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Objective: Age and tooth loss are expected to have a complex relationship with oral health-related quality of life. So the purpose of this study was to explain the impact of age and tooth loss on oral health-related quality of life using the short form 14-item oral health impact profile (OHIP-14) among two population samples of Gujarat and Rajasthan. Materials and Methods: A cross-sectional questionnaire-based survey was conducted among 1441 subjects collected from two major cities of Gujarat and Rajasthan. Both questionnaire approaches using OHIP-14 scale and clinical examination were conducted in accordance with WHO criteria using type III procedure on the same day. Chi square test, ANOVA and stepwise multiple regression analysis were applied using SPSS software version 15.0. Results: With the increase of age, OHIP mean score in both states increased, but that among Rajasthan state was higher, depicting poor oral health. Whereas, in the remaining 23-27 number of teeth both states showed higher OHIP mean, however again the score was much higher among Rajasthan subjects showing worse oral hygiene. Hence, overall all mean OHIP score for Gujarat was lower indicating good oral health; whereas, that among Rajasthan was higher indicating poor oral health-related quality of life. Conclusion: Both age and tooth loss are associated with each other, but they have an independent effect on the oral health-related quality of life. Thus, all studied populations with complete natural dentition showed good oral health-related quality of life. [ABSTRACT FROM AUTHOR]

Automatic abdominal organ segmentation is an essential prerequisite for accurate volumetric analysis, disease diagnosis, and tracking by medical practitioners. However, the deformable shapes, variable locations, overlapping with nearby organs, and similar contrast make the segmentation challenging. Moreover, the requirement of a large manually labeled dataset makes it harder. Hence, a semi-supervised contrastive learning approach is utilized to perform the automatic abdominal organ segmentation. Existing 3D deep learning models based on contrastive learning are not able to capture the 3D context of medical volumetric data along three planes/views: axial, sagittal, and coronal views. In this work, a semi-supervised view-adaptive unified model (VAU-model) is proposed to make the 3D deep learning model as view-adaptive to learn 3D context along each view in a unified manner. This method utilizes the novel optimization function that assists the 3D model to learn the 3D context of volumetric medical data along each view in a single model. The effectiveness of the proposed approach is validated on the three types of datasets: BTCV, NIH, and MSD quantitatively and qualitatively. The results demonstrate that the VAU model achieves an average Dice score of 81.61% which is a 3.89% improvement compared to the previous best results for pancreas segmentation in multi-organ dataset BTCV. It also achieves an average Dice score of 77.76% and 76.76% for the pancreas under the single organ non-pathological NIH dataset, and pathological MSD dataset., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Esophageal carcinoma is a multifaceted and complex disease of rapidly rising incidence that exerts an increasing social and financial burden on global healthcare systems. Esophagectomy is associated with high rates of peri- and post-operative morbidity and mortality because of complex anatomy, frail health of patients, and late diagnosis of the disease. The most common complication seen is post-operative pulmonary complication (PPC). This study was planned to compare and analyze the outcome of two different protocols of preoperative IMT program on the rate of PPCs in patients undergoing esophagectomy. Twenty patients who underwent esophagectomy for carcinoma esophagus were included in the study and were randomly divided into 2 groups of 10 each. Group A received IMT-HI training for 4 weeks, whereas the group B received IMT-E training for 4 weeks pre-operatively. All the patients included in the study underwent a baseline pulmonary assessment which included pulmonary function test (FVC, FEV1, and FEV1/FVC), maximum inspiratory pressure (MIP), and maximum expiratory pressure (MEP). Four-week preoperative IMT-HI lead to better outcome following esophagectomy as compared to IMT-E. Relative risk of PPC was 4:1 (IMT-E:IMT-HI). However, there was no statistically significant improvement in PFTs, MEP, and MIP from baseline or between two groups. The difference in PPC in two groups did not reach statistical significance despite the fact that relative risk of PPC was 4:1 (IMT-E:IMT-HI)., Competing Interests: Conflict of InterestThe authors declare no competing interests., (© The Author(s), under exclusive licence to Indian Association of Surgical Oncology 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Harmony between facial complexion and gingival health goes hand in hand. Gingival depigmentation is an aesthetic correction of hyperactive melanocytes in gingival tissues that lead to hyperpigmentation. Current study compares depigmentation, pain scores, and itching with scalpel technique and nonsurgical intramucosal Vitamin C injection. 30 individuals in the age range of 18-40 years conscious of dark gums were randomly allocated to test and control group by lottery method. Thorough Phase I therapy was performed one week before the procedure. Area and intensity of depigmentation were evaluated preoperatively and postoperatively; pain score, itching, and repigmentation percentage were the postoperative parameters. After 24 hrs, test group showed significantly lesser VAS score for pain as compared to control group. There was no statistically significant difference in preoperative area of pigmentation between the test and control group ( p =0.936). Postoperatively also, there was no statistically significant difference in area of pigmentation between the test and control group ( p =0.932). For comparing area of pigmentation, an independent t -test was applied and Mann-Whitney test was used for differentiating the intensity of pigmentation, repigmentation, and VAS score between the groups. The study concluded that Vitamin C mesotherapy and scalpel technique showed comparable results in reduction of areas and intensity of gingival hyperpigmentation., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Dhanashree S. Chaudhary et al.)

