.4%; p < 0.001) compared with the Lichtenstein technique. CONCLUSION: For a selected group of patients the Shouldice technique can be used for primary unilateral inguinal hernia repair while achieving an outcome comparable to that of Lichtenstein, TEP and TAPP operations.

Evaluation of a novel point-of-care test for active matrix metalloproteinase-8: agreement between qualitative and quantitative measurements and relation to periodontal inflammation.

BACKGROUND AND OBJECTIVES: Severe periodontitis affects about 10% of the world population. In addition, associations between periodontitis and systemic diseases exist. Therefore, the diagnosis should be made quickly and at an early stage. Matrix metalloproteinase-8 (MMP-8) is the most prominent collagenase found in inflamed periodontal tissues. Its active form (aMMP-8) is increasingly used as a diagnostic biomarker. Aim of the present study is to evaluate the diagnostic accuracy of a novel aMMP-8 point-of-care (POC) test in comparison to the standard laboratory test to diagnose the disease rapidly and reliably. MATERIAL AND METHODS: In a prospective, mono-center, double-blinded, case-control study, participants with healthy gums (n = 35), gingivitis (n = 60) and periodontitis (n = 35) were investigated before and after therapy. Beside clinical variables for plaque and inflammation, aMMP-8 concentrations were determined in oral rinsing specimens by the enzyme-linked immunosorbent assay (ELISA) and by POC. Positive and negative percent agreements with their exact one-sided lower 95% confidence limits were calculated. RESULTS: Of 130 participants, 111 finished the study. Overall, positive percent agreements were 75.8% (57.7-88.9) before treatment and 73.7% (56.9-86.6) after treatment. Negative percent agreements were 92.8% (85.7-97.0) before and 93.3% (85.1-97.8) after treatment. Positive test results (POC and ELISA) ranged from 5.7% to 8.6% in healthy patients, 25.0-29.8% in patients with gingivitis and 40.0-48.1% in patients with periodontitis. Patients who had positive aMMP-8 test results (POC) showed higher scores for plaque and inflammation. CONCLUSIONS: The novel POC test to detect aMMP-8 has proved to agree strongly with the standard method, ELISA. The test can be recommended to screen patients at risk for periodontitis in dental offices, at the general practitioner and at specialists for associated diseases.

[Anticoagulation in patients with chronic kidney disease : Recommendations from the working group "Heart-Kidney" of the German Cardiac Society and the German Society of Nephrology]. / Antikoagulation bei Patienten mit chronischer Niereninsuffizienz : Empfehlungen der Arbeitsgemeinschaft "Herz ­ Niere" der Deutschen Gesellschaft für Kardiologie ­ Herz- und Kreislaufforschung und der Deutschen Gesellschaft für Nephrologie.

Indications for anticoagulation are thromboembolic events, prosthetic heart valves, and atrial fibrillation with a corresponding risk score. Clinical trials have excluded patients with advanced chronic kidney disease and these data cannot be always generalized to patients with chronic kidney disease. Non-vitamin K antagonist oral anticoagulants (NOACs) are mostly not recommended or are contraindicated in advanced stages of chronic kidney disease. Observational studies have shown that dialysis patients with atrial fibrillation do not profit from coumarin anticoagulants; prospective studies are lacking.

Magnetostriction and Magnetostructural Domains in Antiferromagnetic YBa2Cu3O6.

We use high-resolution neutron Larmor diffraction and capacitative dilatometry to investigate spontaneous and forced magnetostriction in undoped, antiferromagnetic YBa_{2}Cu_{3}O_{6.0}, the parent compound of a prominent family of high-temperature superconductors. Upon cooling below the Néel temperature T_{N}=420 K, Larmor diffraction reveals the formation of magnetostructural domains of characteristic size ∼240 nm. In the antiferromagnetic state, dilatometry reveals a minute (4×10^{-6}) orthorhombic distortion of the crystal lattice in external magnetic fields. We attribute these observations to exchange striction and spin-orbit coupling induced magnetostriction, respectively, and show that they have an important influence on the thermal and charge transport properties of undoped and lightly doped cuprates.

