Science Daily |
Researchers map 6000 years of urban settlements
Science Daily Date: June 7, 2016; Source: Yale School of Forestry & Environmental Studies; Summary: A new provides the first spatially explicit dataset of the location and size of urban settlements worldwide over the past 6,000 years, offering clarity on long-term ... and more » |
Sebopsoriasis is a term that refers to an inflammatory skin condition with features of both psoriasis and seborrhoeic dermatitis (SD). Despite being a familiar and much used epithet the epidemiological and clinical features of this entity are poorly described in the general dermatology literature. We present a case series of twenty patients with sebopsoriasis in order to characterise further the clinical features of the condition, its association with human immunodeficiency virus (HIV) infection, pathogenic mechanisms and treatment.
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The post Use of Asymmetric Models to Estimate the Distribution of Usual Nutrient Intakes appeared first on Welcome to Avens.
Pregnancy-related deep vein thrombosis (DVT) is most common during the late phase of pregnancy and the first 6-weeks postpartum. Pregnancy-related DVT can have long-term complications, specifically post-thrombotic syndrome (PTS). Fibrin network ultrastructure is altered during pregnancy and post-partum. It is therefore essential to evaluate fibrin fiber diameter during and after pregnancy as this may provide insight into pregnancy-related DVT and subsequent PTS.
The fibrin network ultrastructure of females during different phases of pregnancy was compared to that of non-pregnant females to assess possible changes to the fibrin network morphology and fibrin fiber diameter using scanning electron microscopy micrographs.
The fibrin network arrangement was more densely packed during different phases of pregnancy, corresponding to earlier findings. Fibrin diameter decreased significantly during pregnancy, with the greatest decrease occurring during the late phase of pregnancy. The fractal dimensions of fibrin micrographs increased significantly during pregnancy compared to nonpregnant females. These changes are indicative of a simultaneous hypercoagulable and hypofibrinolytic state and correspond to the increased risk of DVT and subsequent development of PTS.
It is critical to identify “vulnerable” females with an inflammatory predisposition to prevent possible DVT and subsequent PTS. Modifiable risk factors like obesity and smoking should be addressed to alleviate the burden on the coagulation system. Morphological and viscoelastic techniques are crucial in assessing the coagulatory health of females during pregnancy.
Reversible photoswitching has been proposed as a way to identify molecules that are present in small numbers over a large, non-switching, background. This approach, called optical-lock-in-detection (OLID) requires the deterministic control of the fluorescence of a photochromic emitter through optical modulation between a bright (on) and a dark state (off). OLID yields a high-contrast map where the switching molecules are pinpointed, but the fractional intensities of the emitters are not returned. The present work presents a modified OLID approach (quantitative OLID or qOLID) that yields quantitative information of the switching (fSW) and non-switching (fNS) components. After the validation of the method with a sample dataset and image sequence, we apply qOLID to measurements in cells that transiently express the photochromic protein EYQ1. We show that qOLID is efficient in separating the modulated from the non-modulated signal, the latter deriving from background/autofluorescence or fluorophores emitting in the same spectral region. Finally, we apply qOLID to Förster (Fluorescence) Resonance Energy Transfer (FRET) imaging. We here demonstrate that qOLID is able to highlight the distribution of FRET intensity in a sample by using a photochromic donor and a non-photochromic acceptor.
Wound Healing Effect of Curcumin: A Review.
Curr Pharm Biotechnol. 2016 Jul 21;
Authors: Tejada S, Manayi A, Daglia M, Nabavi SF, Sureda A, Hajheydari Z, Gortzi O, Pazoki-Toroudi H, Nabavi SM
Abstract
Wound healing is a complex process that consists of several phases that range from coagulation, inflammation, accumulation of radical substances, to proliferation, formation of fibrous tissues and collagen, contraction of wound with formation of granulation tissue and scar. Since antiquity, vegetable substances have been used as phytotherapeutic agents for wound healing, and more recently natural substances of vegetable origin have been studied with the attempt to show their beneficial effect on wound treatment. Curcumin, the most active component of rhizome of Curcuma longa L. (common name: turmeric), has been studied for many years due to its bio-functional properties, especially antioxidant, radical scavenger, antimicrobial and anti-inflammatory activities, which play a crucial role in the wound healing process. Moreover, curcumin stimulated the production of the growth factors involved in the wound healing process, and so curcumin also accelerated the management of wound restoration. The aim of the present review is collecting and evaluating the literature data regarding curcumin properties potentially relevant for wound healing. Moreover, the investigations on the wound healing effects of curcumin are reported. In order to produce a more complete picture, the chemistry and sources of curcumin are also discussed.
PMID: 27439410 [PubMed - as supplied by publisher]
Regarding "Airway Management in Pierre Robin Sequence: Patterns of Practice".
Cleft Palate Craniofac J. 2016 Jul 21;
Authors: van Lierop ET, Al-Ani SA, Vidyadharan R, Slator R
PMID: 27441703 [PubMed - as supplied by publisher]
Three-Dimensional Analysis of Nasal Symmetry Following Primary Correction of Unilateral Cleft Lip Nasal Deformity.
