Assessing the Influence of Intraoperative Core Body Temperature on Postoperative Venous Thromboembolism after Abdominal Wall Reconstruction.

Background: Venous thromboembolism (VTE) is a dangerous postoperative complication after abdominal wall reconstruction (AWR). Intraoperative core body temperature has been associated with thrombotic events in other surgical contexts. This study examines the effects of intraoperative temperature on VTE rate after AWR. Methods: A retrospective study was performed on AWR patients. Cohorts were defined by postoperative 30-day VTE. Intraoperative core body temperature was recorded as the minimum, maximum, and mean intraoperative temperatures. Study variables were analyzed with logistic regression and cutoff analysis to assess for association with VTE. Results: In total, 344 patients met inclusion criteria. Fourteen patients were diagnosed with 30-day VTE for an incidence of 4.1%. The VTE cohort had a longer median inpatient stay (8 days versus 5 days, P < 0.001) and greater intraoperative change in peak inspiratory pressure (3 mm H2O versus 1 mm H2O, P = 0.01) than the non-VTE cohort. Operative duration [odds ratio (OR) = 1.32, P = 0.01], length of stay (OR = 1.07, P = 0.001), and intraoperative PIP difference (OR = 1.18, P = 0.045) were significantly associated with 30-day VTE on univariable regression. Immunocompromised status (OR = 4.1, P = 0.023; OR = 4.0, P = 0.025) and length of stay (OR = 1.1, P < 0.001; OR = 1.1, P < 0.001) were significant predictors of 30-day VTE on two multivariable regression models. No significant associations were found between temperature metrics and 30-day VTE on cutoff point or regression analysis. Conclusions: Intraoperative core body temperature did not associate with 30-day VTE after AWR, though operative duration, length of stay, immunocompromised status, and intraoperative PIP difference did. Surgeons should remain mindful of VTE risk after AWR, and future research is warranted to elucidate all contributing factors.

A Quality Improvement Initiative for Echocardiogram Ordering Patterns in an Academic Hospital.

Background Appropriate Use Criteria (AUC) for echocardiography are a useful tool to deliver quality healthcare. Our quality-based interventional study was designed to assess the trends in appropriate utilization rates for echocardiography in our institution and improve adherence to the AUC criteria for transthoracic echocardiograms (TTE). Methodology A prospective, time series analysis was conducted at the Upstate University Hospital for the months of July 2019 and August 2020. A chart analysis was performed on 620 consecutive inpatients who underwent TTE for the month of July 2019. We assessed the trends of the appropriate ordering of TTEs. We then updated our order form incorporating the 42 most common appropriate indications. A post-intervention chart analysis was performed on all inpatient TTEs ordered for the month of August 2020 (n = 410). The appropriateness of the TTE for the entire group was determined based on the true indication per chart review. The primary outcome was the proportion of appropriate and inappropriate TTEs ordered. Secondary outcomes included assessing for concordance between the indication on the order requisition form and by chart review. A p-value <0.05 was considered significant. Results Using the 2011 AUC for the entire group, 81% of the pre-intervention TTEs and 79.5% of the post-intervention TTEs were appropriate (p = 0.55). There was a statistically significant reduction in the number of discordant TTE orders before and after the intervention (p < 0.01). In addition, we noted increased appropriateness of TTEs in the concordant group both pre and post-intervention. Conclusions Our study demonstrates a significant increase in the concordance between the TTE order sheet and actual indication per chart review with the intervention. This can translate into improved scanning and physician reading quality and time, thereby increasing focus on areas of interest according to the true indication. There was no significant increase in the appropriate TTEs ordered.

Measuring transversus abdominis activity using pressure biofeedback unit-A technical report.