The outlook of the World toward health infrastructure has drastically changed due to COVID-19 which created the need for the development of emerging technologies where interactions between the patients and the health workers can be minimized. Consequently, a secure and energy-efficient internet of medical things (IoMT) enabled wireless sensor network (WSN) is proposed for communicable infectious diseases that utilizes genetic algorithm. The proposed system makes use of movable sinks in IoT-enabled WSNs for healthcare called OptiGeA. The OptiGeA protocol is depicted for cluster heads (CHs) election by joining the factor of energy, density, distance, and heterogeneous node's capacity for fitness function. Additionally, a novel deployment technique and multiple mobile sink approaches are proposed to reduce transmission distance between sink and CH during system operation which mitigates hotspot issues. It is evident from the simulations that the OptiGeA protocol outflanks state-of-the-art protocols in terms of different performance measurements., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 Elsevier Ltd. All rights reserved.)

As largely documented in the literature, the stark restrictions enforced worldwide in 2020 to curb the COVID-19 pandemic also curtailed the production of air pollutants to some extent. This study investigates the perception of the air pollution as assessed by individuals located in ten countries: Australia, Brazil, China, Ghana, India, Iran, Italy, Norway, South Africa and the USA. The perceptions towards air quality were evaluated by employing an online survey administered in May 2020. Participants (N = 9394) in the ten countries expressed their opinions according to a Likert-scale response. A reduction in pollutant concentration was clearly perceived, albeit to a different extent, by all populations. The survey participants located in India and Italy perceived the largest drop in the air pollution concentration; conversely, the smallest variation was perceived among Chinese and Norwegian respondents. Among all the demographic indicators considered, only gender proved to be statistically significant., (© 2021. The Author(s).)

Ethnographers frequently allude to alcoholism and related harms in Indigenous hunter-gatherer communities, but very few studies have quantified patterns of alcohol consumption or its health and social impacts. We present a case study of the Mbendjele BaYaka, a Congolese population undergoing socioeconomic transition. 83 adults answered questions about their frequency and quantity of alcohol consumption, underwent biometric measurements and reported whether they were currently experiencing a cough or diarrhoea; 56 participated in structured interviews about their experiences with alcohol. Based on WHO standards, we found 44.3% of the full sample, and 51.5% of drinkers (excluding abstainers), had a hazardous volume of alcohol consumption; and 35.1% of the full sample, and 40.9% of drinkers, engaged in heavy episodic drinking; consumption habits varied with sex and age. Total weekly consumption was a positive predictor of blood pressure and the likelihood of experiencing diarrhoea; associations with other biometric variables were not statistically significant. Interview responses indicated numerous other economic, mental and physical health harms of alcohol use, the prevalence of which demonstrate some variability between forest camps and permanent village settlements. These include high rates of drinking during pregnancy and breastfeeding (~40%); frequent alcohol-induced violence; and considerable exchange of foraged foods and engagement in exploitative labour activities to acquire alcohol or repay associated debts. Our findings demonstrate the prevalence of hazardous alcohol consumption among transitioning hunter-gatherers is higher than other segments of the Congolese population and indicate negative impacts on health and wellbeing, highlighting an urgent need for targeted public health interventions., Competing Interests: The authors have declared that no competing interests exist.

The restrictive measures implemented in response to the COVID-19 pandemic have triggered sudden massive changes to travel behaviors of people all around the world. This study examines the individual mobility patterns for all transport modes (walk, bicycle, motorcycle, car driven alone, car driven in company, bus, subway, tram, train, airplane) before and during the restrictions adopted in ten countries on six continents: Australia, Brazil, China, Ghana, India, Iran, Italy, Norway, South Africa and the United States. This cross-country study also aims at understanding the predictors of protective behaviors related to the transport sector and COVID-19. Findings hinge upon an online survey conducted in May 2020 (N = 9,394). The empirical results quantify tremendous disruptions for both commuting and non-commuting travels, highlighting substantial reductions in the frequency of all types of trips and use of all modes. In terms of potential virus spread, airplanes and buses are perceived to be the riskiest transport modes, while avoidance of public transport is consistently found across the countries. According to the Protection Motivation Theory, the study sheds new light on the fact that two indicators, namely income inequality, expressed as Gini index, and the reported number of deaths due to COVID-19 per 100,000 inhabitants, aggravate respondents' perceptions. This research indicates that socio-economic inequality and morbidity are not only related to actual health risks, as well documented in the relevant literature, but also to the perceived risks. These findings document the global impact of the COVID-19 crisis as well as provide guidance for transportation practitioners in developing future strategies., Competing Interests: The authors have declared that no competing interests exist.