Endothelial nitric oxide synthase in the microcirculation.

Endothelial nitric oxide synthase (eNOS, NOS3) is responsible for producing nitric oxide (NO)--a key molecule that can directly (or indirectly) act as a vasodilator and anti-inflammatory mediator. In this review, we examine the structural effects of regulation of the eNOS enzyme, including post-translational modifications and subcellular localization. After production, NO diffuses to surrounding cells with a variety of effects. We focus on the physiological role of NO and NO-derived molecules, including microvascular effects on vessel tone and immune response. Regulation of eNOS and NO action is complicated; we address endogenous and exogenous mechanisms of NO regulation with a discussion of pharmacological agents used in clinical and laboratory settings and a proposed role for eNOS in circulating red blood cells.

Structural and Magnetic Phase Transitions near Optimal Superconductivity in BaFe2(As(1-x)Px)2.

We use nuclear magnetic resonance (NMR), high-resolution x-ray, and neutron scattering studies to study structural and magnetic phase transitions in phosphorus-doped BaFe2(As(1-x)P(x)2. Previous transport, NMR, specific heat, and magnetic penetration depth measurements have provided compelling evidence for the presence of a quantum critical point (QCP) near optimal superconductivity at x=0.3. However, we show that the tetragonal-to-orthorhombic structural (T{s}) and paramagnetic to antiferromagnetic (AF, TN) transitions in BaFe2(As(1-x)Px)2 are always coupled and approach T{N}≈T{s}≥T{c} (≈29 K) for x=0.29 before vanishing abruptly for x≥0.3. These results suggest that AF order in BaFe_{2}(As(1-x)Px)2 disappears in a weakly first-order fashion near optimal superconductivity, much like the electron-doped iron pnictides with an avoided QCP.

TEP versus TAPP: comparison of the perioperative outcome in 17,587 patients with a primary unilateral inguinal hernia.

INTRODUCTION: More than 20 years since the introduction of TAPP and TEP into clinical routine, there is a lack of clarity due to conflicting comparative data. Therefore, more results from registries are needed. PATIENTS AND METHODS: A total of 17,587 patients were enrolled prospectively between September 1, 2009, and April 15, 2013, in the Herniamed registry. Of these patients, 10,887 (61.9%) had a TAPP and 6700 (38.1%) a TEP repair. The dependent variables were intra- and postoperative complication rates, number of reoperations as well as absolute and relative frequencies. The results of unadjusted analyses were verified via multivariable analyses. RESULTS: Multivariable analysis verified the results of unadjusted analysis, indicating that the surgical technique did not have any significant impact, also while taking account of other factors, on occurrence of intraoperative [p = 0.1648; OR = 1.214 (0.923; 1.596)] and general postoperative complications [p = 0.0738; OR = 1.315 (0.974; 1.775)]. Postoperative surgical complications [OR = 2.323 (1.882; 2.866); p < 0.0001] were noted more often after TAPP. Furthermore, the hernia defect size [p < 0.0001; I vs III: OR = 0.439 (0.313; 0.615), II vs III: OR = 0.712 (0.582; 0.872)] or scrotal [p < 0.0001; OR = 2.170 (1.501; 3.137)] hernia and age [p = 0.0002; 10-year OR = 1.135 (1.062; 1.213)] had a significant impact on the occurrence of postoperative complications. Complications were observed more commonly for larger hernia defects and a scrotal hernia. However, the difference in the postoperative complication rate between TEP and TAPP did not result in any difference in the reoperation rate (TEP 0.82% vs TAPP 0.90%; p = 0.6165). CONCLUSION: The intraoperative and general postoperative complication rates as well as the reoperation rate for complications show no significant difference between TEP and TAPP. The higher postoperative complication rate for TAPP, which could be managed conservatively, is partly explained by larger defect sizes, more scrotal hernias and older age.

Do we need antibiotic prophylaxis in endoscopic inguinal hernia repair? Results of the Herniamed Registry.