BACKGROUND AND PURPOSE: Pressure biofeedback is a tool that can detect the movement of a structure and may be used as an indicator of muscle function. It's widely used to measure the transversus abdominis (TrA) muscle activity. Pressure biofeedback (PBU) monitors the abdominal wall movement by measuring the pressure change during abdominal hollowing and can indirectly evaluate the TrA muscle function, which is considered as a valuable tool. The evaluation of the training of core muscles, including the transversus abdominis, requires a reliable outcome. Various methods using different positions are used to evaluate the transversus abdominis muscle function. However, it is noted that a standard way of evaluation and training still needs to be improved in research and clinical practice. This technical report discusses the optimal position and technique to measure the TrA muscle activity using PBU, with discussions on the merits and demerits of the body positions. METHODS: The technical report is presented with a literature review of the PBU measurement of TrA and through observation in the clinical practice. The evaluation methods of TrA, including the position to activate and isolate, are discussed in detail. RESULTS: Training core muscles does not imply TrA activation, and evaluating isolated TrA and multifidus is essential before intervention. The abdominal drawing-in maneuver effectively activates TrA in various evaluation positions of the body, but when using PBUs, it would be valid in a prone position. DISCUSSION: Different body positions are practiced to train TrA and core muscles using PBU, commonly adopted by practice are in supine. It's noted that most of the studies lack in establishing the effectiveness of the position in evaluating the TrA muscle activity using PBU. The need for insight into an appropriate technique for evaluating TrA activity is addressed in this technical report. This report presents key points on the complete technique and concludes that the prone position is superior to other positions and recommended for measuring and recording the TrA activity using a PBU.

Tobacco cessation after head and neck cancer diagnosis is an independent predictor of treatment response and long-term survival.

Head and neck squamous cell carcinoma (HNSCC) patients who are current smokers when diagnosed have inferior clinical outcomes compared to never-smokers or previous smokers. However, the impact of quitting after HNSCC diagnosis has not been quantified. In this retrospective, case-control study (n = 134), the odds of complete response to first-line therapy were 3.7 times higher among smokers at diagnosis who quit before treatment initiation (quitters; n = 55) than among those continuing to smoke (p = 0.03). Disease-free survival was also higher among quitters (aHR, 0.33; 95 % CI, 0.12-0.90; p = 0.029). Quitters were 67 % less likely to die of all causes than active smokers (aHR, 0.33; 95 % CI, 0.15-0.71; p = 0.004). These data show for the first time that, smoking cessation after HNSCC diagnosis is predictive of higher therapy efficacy and long-term survival.

Child and Adolescent Mental Health Training Programs for Non-specialist Mental Health Professionals in Low and Middle Income Countries: A Scoping Review of Literature.

Large treatment deficits in child and adolescent mental health (CAMH) care exist in low and middle income countries (LMICs). This study reviewed CAMH training programs for non-specialist health professionals (NSHPs) in LMICs. Multiple databases were searched for peer-reviewed articles describing programs from 2005 to 2018. Educational source materials, trainee evaluation methods, and perspectives on teaching methods, course content and scheduling were studied. Six programs were identified. NSHPs were most appreciative of training which included case-based discussions, role plays and clinical demonstrations that were relevant to local contexts. A need for less intense and more flexible timetables to enable reflection was identified. WHO's mental health gap action program intervention guide (mhGAP-IG) and international association of child and adolescent psychiatrists and allied professionals resources should be used; they are free, easily accessible, and developed with extensive international contributions. Additionally, mhGAP-IG assessment tool encourages mutual learning, thereby iteratively enhancing training programs.

Cholecalciferol and metformin protect against lipopolysaccharide-induced endothelial dysfunction and senescence by modulating sirtuin-1 and protein arginine methyltransferase-1.

Endothelial cell activation through nuclear factor-kappa-B (NFkB) and mitogen-activated protein kinases leads to increased biosynthesis of pro-inflammatory mediators, cellular injury and vascular inflammation under lipopolysaccharide (LPS) exposure. Recent studies report that LPS up-regulated global methyltransferase activity. In this study, we observed that a combination treatment with metformin (MET) and cholecalciferol (VD) blocked the LPS-induced S-adenosylmethionine (SAM)-dependent methyltransferase (SDM) activity in Eahy926 cells. We found that LPS challenge (i) increased arginine methylation through up-regulated protein arginine methyltransferase-1 (PRMT1) mRNA, intracellular concentrations of asymmetric dimethylarginine (ADMA) and homocysteine (HCY); (ii) up-regulated cell senescence through mitigated sirtuin-1 (SIRT1) mRNA, nicotinamide adenine dinucleotide (NAD+) concentration, telomerase activity and total antioxidant capacity; and (iii) lead to endothelial dysfunction through compromised nitric oxide (NOx) production. However, these LPS-mediated cellular events in Eahy926 cells were restored by the synergistic effect of MET and VD. Taken together, this study identified that the dual compound effect inhibits LPS-induced protein arginine methylation, endothelial senescence and dysfunction through the components of epigenetic machinery, SIRT1 and PRMT1, which is a previously unidentified function of the test compounds. In silico results identified the presence of vitamin D response element (VDRE) sequence on PRMT1 suggesting that VDR could regulate PRMT1 gene expression. Further characterization of the cellular events associated with the dual compound challenge, using gene silencing approach or adenoviral constructs for SIRT1 and/or PRMT1 under inflammatory stress, could identify therapeutic strategies to address the endothelial consequences in vascular inflammation-mediated atherosclerosis.