COVID-19 pandemic has heavily impacted the global community. To curb the viral transmission, travel restrictions have been enforced across the world. The dataset documents the mobility disruptions and the modal shifts that have occurred as a consequence of the restrictive measures implemented in ten countries: Australia, Brazil, China, Ghana, India, Iran, Italy, Norway, South Africa and the United States. An online questionnaire was distributed during the period from the 11st to the 31st of May 2020, with a total of 9 394 respondents. The first part of the survey has characterized the frequency of use of all transport modes before and during the enforcement of the restrictions, while the second part of the survey has dealt with perceived risks of contracting COVID-19 from different transport modes and perceived effectiveness of travel mitigation measures. Overall, the dataset (stored in a repository publicly available) can be conveniently used to quantify and understand the modal shifts and people's cognitive behavior towards travel due to COVID-19. The collected responses can be further analysed by considering other demographic and socioeconomic covariates., Competing Interests: This research has not received any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors declare that they have no known competing financial interests or personal relationships which have or could be perceived to have influenced the work reported in this article., (© 2020 The Author(s).)

The dataset deals with the air quality perceived by citizens before and during the enforcement of COVID-19 restrictions in ten countries around the world: Australia, Brazil, China, Ghana, India, Iran, Italy, Norway, South Africa and the United States. An online survey conveniently translated into Chinese, English, Italian, Norwegian, Persian, Portuguese collected information regarding the perceived quality of air pollution according to a Likert scale. The questionnaire was distributed between 11-05-2020 and 31-05-2020 and 9 394 respondents took part. Both the survey and the dataset (stored in a Microsoft Excel Worksheet) are available in a public repository. The collected data offer the people's subjective perspectives related to the objective improvement in air quality occurred during the COVID-19 restrictions. Furthermore, the dataset can be used for research studies involving the reduction in air pollution as experienced, to a different extent, by populations of all the ten countries., Competing Interests: This research has not received any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (© 2020 The Author(s).)

This article proposes the MapReduce scheduler with deadline and priorities (MRS-DP) scheduler capable of handling jobs with deadlines and priorities. Big data have emerged as a key concept and revolutionized data analytics in the present era. Big data are characterized by multiple dimensions or Vs, namely volume, velocity, variety, veracity, and valence. Recently, a new and important dimension (another V) is added, known as value. Value has emerged as an important characteristic and it can be understood in terms of delay in acquiring information, leading to late decisions that may result in missed opportunities. To gain optimal benefits, this article introduces a scheduler based on jobs with deadlines and priorities intending to improve resource utilization, with efficient job progress monitoring and backup launching mechanism. The proposed scheduler is capable of accommodating multiple jobs to maximize the number of jobs processed successfully and avoid starvation of lower priority jobs while improving the resource utilization and ensuring the assured quality of service (QoS). To evaluate our proposed scheduler, we ran multiple workloads consisting of the WordCount jobs and DataSort jobs. The performance of the proposed MRS-DP scheduler is compared with minimal earliest deadline first-work conserving scheduler and MapReduce Constraint Programming based Resource Management algorithm in terms of the percentage of successful jobs, priority-wise jobs, and resource utilization of the cluster. The result of the proposed scheduler depicts an improvement of around 10%-20% in terms of the percentage of successful jobs, 20%-25% concerning effective resource utilization offered, and the ability to ensure the offered QoS.

Cultures around the world are converging as populations become more connected. On the one hand this increased connectedness can promote the recombination of existing cultural practices to generate new ones, but on the other it may lead to the replacement of traditional practices and global WEIRDing . Here we examine the process and causes of changes in cultural traits concerning wild plant knowledge in Mbendjele BaYaka hunter-gatherers from Congo. Our results show that the BaYaka who were born in town reported knowing and using fewer plants than the BaYaka who were born in forest camps. Plant uses lost in the town-born BaYaka related to medicine. Unlike the forest-born participants, the town-born BaYaka preferred Western medicine over traditional practices, suggesting that the observed decline of plant knowledge and use is the result of replacement of cultural practices with the new products of cumulative culture., Competing Interests: The authors declare no competing interests., (© The Author(s) 2020.)