INTRODUCTION: The use of antibiotic prophylaxis in inguinal hernia repair is a controversial issue. Accepted randomized controlled trials or registry data with specific analysis of endoscopic repaired patients do not exist. PATIENT AND METHODS: The data presented in this study compared the prospectively collected data from the Herniamed Registry on all patients who had undergone unilateral, bilateral or recurrent repair of inguinal hernias using either endoscopic or open techniques between September 1, 2009, and March 5, 2014. In total, 85,033 patients were enrolled. Of these patients, 48,201 (56.7 ) had an endoscopic and 36,832 (43.3%) an open repair. The target variables analyzed were impaired wound healing and deep infections with mesh involvement within 30 days after the operation. RESULTS: Analysis of the patient group with endoscopic/laparoscopic inguinal hernia repair (n = 48,201) did not identify any significant influence of antibiotic prophylaxis on postoperative impaired wound healing, which occurred in 53 cases (p = 0.6431). Nor was it possible to identify any significant impact of antibiotic prophylaxis on the deep infections seen in 27 cases (p = 0.8409). Analysis of the open inguinal hernia repair group revealed that, unlike the laparoscopic/endoscopic group, antibiotic prophylaxis had a significant impact on the postoperative impaired wound healing and deep infection rates. The risk of postoperative impaired wound healing with antibiotic prophylaxis was significantly lower [OR 0.677 (0.479; 0.958), p = 0.027]. CONCLUSION: The positive impact of the endoscopic/laparoscopic technique on avoidance of impaired wound healing and deep infections with mesh involvement is already so great that antibiotic prophylaxis has no additional benefit. In contrast, antibiotic prophylaxis should be administered for open inguinal hernia repair.

Bilateral and Unilateral Total Extraperitoneal Inguinal Hernia Repair (TEP) have Equivalent Early Outcomes: Analysis of 9395 Cases.

INTRODUCTION: To date, no randomized controlled trials have been carried out to compare the perioperative outcome of unilateral and bilateral inguinal hernia repair using an endoscopic technique. In a Swiss registry study comparing unilateral with bilateral inguinal hernias, no further details were given regarding the nature of the intra- and postoperative complications. In addition, some authors have raised the issue of prophylactic repair of a clinically healthy other groin side. PATIENTS AND METHODS: In the Herniamed Registry, in total 9395 patients with a TEP were enrolled. These comprised 6700 patients with unilateral (71.31%) and 2695 patients (28.69%) with bilateral inguinal hernia repair. The outcome variables, analyzed in a multivariable model, were the intra- and postoperative as well as general complication rates, reoperation rate, duration of operation, and length of hospital stay. RESULTS: While no significant difference was found in the overall number of intraoperative complications between the unilateral and bilateral group (p=0.310), a significantly higher number of urinary bladder injuries in the bilateral TEP operation of 0.28% compared with 0.04% for unilateral TEP (p=0,008) were noted. The greater probability of reoperation (0.82% for unilateral vs. 1.78% for bilateral TEP; p<0,001) in the unadjusted analysis was confirmed in the multivariable model [OR 2.35 (1.504; 3.322); p=0.001]. A significantly higher intraoperative urinary bladder injury rate and reoperation rate because of postoperative surgical complications constitute a difference in the perioperative outcome between unilateral and bilateral TEP which that warrants attention. Based on these results, prophylactic operation of the healthy other groin should not be recommended.

Suspicious Prenasal Skin Thickness-to-Nasal Bone Length Ratio: Prevalence and Correlation with Other Markers in Second and Third Trimester Fetuses with Down Syndrome.