Cleft Palate Craniofac J. 2016 Jul 21;
Authors: Linden OE, Taylor HO, Vasudavan S, Byrne ME, Deutsch CK, Mulliken JB, Sullivan SR
Abstract
OBJECTIVE: To evaluate nasal symmetry using three-dimensional photogrammetry following primary tip rhinoplasty with or without an internal splint in patients with unilateral complete cleft lip/palate.
DESIGN: We captured three-dimensional images of patients with unilateral complete cleft lip/palate who underwent nasolabial repair by rotation-advancement of the lip and primary tip rhinoplasty, either with or without an internal resorbable splint, and normal control subjects. We assessed nasal symmetry by identifying the plane of maximum symmetry and the root-mean-square deviation between native and reflected surfaces.
PATIENTS/PARTICIPANTS: We imaged 38 controls and 38 subjects with repaired unilateral complete cleft lip/palate (20 with, 18 without an internal splint).
RESULTS: Nasal asymmetry root-mean-square deviation clustered between 0.19 and 0.50 mm (median = 0.24 ± 0.08 mm) for controls; whereas, those with repaired unilateral complete cleft lip/palate ranged from 0.4 to 1.5 mm (median = 0.75 ± 0.40 mm). Although root-mean-square deviation ranges overlapped, patients with repaired unilateral complete cleft lip/palate had significantly greater asymmetry than controls (P < .001). We found no difference in asymmetry between patients with or without an internal splint (P = .5).
CONCLUSIONS: Three-dimensional photogrammetry was used to successfully compare symmetry among different patient and control groups. Although "normal" nasal symmetry was attained in some patients following cleft lip/nasal repair, most had persistent asymmetry compared with normal controls. Placement of a resorbable internal splint did not improve symmetry in patients with unilateral complete cleft lip/palate.
PMID: 27441702 [PubMed - as supplied by publisher]
About Cuddapah et al. Paper Entitled "IRF6 Sequencing in Interrupted Clefting".
Cleft Palate Craniofac J. 2016 Jul 21;
Authors: Alvarez CW, Guion-Almeida ML, Richieri-Costa A
PMID: 27441701 [PubMed - as supplied by publisher]
Evaluation of Ventilation Tube Placement and Long-term Audiologic Outcome in Children With Cleft Palate.
Cleft Palate Craniofac J. 2016 Jul 21;
Authors: Kim E, Kanack MD, Dang-Vu MD, Carvalho D, Jones MC, Gosman AA
Abstract
OBJECTIVE: The purpose of this study was to assess the effect of ventilation tube (VT) placement on long-term hearing outcomes in children with cleft palate.
STUDY DESIGN: Case series with chart review.
SETTING: Genetic and dysmorphology database at Rady Children's Hospital-San Diego (RCHSD).
PATIENTS: Children with cleft palate diagnosis who underwent surgery at RCHSD between 1995 and 2002.
MAIN OUTCOME MEASURE: The primary outcome studied was hearing acuity at 10 years of age. Independent variables studied included gender, age at palate repair and first VT placement, total number of VTs, number of complications, and presence of tympanic membrane perforation.
RESULTS: An increased number of tubes was associated with a greater incidence of hearing loss at age 10, even after adjusting for total number of otologic complications. The timing of initial tube placement did not have a significant effect on long-term hearing outcome in this study.
CONCLUSIONS: While children with worse middle ear disease are more likely to receive more tubes and have long-term conductive hearing loss as a result of ear disease, the results of this study suggest that multiple tube placements may not contribute to improved long-term hearing outcomes. Further research focusing on long-term outcomes is needed to establish patient-centered criteria guiding decision making for ventilation tube placement in children with cleft palate.
PMID: 27441700 [PubMed - as supplied by publisher]
Cone Beam Computed Tomographic Evaluation of Mandibular Asymmetry in Patients With Cleft Lip and Palate.
Cleft Palate Craniofac J. 2016 Jul 21;
Authors: Paknahad M, Shahidi S, Bahrampour E, Beladi AS, Khojastepour L
Abstract
OBJECTIVE: The purpose of the present study was to compare mandibular vertical asymmetry in patients with unilateral and bilateral cleft lip and palate and subjects with normal occlusion.
MATERIALS AND METHODS: Cone beam computed tomography scans of three groups consisting of 20 patients with unilateral cleft lip and palate, 20 patients affected by bilateral cleft lip and palate, and a control group of 20 subjects with normal occlusion were analyzed for this study. Condylar, ramal, and condylar plus ramal asymmetry indices were measured for all subjects using the method of Habets et al. Kruskal-Wallis and Mann-Whitney tests were used to determine any significant differences between the groups for all indices at the 95% level of confidence.
RESULTS: There were no significant differences regarding sex for all mandibular asymmetry indices in all three groups. All Asymmetry indices (condylar, ramal, and condylar plus ramal asymmetry) were significantly higher in the unilateral cleft group compared with the other two groups.
CONCLUSION: Cone beam computed tomography images showed that patients with cleft lip and palate suffered from mandibular asymmetry. Subjects with unilateral cleft lip and palate had a more asymmetric mandible compared with the bilateral cleft lip and palate and control groups. Therefore, the mandible appears to be the leading factor in facial asymmetry in subjects with unilateral cleft lip and palate.