The MapReduce programming model was designed and developed for Google File System to efficiently process large-scale distributed data sets. The open source implementation of this Google project was called the Apache Hadoop. Hadoop architecture includes Hadoop MapReduce and Hadoop Distributed File System (HDFS). HDFS supports Hadoop in effectively managing data sets over the cluster and MapReduce programming paradigm helps in the efficient processing of large data sets. MapReduce strategically re-executes a speculative task on some other node to finish the computation quickly, enhancing the overall Quality of Service (QoS). Several mechanisms were suggested over the Hadoop's Default Scheduler to improve the speculative task execution over Hadoop cluster. A large number of strategies were also suggested for scheduling jobs with deadlines. The mechanisms for speculative task execution were not developed for or were not well integrated with Deadline Schedulers. This article presents an improved speculative task detection algorithm, designed specifically for Deadline Scheduler. Our studies suggest the importance of keeping a regular track of node's performance to re-execute the speculative tasks more efficiently. We have successfully improved the QoS offered by Hadoop clusters over the jobs arriving with deadlines in terms of the percentage of successfully completed jobs, the detection time of speculative tasks, the accuracy of correct speculative task detection, and the percentage of incorrectly fagged speculative tasks.

Objectives: To determine the incidence of readmission in pediatric patients in a tertiary care hospital in a developing nation and to ascertain factors precipitating readmissions., Methods: A prospective study was conducted from February 2016 through January 2017 at a tertiary care hospital. Children between 1 mo to 15 y of age were included if they were readmitted within 60 d of discharge. The risk factors for readmission were determined on the basis of medical record review and a structured questionnaire and the ascribed cause of readmission was grouped into three categories: Patient specific factors, Hospital specific factors and Unrelated/ New illness., Results: The readmission rate was 3%, out of which 80.66% were found to be causally related to the index admission. Several sociodemographic characteristics i.e. lack of health information like television, lower socioeconomic status, absence of adequate breastfeeding, lower age, migrants were found to be significantly associated with readmission along with other patient specific factors like presence of cardiac disease, presence of comorbid conditions like anemia, malnutrition, and global developmental delay. The most important cause for readmission was determined as patient specific (48.66%) followed by hospital specific (38%) and unknown/unrelated factors (13.33%)., Conclusions: The progression of the primary illness and social determinants of pediatric readmissions are important contributing risk factors for readmission in developing countries in pediatric patients. Multicentric studies are needed from this region of the world to include different hospital readmissions rate and to address the issue of potential preventability of pediatric readmissions.

Pulmonary hypertension (PH) is a deadly condition with limited treatment options. Early studies implicated hypoxia-inducible factors as contributing to the development of hypoxia-induced PH. Recently, the use of cells derived from patients and transgenic animals with cell specific deletions for various parts of the HIF system have furthered our understanding of the mechanisms by which HIFs control pulmonary vascular tone and remodeling to promote PH. Additionally, identification of HIF inhibitors further allows assessment of the potential for targeting HIFs to prevent and/or reverse PH. In this review, recent findings exploring the role of HIFs as potential mediators and therapeutic targets for PH are discussed.

Purpose: To determine whether the absence of transglutaminase 2 enzyme (TG2) in TG2 knockout mice (TG2-/-) protect them against early age-related functional and histological arterial changes., Methods: Pulse wave velocity (PWV) was measured using non-invasive Doppler and mean arterial pressure (MAP) was measured in awake mice using tail-cuff system. Thoracic aortas were excised for evaluation of endothelial dependent vasodilation (EDV) by wire myography, as well as histological analyses., Results: PWV and MAP were similar in TG2-/-mice to age-matched wild type (WT) control mice. Old WT mice exhibited a markedly attenuated EDV as compared to young WT animals. The TG2-/-young and old mice had enhanced EDV responses (p<0.01) as compared to WT mice. There was a significant increase in TG2 crosslinks by IHC in WT old group compared to Young, with no stain in the TG2-/-animals. Optical microscopy examination of Old WT mice aorta showed thinning and fragmentation of elastic laminae. Young WT mice, old and young TG2-/-mice presented regularly arranged and parallel elastic laminae of the tunica media., Conclusion: The genetic suppression of TG2 delays the age-induced endothelial dysfunction and histological modifications.