Traumatic aortic root rupture leading to acute aortic regurgitation and acute type A aortic dissection.

A 17-year-old male sustained a blunt thoracic trauma after he had a dirt bike accident. He was admitted for the management of multiple fractures, was hemodynamically stable, and presented without any cardiac symptoms. The patient underwent transthoracic echocardiography and CT angiogram of the thorax as the workup of possible cardiac injury as he had a new aortic regurgitation murmur, troponin rise, and a new RBBB. Imaging showed aortic root rupture, type A aortic dissection involving aortic root and proximal ascending aorta, and acute severe aortic regurgitation, not typically seen with blunt thoracic trauma. The patient was immediately taken to the operating room, underwent a surgical aortic valve and root replacement with the Bentall procedure, and had a good outcome.

Assessment of Peripheral Blood Mononuclear Cells Senescence and Endothelial Dysfunction among Adults with High Cardiovascular Risk. / Avaliação da Senescência de Células Sanguíneas Mononucleares Periféricas e na Disfunção Endotelial entre Adultos com Alto Risco Cardiovascular.

BACKGROUND: Cardiovascular diseases (CVD) are one of the leading causes of mortality and morbidity worldwide. Biological aging has been associated with the occurrence of adverse cardiovascular outcomes; however, the underlying mechanism of this process remains unknown. OBJECTIVES: This study sought to evaluate if peripheral blood mononuclear cell (PBMC) senescence and endothelial biomarkers could influence cardiovascular (CV) risk and be suitable markers for the early detection of cardiovascular diseases in adults. METHODS: In this cross-sectional study patients free of CVD were classified as lower (n=32) and higher Interheart Risk (IHR) scores (n=28). PBMC senescence was assessed by estimating the telomerase activity (TA) and detecting the presence of senescent cells and endothelial dysfunction by estimating the concentration of nitrite and nitrate and of total antioxidant capacity (TAC). Statistical analysis was performed with SPSS version 16.0 (SPSS Inc., Chicago, IL). All p-values <0.05 were considered statistically significant. RESULTS: PBMC senescence 0.95 [p-value = 0.0001; 95% CI (0.874-1.026)] was a significant predictor of patients with higher IHR scores with a cut-off value of 21.65 with a sensitivity and specificity of 92% and 88% respectively. PBMC senescence, nitrite and nitrate and TA were found to be independently associated with high IHR scores. CONCLUSION: PBMC senescence, TA and nitrite, and nitrate status are suitable measures to predict high cardiovascular risk in adults with CV risk. Nevertheless, long-term follow-up studies are needed to confirm these findings. (Arq Bras Cardiol. 2021; 116(1):37-47).

FUNDAMENTO: Doenças cardiovasculares (DCV) são uma das principais causas de mortalidade e morbidade em todo o mundo. O envelhecimento biológico tem sido associado à ocorrência de resultados cardiovasculares. Entretanto, o mecanismo subjacente desse processo ainda é desconhecido. OBJETIVOS: Buscamos avaliar se a senescência das células sanguíneas mononucleares periféricas (CSMP) e biomarcadores endoteliais poderiam influenciar o risco cardiovascular (CV) e ser marcadores adequados para a detecção precoce de doenças cardiovasculares em adultos. MÉTODOS: Neste estudo transversal, pacientes livres de DCV foram classificados como baixo (n=32) e alto (n=28) escore de risco intracardaco (IHR) A senescência das CSMP foi avaliada estimando-se a atividade de telomerase (AT) e detectando-se a presença de células senescentes e disfunção endotelial, estimando-se a concentração de nitrito e nitrato e a capacidade antioxidante total (CAT). A análise estatística foi realizada com o software SPSS, versão 16.0 (SPSS Inc., Chicago, IL). Todos os p-valores <0,05 foram considerados estatisticamente significativos. RESULTADOS: A senescência de CSMP de 0,95 [p-valor = 0,0001; 95% IC (0,874-1,026)] foi um indicador significativo de pacientes com escore de IHR mais alto, com um valor de corte de 21,65, com sensibilidade e especificidade de 92% e 88% respectivamente. Identificou-se que a senescência de CSMP, nitrito e nitrato, e AT eram independentemente associadas a um escore de IHR alto. CONCLUSÃO: Os status de nitrito e nitrato e AT, e a senescência de CSMP são medidas adequadas para prever o alto risco cardiovascular em adultos com risco CV. Entretanto devem ser realizados estudos de acompanhamento de longo prazo para confirmar esses achados. (Arq Bras Cardiol. 2021; 116(1):37-47).