PMID: 27441699 [PubMed - as supplied by publisher]
Response to the Article "Primary Premaxillary Setback and Repair of Bilateral Complete Cleft Lip: Indications, Technique, and Outcomes".
Cleft Palate Craniofac J. 2016 Jul 21;
Authors: Berkowitz S
PMID: 27441698 [PubMed - as supplied by publisher]
Reliability of the SWAG-The Standardized Way to Assess Grafts Method for Alveolar Bone Grafting in Patients With Cleft Lip and Palate.
Cleft Palate Craniofac J. 2016 Jul 21;
Authors: Russell K, Long RE, Daskalogiannakis J, Mercado A, Hathaway R, Semb G, Shaw W
Abstract
OBJECTIVE: The objective of this study was to test a new method, a Standardized Way to Assess Grafts (SWAG), to rate alveolar bone graft (ABG) outcomes for patients with cleft lip and palate.
DESIGN: This was a retrospective comparison using the SWAG scale.
SETTING: This study took place in four cleft palate centers with different treatment protocols.
METHODS: A total of 160 maxillary occlusal radiographs taken 3 to 18 months post-ABG for sequentially treated patients with cleft lip and palate were assessed using the SWAG scale. Radiographs were scanned, standardized, blinded, and rated by 6 calibrated orthodontists to assess vertical thirds, bony root coverage, and complete bony fill. All radiographs were rated twice, 24 hours apart, by the same raters.
MAIN OUTCOMES: Intra- and interrater reliabilities were assessed.
RESULTS: Intrarater reliability was good to very good (.760; .652-.834), and interrater reliability was moderate to good (.606; .569-.681), comparable to previously published methods.
CONCLUSIONS: Rater reliabilities were shown to be comparable to or better than existing methods. The SWAG method was validated for ABG assessments in the mixed and permanent dentitions based on reliabilities in an intercenter outcome comparison.
PMID: 27441697 [PubMed - as supplied by publisher]
Comparative Evaluation of the Pharyngeal Airway Space in Unilateral and Bilateral Cleft Lip and Palate Individuals With Noncleft Individuals: A Cone Beam Computed Tomography Study.
Cleft Palate Craniofac J. 2016 Jul 21;
Authors: Gandedkar NH, Kiat CC, Basheer MA, Chen PY, Vincent YK
Abstract
OBJECTIVE: To evaluate the pharyngeal airway space changes in complete unilateral cleft lip and palate (UCLP) and bilateral cleft lip and palate (BCLP) individuals, and compare with age and sex-matched noncleft (NC) control subjects.
DESIGN: Retrospective study.
SETTING: Cleft and Craniofacial Centre, KK Women's and Children's Hospital, Singapore.
MATERIALS AND METHODS: Twenty UCLP (mean age: 13.4 ± 0.5 years), 18 BCLP (mean age: 13.5 ± 0.5 years) and 20 skeletal Class I subjects (mean age: 13.4 ± 0.6 years) were included in the study. Cone beam computed tomography scans were assessed for pharyngeal airway space (PAS) (oropharyngeal, nasopharyngeal, total airway space volume), and compared with PAS of age and sex-matched skeletal Class I NC individuals.
RESULTS: Pharyngeal airway space showed statistically significant differences in the UCLP, BCLP, and NC control subjects. Oropharyngeal (9338 ± 1108 mm(3), P < .05), nasopharyngeal (2911 ± 401 mm(3), P < .05), and total airway space (12 250 ± 1185 mm(3), P <0 05) volumes of BCLP individuals showed significant reduction in comparison to UCLP and NC. There were no gender differences of PAS in any of the groups tested (P > .05).
CONCLUSION: The pharyngeal airway space was significantly reduced in the BCLP group than were those in UCLP and control groups. This reduced PAS should be taken into account when planning treatment for these individuals.
PMID: 27441696 [PubMed - as supplied by publisher]
Systematic Review and Meta-analysis of the Birth Prevalence of Orofacial Clefts in Low- and Middle-Income Countries.
Cleft Palate Craniofac J. 2016 Jul 19;
Authors: Kadir A, Mossey PA, Blencowe H, Moorthie S, Lawn JE, Mastroiacovo P, Modell B
Abstract
BACKGROUND: In the last comprehensive review of the literature published in 2002, little information on the prevalence of orofacial clefts was available from low- and middle-income countries (LMICs).
OBJECTIVE: To analyze published data on the birth prevalence of cleft lip and/or palate (CL/P) from (LMIC).
DESIGN: Systematic review of the literature and meta-analysis of data from original papers on the birth prevalence of cleft lip and/or cleft palate (CL/P) in LMICs between 1990 and 2014. Secondary inclusion criteria were developed to analyze lower-quality studies from countries with scarce data.
MAIN OUTCOME MEASURE: Birth prevalence of undifferentiated CL/P (with or without associated syndrome or other anomaly).