Study Design: Phase I Clinical Trial., Objectives: In this proof-of-principle study, the effectiveness and safety of transdermal administration of neostigmine/glycopyrrolate to elicit a bowel movement was compared to intravenous administration in patients with spinal cord injury., Setting: James J. Peters Veterans Affairs Medical Center (Bronx, NY)., Methods: Individuals were screened for responsiveness (Physical Response) to intravenous neostigmine (0.03 mg/kg)/glycopyrrolate (0.006 mg/kg). Intravenous neostigmine/glycopyrrolate responders (Therapeutic Response) were administered low-dose transdermal neostigmine/glycopyrrolate [(0.05 mg/kg)/(0.01 mg/kg)] by iontophoresis. Non-responders to low-dose transdermal neostigmine/glycopyrrolate were administered high-dose transdermal neostigmine/glycopyrrolate [(0.07 mg/kg)/(0.014 mg/kg)] by iontophoresis. Bowel movement, bowel evacuation time, and cholinergic side effects were recorded. Visits were separated by 2 to 14 days., Results: Eighteen of 25 individuals (72.0%) had a bowel movement (20 ± 22 min) after intravenous neostigmine/glycopyrrolate. Of these 18 individuals, 5 individuals experienced a bowel movement with low-dose transdermal neostigmine/glycopyrrolate. Another five individuals had a bowel movement after high-dose transdermal neostigmine/glycopyrrolate administration. Fewer side effects were observed in individuals who received neostigmine/glycopyrrolate transdermally compared to those who were administered intravenous neostigmine/glycopyrrolate., Conclusions: Transdermal administration of neostigmine/glycopyrrolate by iontophoresis appears to be a practical, safe, and effective approach to induce bowel evacuation in individuals with spinal cord injury.

We recently demonstrated that blue light induces vasorelaxation in the systemic mouse circulation, a phenomenon mediated by the nonvisual G protein-coupled receptor melanopsin (Opsin 4; Opn4). Here we tested the hypothesis that nonvisual opsins mediate photorelaxation in the pulmonary circulation. We discovered Opsin 3 (Opn3), Opn4, and G protein-coupled receptor kinase 2 (GRK2) in rat pulmonary arteries (PAs) and in pulmonary arterial smooth muscle cells (PASMCs), where the opsins interact directly with GRK2, as demonstrated with a proximity ligation assay. Light elicited an intensity-dependent relaxation of PAs preconstricted with phenylephrine (PE), with a maximum response between 400 and 460 nm (blue light). Wavelength-specific photorelaxation was attenuated in PAs from Opn4 -/- mice and further reduced following shRNA-mediated knockdown of Opn3. Inhibition of GRK2 amplified the response and prevented physiological desensitization to repeated light exposure. Blue light also prevented PE-induced constriction in isolated PAs, decreased basal tone, ablated PE-induced single-cell contraction of PASMCs, and reversed PE-induced depolarization in PASMCs when GRK2 was inhibited. The photorelaxation response was modulated by soluble guanylyl cyclase but not by protein kinase G or nitric oxide. Most importantly, blue light induced significant vasorelaxation of PAs from rats with chronic pulmonary hypertension and effectively lowered pulmonary arterial pressure in isolated intact perfused rat lungs subjected to acute hypoxia. These findings show that functional Opn3 and Opn4 in PAs represent an endogenous "optogenetic system" that mediates photorelaxation in the pulmonary vasculature. Phototherapy in conjunction with GRK2 inhibition could therefore provide an alternative treatment strategy for pulmonary vasoconstrictive disorders.

Aging is associated with increased cardiomyocyte loss, left-ventricular hypertrophy, and the accumulation of extracellular matrix, which results in declining cardiac function. The role of the matrix crosslinking enzyme, tissue transglutaminase (TG2), in age-related myocardial stiffness, and contractile function remains incompletely understood. In this study, we examined the role of TG2 in cardiac function, and determined whether TG2 inhibition can prevent age-associated changes in cardiac function. Male Fisher rats (18-month-old) were administered the transglutaminase inhibitor cystamine (study group) or saline (age-matched controls) for 12 weeks via osmotic mini-pumps. Cardiac function was determined by echocardiography and invasive pressure-volume loops. Rat hearts were dissected out, and TG2 expression, activity, and S-nitrosation were determined. Young (6-month-old) males were used as controls. TG2 activity significantly increased in the saline-treated but not in the cystamine-treated aging rat hearts. TG2 expression also increased with age and was unaltered by cystamine treatment. Aged rats showed increased left ventricular (LV) end-systolic dimension and a decrease in fractional shortening compared with young, which was not affected by cystamine. However, cystamine treatment preserved the preload-independent index of LV filling pressure and restored end-diastolic pressure, end-diastolic pressure-volume relationships, and arterial elastance toward young. An increase in TG2 activity contributes to age-associated increase in diastolic stiffness, thereby contributing to age-associated diastolic dysfunction. TG2 may thus represent a novel target for age-associated diastolic heart failure.