Avaliação da Senescência de Células Sanguíneas Mononucleares Periféricas e na Disfunção Endotelial entre Adultos com Alto Risco Cardiovascular / Assessment of Peripheral Blood Mononuclear Cells Senescence and Endothelial Dysfunction among Adults with High Cardiovascular Risk

Resumo Fundamento Doenças cardiovasculares (DCV) são uma das principais causas de mortalidade e morbidade em todo o mundo. O envelhecimento biológico tem sido associado à ocorrência de resultados cardiovasculares. Entretanto, o mecanismo subjacente desse processo ainda é desconhecido. Objetivos Buscamos avaliar se a senescência das células sanguíneas mononucleares periféricas (CSMP) e biomarcadores endoteliais poderiam influenciar o risco cardiovascular (CV) e ser marcadores adequados para a detecção precoce de doenças cardiovasculares em adultos. Métodos Neste estudo transversal, pacientes livres de DCV foram classificados como baixo (n=32) e alto (n=28) escore de risco intracardaco (IHR) A senescência das CSMP foi avaliada estimando-se a atividade de telomerase (AT) e detectando-se a presença de células senescentes e disfunção endotelial, estimando-se a concentração de nitrito e nitrato e a capacidade antioxidante total (CAT). A análise estatística foi realizada com o software SPSS, versão 16.0 (SPSS Inc., Chicago, IL). Todos os p-valores <0,05 foram considerados estatisticamente significativos. Resultados A senescência de CSMP de 0,95 [p-valor = 0,0001; 95% IC (0,874-1,026)] foi um indicador significativo de pacientes com escore de IHR mais alto, com um valor de corte de 21,65, com sensibilidade e especificidade de 92% e 88% respectivamente. Identificou-se que a senescência de CSMP, nitrito e nitrato, e AT eram independentemente associadas a um escore de IHR alto. Conclusão Os status de nitrito e nitrato e AT, e a senescência de CSMP são medidas adequadas para prever o alto risco cardiovascular em adultos com risco CV. Entretanto devem ser realizados estudos de acompanhamento de longo prazo para confirmar esses achados. (Arq Bras Cardiol. 2021; 116(1):37-47)

Abstract Background Cardiovascular diseases (CVD) are one of the leading causes of mortality and morbidity worldwide. Biological aging has been associated with the occurrence of adverse cardiovascular outcomes; however, the underlying mechanism of this process remains unknown. Objectives This study sought to evaluate if peripheral blood mononuclear cell (PBMC) senescence and endothelial biomarkers could influence cardiovascular (CV) risk and be suitable markers for the early detection of cardiovascular diseases in adults. Methods In this cross-sectional study patients free of CVD were classified as lower (n=32) and higher Interheart Risk (IHR) scores (n=28). PBMC senescence was assessed by estimating the telomerase activity (TA) and detecting the presence of senescent cells and endothelial dysfunction by estimating the concentration of nitrite and nitrate and of total antioxidant capacity (TAC). Statistical analysis was performed with SPSS version 16.0 (SPSS Inc., Chicago, IL). All p-values <0.05 were considered statistically significant. Results PBMC senescence 0.95 [p-value = 0.0001; 95% CI (0.874-1.026)] was a significant predictor of patients with higher IHR scores with a cut-off value of 21.65 with a sensitivity and specificity of 92% and 88% respectively. PBMC senescence, nitrite and nitrate and TA were found to be independently associated with high IHR scores. Conclusion PBMC senescence, TA and nitrite, and nitrate status are suitable measures to predict high cardiovascular risk in adults with CV risk. Nevertheless, long-term follow-up studies are needed to confirm these findings. (Arq Bras Cardiol. 2021; 116(1):37-47)

Impact of atrial fibrillation on the outcomes of transcatheter mitral valve repair using MitraClip: a systematic review and meta-analysis.