RESULTS: Twenty-eight studies met strict inclusion criteria. Among 31,475,278 total births, the pooled birth prevalence of undifferentiated CL/P was 1.38 per 1000 births (95% confidence interval [CI]: 1.20 to 1.56). Four studies met criteria for secondary analysis, providing data on 75,627 births, with a pooled prevalence of 0.75 CL/P cases per 1000 births (95% CI: 0.56 to 0.95). Comparison of studies was limited by variable definitions of cases and of the reference population and by inconsistent reporting of outcomes. There is significant heterogeneity in the findings.
CONCLUSIONS: In LMICs, approximately 1 in every 730 children is born with CL/P. To optimize comparability across settings, future research should use a standard classification system and standard criteria for data collection and presentation. As clefting is associated with deprivation, understanding the true scale, risks, and preventive measures for orofacial clefts in LMIC is a matter of both scientific and humanitarian importance.
PMID: 27440051 [PubMed - as supplied by publisher]
Prospective Patient-Related Outcome Evaluation of Secondary Cleft Rhinoplasty Using a Validated Questionnaire.
Cleft Palate Craniofac J. 2016 Jul 19;
Authors: Sawyer AR, Robinson S, Cadier M
Abstract
OBJECTIVE: To evaluate patient satisfaction and quality of life following secondary cleft rhinoplasty.
DESIGN: Prospective consecutive patient, single unit, single surgeon study.
SETTING: Spires Cleft Centre, Salisbury, Wilshire, United Kingdom, and private practice.
PATIENTS, PARTICIPANTS: 56 (27 secondary cleft rhinoplasty) patients completed evaluation forms preoperatively and 3 to 6 months postoperatively.
INTERVENTIONS: Subjective assessment was performed using a validated Rhinoplasty Outcomes Evaluation (ROE) questionnaire. This instrument comprises six questions that capture three quality-of-life domains: physical, mental/emotional, and social..
MAIN OUTCOME: Rhinoplasty outcomes evaluation scores were calculated (range = 0 to 100) to indication satisfaction with rhinoplasty outcomes.
RESULTS: Average age was 28 years (range = 18 to 59 years). There was a significant subjective improvement in the total ROE evaluation scores from 28 ± 10 to 80± 11 (P < .01) in secondary cleft rhinoplasty. Similar results were achieved in noncleft rhinoplasty 34 ± 9 to 84 ± 9 (P < .01). Specific scores for nasal aesthetic appearance improved from 0.3 ± 0.2 to 3.2 ± 0.3 (P < .01) in secondary cleft rhinoplasty. No significant change was seen in breathing capacity in secondary cleft rhinoplasty (from 2.7 ± 0.3 to 3.2 ± 0.2; P = .29). All patients said they would undergo the procedure again.
CONCLUSION: Our results demonstrate high patient satisfaction after cleft rhinoplasty with particular regard to cosmetic appearance. These results are similar to those for noncleft rhinoplasty. We would recommend the use of this simple and quick validated outcome tool with all rhinoplasty patients.
PMID: 27439951 [PubMed - as supplied by publisher]
The cysteinyl leukotrienes (cysLTs) play a key role in the pathophysiology of asthma. In addition to functioning as potent bronchoconstrictors, cysLTs contribute to airway inflammation through eosinophil and neutrophil chemotaxis, plasma exudation and mucus secretion. We tested the activity of the dual cysLT1/2 antagonist, ONO-6950, against allergen-induced airway responses.
Subjects with documented allergen-induced early (EAR) and late asthmatic response (LAR) were randomized in a 3-way crossover study to receive ONO-6950 (200 mg) or montelukast (10 mg) or placebo q.d. on Days 1-8 of the 3 treatment periods. Allergen was inhaled on Day 7 two hours post-dose,and forced expiratory volume in 1 second (FEV1) was measured for 7 hours following challenge. Sputum eosinophils, and airway hyperresponsiveness were measured before and after allergen challenge. The primary outcome was the effect of ONO-6950 versus placebo on the EAR and LAR.
Twenty-five non-smoking subjects with mild allergic asthma were enrolled and 20 subjects completed all 3 treatment periods per protocol. ONO-6950 was well tolerated. Compared to placebo, ONO-6950 significantly attenuated the maximum % fall in FEV1 and area under the %FEV1/time curve during the EAR and LAR asthmatic responses (p<0.05), and allergen-induced sputum eosinophils. There were no significant differences between ONO-6950 and montelukast.
Attenuation of EAR, LAR, and airway inflammation is consistent with cysLT1 blockade. Whether dual cysLT1/2 antagonism offers additional benefit for treatment of asthma requires further study.
This article is protected by copyright. All rights reserved.
Firstpost |
Is it time to rethink NGT's ban on diesel vehicles in Delhi with a more holistic approach?
Firstpost According to the Indian Council of Medical Research's (ICMR), lung cancer is the most common cancer among men in Delhi (10 percent), followed by tongue cancer (6.8 percent) and larynx cancer (5.9 percent). In case of women, it is breast, ovary and ... and more » |
Loss-of-function mutations in the cytoskeletal protein ankyrin-B (AnkB) cause ventricular tachyarrhythmias in humans. Previously, we found that a larger fraction of the sarcoplasmic reticulum (SR) Ca2+ leak occurs through Ca2+ sparks in AnkB-deficient (AnkB+/–) mice, which may contribute to arrhythmogenicity via Ca2+ waves. Here, we investigated the mechanisms responsible for increased Ca2+ spark frequency in AnkB+/– hearts.