Background: In sickle cell disease (SCD), hemolysis results in the release and activation of arginase, an enzyme that reciprocally regulates nitric oxide (NO) synthase activity and thus, NO production. Simply supplementing the common substrate L-arginine, however, fails to improve NO bioavailability. In this study, we tested the hypothesis that arginase inhibition would improve NO bioavailability and thereby attenuate systemic and pulmonary vascular endothelial dysfunction in transgenic mice with SCD., Methods: We studied 5-month-old transgenic sickle cell (SC) mice and age matched wild-type (WT) controls. SC mice were treated with the arginase inhibitor, 2(S)-amino-6-boronohexanoic acid (ABH; approximately 400 μg/d) for 4 weeks or left untreated., Results: Vascular arginase activity was significantly higher at baseline in untreated SC mice compared to WT controls (SC versus WT, 346 ± 69.3 vs 69 ± 17.3 pmol urea/mg protein/minute; P = 0.0043; n = 4-5 animals per group). Treatment with ABH may significantly decrease arginase activity to levels near WT controls (SC + ABH 125.2 ± 17.3 pmol urea/mg protein/minute; P = 0.0213). Aortic strips from untreated SC mice showed decreased NO and increased reactive oxygen species (ROS) production (NO: fluorescence rate 0.76 ± 0.14 vs 1.34 ± 0.17 RFU/s; P = 0.0005 and ROS: fluorescence rate 3.96 ± 1.70 vs 1.63 ± 1.20 RFU/s, P = 0.0039; n = 3- animals per group). SC animals treated with ABH for 4 weeks demonstrated NO (fluorescence rate: 1.16 ± 0.16) and ROS (fluorescence rate: 2.02 ± 0.45) levels comparable with age-matched WT controls (n = 3- animals per group). The maximal endothelial-dependent vasorelaxation response to acetylcholine was impaired in aortic rings from SC mice compared with WT (57.7% ± 8.4% vs 80.3% ± 11.0%; P = 0.02; n = 6 animals per group). The endothelial-independent response was not different between groups. In SC mice, the right ventricular cardiac output index and end-systolic elastance were similar (4.60 ± 0.51 vs 2.9 ± 0.85 mL/min/100 g and 0.89 ± 0.48 vs 0.58 ± 0.11 mm Hg/μL), whereas the pulmonary vascular resistance index and right ventricular end-systolic pressure were greater (2.9 ± 0.28 vs 5.5 ± 2.0 mm Hg × min/μL/100 g and 18.9 ± 1.1 vs 23.1 ± 4.0 mm Hg; n = 8 animals per group). Pulse wave velocity (a measure of arterial stiffness) was greater in SC mice compared with WT (3.74 ± 0.54 vs 3.25 ± 0.21 m/s; n = 20 animals per group), arginase inhibition for 4 weeks significantly reduced the vascular SC phenotype to one similar to WT animals (P = 0.0009)., Conclusions: Arginase inhibition improves NO bioavailability and thereby attenuates systemic and pulmonary vascular endothelial dysfunction in transgenic mice with SCD. Therefore, arginase is a potential therapeutic target in the treatment of cardiovascular dysfunction in SCD., Competing Interests: The authors declare no conflicts of interest.

Pulse wave velocity (PWV) and pulse pressure (PP) are blood pressure (BP)-dependent surrogates for vascular stiffness. Considering that there are no clinically useful markers for arterial stiffness that are BP-independent, our objective was to identify novel indices of arterial stiffness and compare them with previously described markers. PWV and PP were measured in young and old male Fisher rats and in young and old male spontaneously hypertensive rats (SHR) over a wide range of BPs. The BP dependence of these and several other indices of vascular stiffness were evaluated. An index incorporating PWV and PP was also constructed. Both PWV and PP increase in a non-linear manner with rising BP for both strains of animals (Fisher and SHRs). Age markedly changes the relationship between PWV or PP and BP. The previously described Ambulatory Arterial Stiffness Index (AASI) was able to differentiate between young and old vasculature, whereas the Cardio-Ankle Vascular Index (CAVI) did not reliably differentiate between the two. The novel Arterial Stiffness Index (ASI) differentiated stiffer from more compliant vasculature. Considering the limitations of the currently available indices of arterial stiffness, we propose a novel index of intrinsic arterial stiffness, the ASI, which is robust over a range of BPs and allows one to distinguish between compliant and stiff vasculature in both Fisher rats and SHRs. Further studies are necessary to validate this index in other settings.

Nitroxyl (HNO), the reduced and protonated form of nitric oxide (NO·), confers unique physiological effects including vasorelaxation and enhanced cardiac contractility. These features have spawned current pharmaceutical development of HNO donors as heart failure therapeutics. HNO interacts with selective redox sensitive cysteines to effect signaling but is also proposed to activate soluble guanylate cyclase (sGC) in vitro to induce vasodilation and potentially enhance contractility. Here, we tested whether sGC stimulation is required for these HNO effects in vivo and if HNO also modifies a redox-sensitive cysteine (C42) in protein kinase G-1α to control vasorelaxation. Intact mice and isolated arteries lacking the sGC-β subunit (sGCKO, results in full sGC deficiency) or expressing solely a redox-dead C42S mutant protein kinase G-1α were exposed to the pure HNO donor, CXL-1020. CXL-1020 induced dose-dependent systemic vasodilation while increasing contractility in controls; however, vasodilator effects were absent in sGCKO mice whereas contractility response remained. The CXL-1020 dose reversing 50% of preconstricted force in aortic rings was ≈400-fold greater in sGCKO than controls. Cyclic-GMP and cAMP levels were unaltered in myocardium exposed to CXL-1020, despite its inotropic-vasodilator activity. In protein kinase G-1α(C42S) mice, CXL-1020 induced identical vasorelaxation in vivo and in isolated aortic and mesenteric vessels as in littermate controls. In both groups, dilation was near fully blocked by pharmacologically inhibiting sGC. Thus, sGC and cGMP-dependent signaling are necessary and sufficient for HNO-induced vasodilation in vivo but are not required for positive inotropic action. Redox modulation of protein kinase G-1α is not a mechanism for HNO-mediated vasodilation., (© 2014 American Heart Association, Inc.)