Atrial fibrillation (AF) is a common arrhythmia in patients with mitral regurgitation (MR) undergoing transcatheter mitral valve repair (TMVR). In this systematic review, we aimed to investigate the outcomes of TMVR using MitraClip in AF patients. We performed a systematic search using PubMed, SCOPUS, EMBASE, and Google Scholar, from inception to May 10, 2020, for studies that reported outcomes following MitraClip, in patients with AF versus without AF. Seven studies with a total of 7678 patients met the inclusion criteria. The risk of 1-year all-cause mortality following TMVR was higher in AF patients (RR 1.40, 95% CI 1.27-1.54, p ≤ 0.001). Similarly, the risk of heart failure hospitalization was higher in patients with AF (RR 1.17, 95% CI 1.06-1.30, p = 0.002) and the risk of bleeding was elevated in AF patients (RR 1.29, 95% CI 1.15-1.45, p ≤ 0.001). The risk of procedural failure, in-hospital mortality, cardiovascular mortality, and stroke was not significantly different between the two groups. The higher risk of all-cause mortality, HF hospitalization, and risk of bleeding in AF patients undergoing MitraClip warrants attention.

Radiation Oncologist Perceptions and Utilization of Digital Patient Assessment Platforms.

BACKGROUND: Patient engagement is increasing in the presence of digital patient assessment platforms, or physician rating websites. Despite this rapid growth, data remains insufficient regarding how these evaluations impact radiation oncologists. OBJECTIVES: The purpose of this study was to assess radiation oncologists worldwide on their awareness and noted effects of digital patient assessment platforms. METHODS: An electronic survey was delivered to 6,199 members of the American Society of Radiation Oncology. Subjects were radiation oncologists practicing throughout the world. The survey consisted of 14 questions focused on demographics, practice details, patient volume, institutional utilization of patient reviews, and perceptions of radiation oncologists on health care reviews provided by patients. RESULTS: There were 447 responses from practicing radiation oncologists in total, 321 (72%) of which are in the US. Most respondents (228; 51%) either agreed or strongly agreed that patients consider online reviews when deciding which physician to visit. Of all respondents, 188 (42%) reported that their institution checks their online feedback, whereas 157 (36%) and 99 (22%) respectively reported not knowing, or to their knowledge their institution does not check their online feedback. Respondents who saw more than the average number of consults per week were significantly more likely to receive negative feedback (P = 0.005). Forty-five percent of respondents agreed or strongly agreed that online virtual assessment tools contribute to physician burnout. Respondents (100; 22%) who received inappropriate or misdirected feedback were significantly more likely to report that virtual reviews contribute to burnout (P = 0.001). CONCLUSIONS: Radiation oncologists need to be aware that self-reported patient assessments are a data point in the quality of a physician and health care establishment. To best ensure appropriate feedback of a physician's capabilities as a doctor, leadership and employee alignment for patient experience are now more important than ever.

Refractory Vasospastic Angina and Sudden Cardiac Arrest: Is Implantable Cardioverter Defibrillator Indicated and Is It Always Protective?

Vasospastic angina (VSA) is characterized by episodic chest pain associated with transient ST-segment abnormalities on electrocardiogram, secondary to vasospasm of the epicardial coronary artery. We report the rare case of a 46-year-old female with refractory VSA secondary to multivessel coronary vasospasm causing an anterior myocardial infarction. She succumbed secondary to ventricular tachycardia (VT) storm, in spite of being on maximally tolerated medical therapy and having an implantable cardioverter defibrillator (ICD) for secondary prevention of VT. Contemporary guidelines recommend ICD implantation (class IIa) in VSA patients who survived sudden cardiac arrest (SCA), if they are already on optimal medical therapy or if medical therapy is not tolerated. Whether ICD implantation is appropriate in VSA patients with aborted SCA, even before assessing the response to medical therapy, is not well known and requires further studies.

Right Coronary Artery Pseudoaneurysm With Hemopericardium: A Rare Complication of Percutaneous Coronary Intervention.