Methods and resultsUsing immunoblots and phospho-specific antibodies, we found that phosphorylation of ryanodine receptors (RyRs) by CaMKII is enhanced in AnkB+/– hearts. In contrast, the PKA-mediated RyR phosphorylation was comparable in AnkB+/– and wild-type (WT) mice. CaMKII inhibition greatly reduced Ca2+ spark frequency in myocytes from AnkB+/– mice but had little effect in the WT. Global activities of the major phosphatases PP1 and PP2A were similar in AnkB+/– and WT hearts, while CaMKII autophosphorylation, a marker of CaMKII activation, was increased in AnkB+/– hearts. Thus, CaMKII-dependent RyR hyperphosphorylation in AnkB+/– hearts is caused by augmented CaMKII activity. Intriguingly, CaMKII activation is limited to the sarcolemma–SR junctions since non-junctional CaMKII targets (phospholamban, HDAC4) are not hyperphosphorylated in AnkB+/– myocytes. This local CaMKII activation may be the consequence of elevated [Ca2+] in the junctional cleft caused by reduced Na+/Ca2+ exchange activity. Indeed, using the RyR-targeted Ca2+ sensor GCaMP2.2-FBKP12.6, we found that local junctional [Ca2+] is significantly elevated in AnkB+/– myocytes.
ConclusionsThe increased incidence of pro-arrhythmogenic Ca2+ sparks and waves in AnkB+/– hearts is due to enhanced CaMKII-mediated RyR phosphorylation, which is caused by higher junctional [Ca2+] and consequent local CaMKII activation.
Current mechanisms driving cardiac pacemaker function have focused on ion channel and gap junction channel function, which are essential for action potential generation and propagation between pacemaker cells. However, pacemaker cells also harbour desmosomes that structurally anchor pacemaker cells to each other in tissue, but their role in pacemaker function remains unknown.
Methods and resultsTo determine the role of desmosomes in pacemaker function, we generated a novel mouse model harbouring cardiac conduction-specific ablation (csKO) of the central desmosomal protein, desmoplakin (DSP) using the Hcn4-Cre-ERT2 mouse line. Hcn4-Cre targets cells of the adult mouse sinoatrial node (SAN) and can ablate DSP expression in the adult DSP csKO SAN resulting in specific loss of desmosomal proteins and structures. Dysregulation of DSP via loss-of-function (adult DSP csKO mice) and mutation (clinical case of a patient harbouring a pathogenic DSP variant) in mice and man, respectively, revealed that desmosomal dysregulation is associated with a primary phenotype of increased sinus pauses/dysfunction in the absence of cardiomyopathy. Underlying defects in beat-to-beat regulation were also observed in DSP csKO mice in vivo and intact atria ex vivo. DSP csKO SAN exhibited migrating lead pacemaker sites associated with connexin 45 loss. In vitro studies exploiting ventricular cardiomyocytes that harbour DSP loss and concurrent early connexin loss phenocopied the loss of beat-to-beat regulation observed in DSP csKO mice and atria, extending the importance of DSP-associated mechanisms in driving beat-to-beat regulation of working cardiomyocytes.
ConclusionWe provide evidence of a mechanism that implicates an essential role for desmosomes in cardiac pacemaker function, which has broad implications in better understanding mechanisms underlying beat-to-beat regulation as well as sinus node disease and dysfunction.
Catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1) is caused by mutations in the cardiac ryanodine receptor (RyR2) that lead to disrupted Ca2+ handling in cardiomyocytes and ventricular tachycardia. The aim of this study was to test whether exercise training could reduce the propensity for arrhythmias in mice with the CPVT1-causative missense mutation Ryr2-R2474S by restoring normal Ca2+ handling.
Methods and resultsRyr2-R2474S mice (RyR-RS) performed a 2 week interval treadmill exercise training protocol. Each exercise session comprised five 8 min intervals at 80–90% of the running speed at maximal oxygen uptake (VO2max) and 2 min active rest periods at 60%. VO2max increased by 10 ± 2% in exercise trained RyR-RS (ET), while no changes were found in sedentary controls (SED). RyR-RS ET showed fewer episodes of ventricular tachycardia compared with RyR-RS SED, coinciding with fewer Ca2+ sparks and waves, less diastolic Ca2+ leak from the sarcoplasmic reticulum, and lower phosphorylation levels at RyR2 sites associated with Ca2+–calmodulin-dependent kinase type II (CaMKII) compared with RyR-RS SED. The CaMKII inhibitor autocamtide-2-related inhibitory peptide and also the antioxidant N-acetyl-l-cysteine reduced Ca2+ wave frequency in RyR-RS equally to exercise training. Protein analysis as well as functional data indicated a mechanism depending on reduced levels of oxidized CaMKII after exercise training. Two weeks of detraining reversed the beneficial effects of the interval treadmill exercise training protocol in RyR-RS ET.