Melanopsin (opsin4; Opn4), a non-image-forming opsin, has been linked to a number of behavioral responses to light, including circadian photo-entrainment, light suppression of activity in nocturnal animals, and alertness in diurnal animals. We report a physiological role for Opn4 in regulating blood vessel function, particularly in the context of photorelaxation. Using PCR, we demonstrate that Opn4 (a classic G protein-coupled receptor) is expressed in blood vessels. Force-tension myography demonstrates that vessels from Opn4(-/-) mice fail to display photorelaxation, which is also inhibited by an Opn4-specific small-molecule inhibitor. The vasorelaxation is wavelength-specific, with a maximal response at ∼430-460 nm. Photorelaxation does not involve endothelial-, nitric oxide-, carbon monoxide-, or cytochrome p450-derived vasoactive prostanoid signaling but is associated with vascular hyperpolarization, as shown by intracellular membrane potential measurements. Signaling is both soluble guanylyl cyclase- and phosphodiesterase 6-dependent but protein kinase G-independent. β-Adrenergic receptor kinase 1 (βARK 1 or GRK2) mediates desensitization of photorelaxation, which is greatly reduced by GRK2 inhibitors. Blue light (455 nM) regulates tail artery vasoreactivity ex vivo and tail blood blood flow in vivo, supporting a potential physiological role for this signaling system. This endogenous opsin-mediated, light-activated molecular switch for vasorelaxation might be harnessed for therapy in diseases in which altered vasoreactivity is a significant pathophysiologic contributor.

Objective: Arginase 2 (Arg2) is a critical target in atherosclerosis because it controls endothelial nitric oxide, proliferation, fibrosis, and inflammation. Regulators of Arg2 transcription in the endothelium have not been characterized. The goal of the current study is to determine the role of specific histone deacetylases (HDACs) in the regulation of endothelial Arg2 transcription and endothelial function., Approach and Results: The HDAC inhibitor trichostatin A increased levels of Arg2 mRNA, protein, and activity in both human aortic endothelial cells and mouse aortic rings. These changes occurred in both time- and dose-dependent patterns and resulted in Arg2-dependent endothelial dysfunction. Trichostatin A and the atherogenic stimulus oxidized low-density lipoprotein enhanced the activity of common promoter regions of Arg2. HDAC inhibition with trichostatin A also decreased endothelial nitric oxide, and these effects were blunted by arginase inhibition. Nonselective class I HDAC inhibitors enhanced Arg2 expression, whereas the only selective inhibitor that increased Arg2 expression was mocetinostat, a selective inhibitor of HDACs 1 and 2. Additionally, mouse aortic rings preincubated with mocetinostat exhibited dysfunctional relaxation. Overexpression of HDAC2 (but not HDAC 1, 3, or 8) cDNA in human aortic endothelial cells suppressed Arg2 expression in a concentration-dependent manner, and siRNA knockdown of HDAC2 enhanced Arg2 expression. Chromatin immunoprecipitation indicated direct binding of HDAC2 to the Arg2 promoter, and HDAC2 overexpression in human aortic endothelial cells blocked oxidized low-density lipoprotein-mediated activation of the Arg2 promoter. Finally, overexpression of HDAC2 blocked oxidized low-density lipoprotein-mediated vascular dysfunction., Conclusions: HDAC2 is a critical regulator of Arg2 expression and thereby endothelial nitric oxide and endothelial function. Overexpression or activation of HDAC2 represents a novel therapy for endothelial dysfunction and atherosclerosis., (© 2014 American Heart Association, Inc.)