PURPOSE: To assess the prevalence and value of a suspicious prenasal skin thickness-to-nasal bone length ratio (PT/NB ratio) in comparison to other established markers in a large population of Down syndrome (DS) fetuses. MATERIALS AND METHODS: This was a retrospective study of 139 DS fetuses and 530 normal fetuses scanned after 14 + 0 weeks of gestation. To characterize diagnostic performance, we used the ROC curve approach. The presence or absence of a PT/NB ratio > 0.8 and 11 other markers were assessed in the group of DS fetuses. A correlation analysis was performed in order to investigate associations between PT/NB ratio and other markers. RESULTS: Among DS fetuses the median PT/NB ratio was 1.06 (IQR 0.729) and was significantly higher compared to normal fetuses with 0.62 (IQR 0.148), (p < 0.001). Gestational age had no influence on the PT/NB ratio. A PT/NB ratio > 0.8 had the highest prevalence of all markers with 89.2 % in the group of DS fetuses, 3 cases were negative for all markers and 3 cases were positive only for PT/NB ratio > 0.8. Marker-specific comparison between prevalences of a suspicious PT/NB ratio with respect to the presence or absence of other markers was statistically significant for hypoplastic NB and major anomalies (p < 0.05). Utilization of at least one of the following five markers was sufficient for detecting 136 out of 139 fetuses with trisomy 21: suspicious PT/NB ratio, hypoplastic NB, nuchal fold thickness, white spot, shortened femur. CONCLUSION: The PT/NB ratio is one of the most powerful indicators of DS in the second trimester. It is objective to interpret, easy to measure, and is reproducible.

Effectiveness of hand hygiene campaigns and interventions across the League of Arab States: a region-wide scoping review.

Hand hygiene is a standard public health practice for limiting the spread of infectious diseases, yet they are still not routine global health behaviours. This review aimed to examine the effectiveness of various hand hygiene interventions conducted across the League of Arab States, identify gaps in the existing literature, and propose areas for future research and intervention development. A scoping review was conducted across 16 databases for relevant publications published up to and including October 2023. Forty studies met the inclusion criteria; of these, 34 were hospital-based and six community-based. Of the reviewed studies, 24 provided adequate details that would enable replication of their intervention. Eighteen of the studies used some variation of the World Health Organization's Five Moments for intervention content or assessment. More than half (N = 25) reported healthcare worker or student hand hygiene behaviours as an outcome and 15 studies also included some form of patient-centred outcomes. Six studies specified the use of theory or framework for their evaluation design or intervention content, and four studies mentioned use of local government guidelines or recommendations. Future research should focus on bridging the literature gaps by emphasizing community-based studies and integrating cultural nuances into intervention designs. Additionally, applying theoretical frameworks to hand hygiene studies could enhance understanding and effectiveness, ensuring sustainable improvements in hygiene practices across diverse settings in the League of Arab States.

Bay11-7082 inhibits the disintegration of the lymphendothelial barrier triggered by MCF-7 breast cancer spheroids; the role of ICAM-1 and adhesion.

BACKGROUND: Many cancers spread through lymphatic routes, and mechanistic insights of tumour intravasation into the lymphatic vasculature and targets for intervention are limited. The major emphasis of research focuses currently on the molecular biology of tumour cells, while still little is known regarding the contribution of lymphatics. METHODS: Breast cancer cell spheroids attached to lymphendothelial cell (LEC) monolayers were used to investigate the process of intravasation by measuring the areas of 'circular chemorepellent-induced defects' (CCID), which can be considered as entry gates for bulky tumour intravasation. Aspects of tumour cell intravasation were furthermore studied by adhesion assay, and siRNA-mediated knockdown of intracellular adhesion molecule-1 (ICAM-1). Replacing cancer spheroids with the CCID-triggering compound 12(S)-hydroxyeicosatetraenoic acid (HETE) facilitated western blot analyses of Bay11-7082- and baicalein-treated LECs. RESULTS: Binding of LECs to MCF-7 spheroids, which is a prerequisite for CCID formation, was mediated by ICAM-1 expression, and this depended on NF-κB and correlated with the expression of the prometastatic factor S100A4. Simultaneous inhibition of NF-κB with Bay11-7082 and of arachidonate lipoxygenase (ALOX)-15 with baicalein prevented CCID formation additively. CONCLUSION: Two mechanisms contribute to CCID formation: ALOX15 via the generation of 12(S)-HETE by MCF-7 cells, which induces directional migration of LECs, and ICAM-1 in LECs under control of NF-κB, which facilitates adhesion of MCF-7 cells to LECs.