ConclusionLong-term effects of interval treadmill exercise training reduce ventricular tachycardia episodes in mice with a CPVT1-causative Ryr2 mutation through lower CaMKII-dependent phosphorylation of RyR2.
To study the role of lipocalin-2 (Lcn2) and the effect of Lcn2 blockade via anti-Lcn2 antibody in the development of abdominal aortic aneurysm (AAA).
Methods and resultsExpression mRNA and protein levels of Lcn2 and its human orthologue neutrophil gelatinase-associated lipocalin (NGAL) in aortic wall samples from experimental mouse and human AAA samples, respectively, were analysed by real-time PCR and immunohistochemistry. Experimental AAA was induced by aortic elastase perfusion in wild-type mice (WT) and Lcn2-deficient mice (Lcn2–/–). NGAL/Lcn2 mRNA and protein levels in human and murine AAA samples were increased compared with healthy aortas. Decreased AAA incidence and reduced aortic expansion were observed in Lcn2–/– mice or mice preoperative treated with a polyclonal anti-Lcn2 antibody compared with WT mice or mice treated with control IgG, respectively, at Day 14 after elastase perfusion. Moreover, immunohistochemical analysis of AAA tissues from Lcn2–/– or anti-Lcn2-treated mice showed diminished elastin damage, reduced microvessels and polymorphonuclear neutrophil (PMN) infiltration, and enhanced preservation of vascular smooth muscle cells compared with WT aortas. Fluorescent molecular tomography revealed decreased MMP activity in AAA of Lcn2–/– mice compared with WT controls. Therapeutic administration of anti-Lcn2 antibody to WT mice 3 days after elastase perfusion decreased aortic dilatation and PMN infiltration compared with WT mice treated with control IgG.
ConclusionEither Lcn2 deficiency or anti-Lcn2 antibody blockade limits AAA expansion in mice by decreasing PMN infiltration in the aorta. Lcn2 modulation may therefore be a viable new therapeutic option for the treatment of AAA.
A kinase interacting protein 1 (AKIP1) stimulates physiological growth in cultured cardiomyocytes and attenuates ischaemia/reperfusion (I/R) injury in ex vivo perfused hearts. We aimed to determine whether AKIP1 modulates the cardiac response to acute and chronic cardiac stresses in vivo.
Methods and resultsTransgenic mice with cardiac-specific overexpression of AKIP1 (AKIP1-TG) were created. AKIP1-TG mice and their wild-type (WT) littermates displayed similar cardiac structure and function. Likewise, cardiac remodelling in response to transverse aortic constriction or permanent coronary artery ligation was identical in AKIP1-TG and WT littermates, as evidenced by serial cardiac magnetic resonance imaging and pressure–volume loop analysis. Histological indices of remodelling, including cardiomyocyte cross-sectional diameter, capillary density, and left ventricular fibrosis were also similar in AKIP1-TG mice and WT littermates. When subjected to 45 min of ischaemia followed by 24 h of reperfusion, AKIP1-TG mice displayed a significant two-fold reduction in myocardial infarct size and reductions in cardiac apoptosis. In contrast to previous reports, AKIP1 did not co-immunoprecipitate with or regulate the activity of the signalling molecules NF-B, protein kinase A, or AKT. AKIP1 was, however, enriched in cardiac mitochondria and co-immunoprecipitated with a key component of the mitochondrial permeability transition (MPT) pore, ATP synthase. Finally, mitochondria isolated from AKIP1-TG hearts displayed markedly reduced calcium-induced swelling, indicative of reduced MPT pore formation.
ConclusionsIn contrast to in vitro studies, AKIP1 overexpression does not influence cardiac remodelling in response to chronic cardiac stress. AKIP1 does, however, reduce myocardial I/R injury through stabilization of the MPT pore. These findings suggest that AKIP1 deserves further investigation as a putative treatment target for cardioprotection from I/R injury during acute myocardial infarction.
The incidence of diabetes is increasing globally, with cardiovascular disease accounting for a substantial number of diabetes-related deaths. Although atherosclerotic vascular disease is a primary reason for this cardiovascular dysfunction, heart failure in patients with diabetes might also be an outcome of an intrinsic heart muscle malfunction, labelled diabetic cardiomyopathy. Changes in cardiomyocyte metabolism, which encompasses a shift to exclusive fatty acid utilization, are considered a leading stimulus for this cardiomyopathy. In addition to cardiomyocytes, endothelial cells (ECs) make up a significant proportion of the heart, with the majority of ATP generation in these cells provided by glucose. In this review, we will discuss the metabolic machinery that drives energy metabolism in the cardiomyocyte and EC, its breakdown following diabetes, and the research direction necessary to assist in devising novel therapeutic strategies to prevent or delay diabetic heart disease.
Endothelial colony-forming cells (ECFC) constitute an endothelial progenitor fraction with a promising interest for the treatment of ischaemic cardiovascular diseases. As soluble CD146 (sCD146) is a new factor promoting angiogenesis, we examined whether sCD146 priming could improve the therapeutic potential of ECFC and defined the involved mechanism.