Background: Vascular aging is closely associated with increased vascular stiffness. It has recently been demonstrated that decreased nitric oxide (NO)-induced S-nitrosylation of tissue transglutaminase (TG2) contributes to age-related vascular stiffness. In the current study, we tested the hypothesis that exercise restores NO signaling and attenuates vascular stiffness by decreasing TG2 activity and cross-linking in an aging rat model., Methods and Results: Rats were subjected to 12 weeks of moderate aerobic exercise. Aging was associated with diminished phosphorylated endothelial nitric oxide synthase and phosphorylated vasodilator-stimulated phosphoprotein abundance, suggesting reduced NO signaling. TG2 cross-linking activity was significantly increased in old animals, whereas TG2 abundance remained unchanged. These alterations were attenuated in the exercise cohort. Simultaneous measurement of blood pressure and pulse wave velocity (PWV) demonstrated increased aortic stiffness in old rats, compared to young, at all values of mean arterial pressure (MAP). The PWV-MAP correlation in the old sedentary and old exercise cohorts was similar. Tensile testing of the vessels showed increased stiffness of the aorta in the old phenotype with a modest restoration of mechanical properties toward the young phenotype with exercise., Conclusions: Increased vascular stiffness during aging is associated with decreased TG2 S-nitrosylation, increased TG2 cross-linking activity, and increased vascular stiffness likely the result of decreased NO bioavailability. In this study, a brief period of moderate aerobic exercise enhanced NO signaling, attenuated TG cross-linking activity, and reduced ex vivo tensile properties, but failed to reverse functional vascular stiffness in vivo, as measured by PWV.

Background: Red blood cell (RBC) deformation is critical for microvascular perfusion and oxygen delivery to tissues. Abnormalities in RBC deformability have been observed in aging, sickle cell disease, diabetes, and preeclampsia. Although nitric oxide (NO) prevents decreases in RBC deformability, the underlying mechanism is unknown., Study Design and Methods: As an experimental model, we used ionophore A23187-mediated calcium influx in RBCs to reduce their deformability and investigated the role of NO donor sodium nitroprusside (SNP) and KCa3.1 (Gardos) channel blockers on RBC deformability (measured as elongation index [EI] by microfluidic ektacytometry). RBC intracellular Ca(2+) and extracellular K(+) were measured by inductively coupled plasma mass spectrometry and potassium ion selective electrode, respectively., Results: SNP treatment of RBCs blocked the Ca(2+) (approx. 10 μmol/L)-induced decrease in RBC deformability (EI 0.34 ± 0.02 vs. 0.09 ± 0.01, control vs. Ca(2+) loaded, p < 0.001; and EI 0.37 ± 0.02 vs. 0.30 ± 0.01, SNP vs. SNP plus Ca(2+) loaded) as well as Ca(2+) influx and K(+) efflux. The SNP effect was similar to that observed after pharmacologic blockade of the KCa3.1 channel (with charybdotoxin or extracellular medium containing isotonic K(+) concentration). In RBCs from KCa3.1(-/-) mice, 10 μmol/L Ca(2+) loading did not decrease cellular deformability. A preliminary attempt to address the molecular mechanism of SNP protection suggests the involvement of cell surface thiols., Conclusion: Our results suggest that nitroprusside treatment of RBCs may protect them from intracellular calcium increase-mediated stiffness, which may occur during microvascular perfusion in diseased states, as well as during RBC storage., (Published 2013. This article is a U.S. Government work and is in the public domain in the USA.)

Background: Cigarette smoke increases the risk of several cardiovascular diseases and has synergistic detrimental effects when present with other risks that contribute to its pathogenesis. Oxidative injury to the endothelium via reactive oxygen species (ROS) and nitric oxide (NO) dysregulation is a common denominator of smoking-induced alterations in vascular function. However, the mechanisms underlying ROS and NO dysregulation due to smoking remain unclear. We tested if arginase (Arg) activation/upregulation contributes to this phenomenon by constraining nitric oxide synthase (NOS) activity., Methods: Arg2 knockout (Arg2(-/-)) and control C57BL/6J mice were either exposed to cigarette smoke, 6 h/day/2 weeks (Second Hand Smoking; SHS) or housed in normal environment (Non Smoking; NS). Arg activity, NO and ROS levels were determined by measuring urea production, fluorescent dye (DAF), and dihydroethedium (DHE) respectively in isolated mouse aorta., Results: Arg activity and ROS levels were higher NO lower in SHS compared to NS mice. SHS failed to lower NO levels in Arg2(-/-) mice. Endothelial dependent vasodilation (EDV) was attenuated in SHS mice as compared to controls (78.80% ± 8 vs 46.58% ± 5). This impaired EDV was abolished in Arg2(-/-) mice (67.48% ± 7 in SHS vs. 78.80% ± 8 in NS). Vascular stiffness was increased in SHS mice as compared to NS controls but remained unchanged in Arg2(-/-) mice., Conclusion: Endothelial NOS is uncoupled by smoking exposure, leading to endothelial dysfunction and vascular stiffness, a process that is prevented by Arg2 deletion. Hence, we identify Arg2 upregulation as a critical pathogenic factor and target for therapy in oxidative injury following smoking exposure through reciprocal regulation of endothelial NOS., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)