Methods and resultsWe investigated the effects of sCD146 priming on regenerative properties of ECFC in vivo. In a mouse model of hindlimb ischaemia, the homing of radiolabelled cells to ischaemic tissue was assessed by SPECT-CT imaging. Soluble CD146 priming did not modify the number of engrafted ECFC but improved their survival capacity, leading to an enhanced revascularization. The mechanism of action of sCD146 on ECFC was studied in vitro. We showed that sCD146 acts in ECFC through a signalosome, located in lipid rafts, containing angiomotin, the short isoform of CD146 (shCD146), VEGFR1, VEGFR2, and presenilin-1. Soluble CD146 induced a sequential proteolytic cleavage of shCD146, with an extracellular shedding followed by an intramembrane cleavage mediated by matrix metalloprotease (MMP)/ADAM and presenilin-1, respectively. The generated intracellular part of shCD146 was directed towards the nucleus where it associated with the transcription factor CSL and modulated the transcription of genes involved in cell survival (FADD, Bcl-xl) and angiogenesis (eNOS). This effect was dependent on both VEGFR1 and VEGFR2, which were rapidly phosphorylated by sCD146.
ConclusionsThese findings establish that activation of the proteolytic processing of shCD146, in particular by sCD146, constitutes a promising pathway to improve endothelial progenitors' regenerative properties for the treatment of cardiovascular diseases.
Pulmonary hypertension is a progressive disease with poor prognosis, characterized by pathological inward remodelling and loss of patency of the lung vasculature. The right ventricle is co-affected by pulmonary hypertension, which triggers events such as hypoxia and/or increased mechanical load. Initially the right ventricle responds with ‘adaptive’ hypertrophy, which is often rapidly followed by ‘maladaptive’ changes leading to right heart decompensation and failure, which is the ultimate cause of death.
Methods and resultsWe report here that miR-223 is expressed in the murine lung and right ventricle at higher levels than in the left ventricle. Moreover, lung and right-ventricular miR-223 levels were markedly down-regulated by hypoxia. Correspondingly, increasing right-ventricular load by pulmonary artery banding, induced right-ventricular ischaemia, and the down-regulation of miR-223. Lung and right ventricle miR-223 down-regulation were linked with increased expression of the miR-223 target; insulin-like growth factor-I receptor (IGF-IR) and IGF-I downstream signalling. Similarly, miR-223 was decreased and IGF-IR increased in human pulmonary hypertension. Notably in young mice, miR-223 overexpression, the genetic inactivation or pharmacological inhibition of IGF-IR, all attenuated right-ventricular hypertrophy and improved right heart function under conditions of hypoxia or increased afterload.
ConclusionThese findings highlight the early role of pulmonary and right-ventricular miR-223 and the IGF-IR in the right heart failure programme initiated by pulmonary hypoxia and increased mechanical load and may lead to the development of novel therapeutic strategies that target the development of PH and right heart failure.
Arterial remodelling can cause luminal narrowing and obstruct blood flow. We tested the hypothesis that cellular acid–base transport facilitates proliferation and migration of vascular smooth muscle cells (VSMCs) and enhances remodelling of conduit arteries.
Methods and resultsNa+,HCO3–-cotransport via NBCn1 (Slc4a7) mediates net acid extrusion and controls steady-state intracellular pH (pHi) in VSMCs of mouse carotid arteries and primary aortic explants. Carotid arteries undergo hypertrophic inward remodelling in response to partial or complete ligation in vivo, but the increase in media area and thickness and reduction in lumen diameter are attenuated in arteries from NBCn1 knock-out compared with wild-type mice. With CO2/HCO3– present, gradients for pHi (~0.2 units magnitude) exist along the axis of VSMC migration in primary explants from wild-type but not NBCn1 knock-out mice. Knock-out or pharmacological inhibition of NBCn1 also reduces filopodia and lowers initial rates of VSMC migration after scratch-wound infliction. Interventions to reduce H+-buffer mobility (omission of CO2/HCO3– or inhibition of carbonic anhydrases) re-establish axial pHi gradients, filopodia, and migration rates in explants from NBCn1 knock-out mice. The omission of CO2/HCO3– also lowers global pHi and inhibits proliferation in primary explants.
ConclusionUnder physiological conditions (i.e. with CO2/HCO3– present), NBCn1-mediated HCO3– uptake raises VSMC pHi and promotes filopodia, VSMC migration, and hypertrophic inward remodelling. We propose that axial pHi gradients enhance VSMC migration whereas global acidification inhibits VSMC proliferation and media hypertrophy after carotid artery ligation. These findings support a key role of acid–base transport, particularly via NBCn1, for development of occlusive artery disease.
Myeloid-derived suppressor cells (MDSCs) form a heterogeneous population of cells composed of early myeloid progenitor cells and immature myeloid cells, which strongly suppress pro-inflammatory immune cells in inflammatory diseases. Currently, it is unknown whether MDSCs contribute to atherosclerosis, a chronic inflammatory disease in which accumulation of lipoproteins in the arterial wall activates the immune system causing abnormal vascular remodelling and vessel occlusion. Here, we investigated whether and how MDSCs contribute to the development of atherosclerosis.
Methods and resultsWe show that MDSCs arise in the bone marrow of LDLr–/– mice during atherosclerosis and strongly suppress proliferation of T cells. Adoptive transfer of MDSCs into both female and male LDLr–/– mice fed a Western-type diet (WTD) ameliorates atherosclerosis with 35%. We observed a 54% reduction in adventitial T cells, and more specifically, MDSCs suppress Th1 and Th17 cells. In addition, treatment with MDSCs reduces circulating pro-atherogenic B2 cells. We found two subsets of MDSCs in the bone marrow of hypercholesterolemic mice, monocytic and granulocytic MDSCs (mo- and gr-MDSCs, respectively), of which the percentage of mo-MDSCs significantly increased during WTD feeding. Moreover, mo-MDSCs completely abolished splenocyte proliferation, whereas gr-MDSCs were unable to suppress proliferation. Mechanistically, we show that MDSCs from atherosclerotic mice suppress T cells in an IFN-- and nitric oxide-dependent manner, which is associated with the action of mo-MDSCs.
ConclusionThis study demonstrates that MDSCs develop during atherosclerosis and reduce atherosclerosis via suppression of pro-inflammatory immune responses.
ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13, is a metalloprotease that cleaves von Willebrand factor (VWF). There is considerable evidence that VWF levels increase and ADAMTS13 levels decrease in ST-elevation myocardial infarction (STEMI) patients. It is unclear whether this contributes to no reflow, infarct size, and intramyocardial haemorrhage (IMH). We aimed to determine the role of ADAMTS13 in STEMI patients and to investigate the benefits of recombinant ADAMTS13 (rADAMTS13) in a porcine model of myocardial ischaemia-reperfusion.
Methods and resultsIn 49 consecutive percutaneous coronary intervention (PCI)-treated STEMI patients, blood samples were collected directly after through 7 days following PCI. Cardiac magnetic resonance was performed 4–6 days after PCI to determine infarct size and IMH. In 23 Yorkshire swine, the circumflex coronary artery was occluded for 75 min. rADAMTS13 or vehicle was administered intracoronary following reperfusion. Myocardial injury and infarct characteristics were assessed using cardiac enzymes, ECG, and histopathology. In patients with IMH, VWF activity and VWF antigen were significantly elevated directly after PCI and for all subsequent measurements, and ADAMTS13 activity significantly decreased at 4 and 7 days following PCI, in comparison with patients without IMH. VWF activity and ADAMTS13 activity were not related to infarct size. In rADAMTS13-treated animals, no differences in infarct size, IMH, or formation of microthrombi were witnessed compared with controls.
ConclusionsNo correlation was found between VWF/ADAMTS13 and infarct size in patients. However, patients suffering from IMH had significantly higher VWF activity and lower ADAMTS13 activity. Intracoronary administration of rADAMTS13 did not decrease infarct size or IMH in a porcine model of myocardial ischaemia-reperfusion. These data dispute the imbalance in ADAMTS13 and VWF as the cause of no reflow.
Cardiac angiogenesis is an important determinant of heart failure. We examined the hypothesis that protein tyrosine phosphatase (PTP)-1B, a negative regulator of vascular endothelial growth factor (VEGF) receptor-2 activation, is causally involved in the cardiac microvasculature rarefaction during hypertrophy and that deletion of PTP1B in endothelial cells prevents the development of heart failure.
Methods and resultsCardiac hypertrophy was induced by transverse aortic constriction (TAC) in mice with endothelial-specific deletion of PTP1B (End.PTP1B-KO) and controls (End.PTP1B-WT). Survival up to 20 weeks after TAC was significantly improved in mice lacking endothelial PTP1B. Serial echocardiography revealed a better systolic pump function, less pronounced cardiac hypertrophy, and left ventricular dilation compared with End.PTP1B-WT controls. Histologically, banded hearts from End.PTP1B-KO mice exhibited increased numbers of PCNA-positive, proliferating endothelial cells resulting in preserved cardiac capillary density and improved perfusion as well as reduced hypoxia, apoptotic cell death, and fibrosis. Increased relative VEGFR2 and ERK1/2 phosphorylation and greater eNOS expression were present in the hearts of End.PTP1B-KO mice. The absence of PTP1B in endothelial cells also promoted neovascularization following peripheral ischaemia, and bone marrow transplantation excluded a major contribution of Tie2-positive haematopoietic cells to the improved angiogenesis in End.PTP1B-KO mice. Increased expression of caveolin-1 as well as reduced NADPH oxidase-4 expression, ROS generation and TGFβ signalling were observed and may have mediated the cardioprotective effects of endothelial PTP1B deletion.
ConclusionsEndothelial PTP1B deletion improves cardiac VEGF signalling and angiogenesis and protects against chronic afterload-induced heart failure. PTP1B may represent a useful target to preserve cardiac function during hypertrophy.
Every song on My Chemical Romance's The Black Parade, ranked
Entertainment Weekly The record follows a character titled The Patient who's dying of cancer and visited by the Black Parade — a.k.a. death, a.k.a. My Chemical Romance. The fivesome — consisting then of brothers Gerard and Mikey Way along with Ray Toro, Frank Iero, and ... and more » |