While percutaneous coronary intervention (PCI) is a commonly performed procedure, it still has many serious complications. Coronary artery pseudoaneurysms can form after PCI and can progress to cardiac tamponade. We report the case of an 80-year-old male who presented for an inferior wall ST elevation myocardial infarction, had drug-eluting stents placed to the right coronary artery (RCA), and subsequently suffered a RCA pseudoaneurysm with hemopericardium. He eventually underwent pseudoaneurysm repair with off pump coronary artery bypass graft. There is no established treatment protocol, and involvement of a multidisciplinary team improves outcomes.

Carbon monoxide poisoning and its effect on QTc prolongation.

Carbon monoxide (CO) poisoning has been associated with direct toxicity to the cardiovascular system by causing arrhythmias through prolongation of QTc. It has been reported to have arrhythmogenic potential likely due to its action on the cardiac membranes. We present a case of a 69-year-old man who presented to the emergency department for evaluation of a syncopal episode after exposure to CO. His carboxyhemoglobin level was elevated at 10.5% on admission, electrocardiogram revealed QTc interval of 622 msec. He was treated with hyperbaric oxygen and a repeat electrocardiogram 15 h after hyperbaric oxygen initiation showed improvement in QTc to 490 msec and his carboxyhemoglobin level decreased to 1.8%. There is a direct association between acute CO poisoning and QTc prolongation as reported in patient cases and evidence of it was seen by investigators who worked on rats and found that this phenomenon occurs due to the action of nitric oxide on the late Na + channels affecting repolarization. The resolution after hyperbaric oxygen could be due to decrease in the CO concentration and the absence of nitric oxide synthase activation further propagating the QT prolongation, however, further research would have to be performed to consolidate this.

Atypical Cardiac Tamponade Manifesting as Left Ventricular Diastolic Collapse: A Case Report.

Cardiac tamponade is a medical emergency, the diagnosis of which is predominantly clinical with supportive echocardiographic findings. Echocardiographic findings highly suggestive of cardiac tamponade include chamber collapse, inferior vena cava (IVC) plethora, and respiratory volume/flow variations. The right-sided cardiac chambers are a low-pressure system and are the first to show signs of collapse with high specificity for tamponade. We report the case of a 35-year-old woman who demonstrated left ventricular (LV) diastolic collapse on echocardiogram following a tricuspid valve replacement. Although left-sided chamber collapse with tamponade has been reported with localized pericardial effusions postoperatively, our patient had a large circumferential pericardial effusion. Selective chamber compression can be a presenting sign of postoperative tamponade after cardiac surgery. Our case highlights the importance of recognizing atypical forms of cardiac tamponade to help in early identification and emergent management in such patients.

Pharmacological inhibition of guanosine triphosphate cyclohydrolase1 elevates tyrosine phosphorylation of caveolin1 and cellular senescence.

The role of 2,4-diamino-6-hydroxypyrimidine (DAHP), on cellular-senescence remains unclear as differential effects of DAHP have been reported in cardiovascular and cerebrovascular systems. We investigated the effect of pharmacologically-induced guanosine-triphosphate-cyclohydrolase1 (GTPCH1)-inhibition, through DAHP, on cellular-senescence in experimentally-induced diabetic and non-diabetic Wistar rats. Cellular-senescence was evaluated through senescence-associated events, namely, cell-cycle-arrest of peripheral blood mononuclear cells (PBMNCs); myocardial DNA fragmentation, total antioxidant capacity (TAC), telomerase-activity, nicotinamide adenine dinucleotide (NAD+)-content and tyrosine14-phosphorylation of caveolin1 (pY14) in similarly-aged, pubertal Wistar rats with streptozotocin (STZ) and/or DAHP. Oxidative stress (OS) indices such as myocardial biopterin concentrations (tetrahydrobiopterin-BH4 and dihydrobiopterin-BH2) and plasma total nitrite and nitrate (NOx) were determined. DAHP, per se, exhibited distinct senescence; in addition, in STZ+DAHP (the cardiomyopathy model), there was a marked accumulation of cells in G0G1 phase, as evidenced through flow-cytometry analysis, as-well-as fragmented DNA, than the respective controls suggesting the DAHP-mediated onset of senescence in circulating cells and the myocardium, with or without STZ. Concentrations of BH4 and BH2, and NOx were impaired in STZ and/or DAHP, indicating elevated OS in the treatment groups. In the independent treatment groups or the combination treatment, typical senescence indicators including myocardial telomerase-activity, NAD+-content and TAC were significantly reduced, while there was a marked elevation in the concentrations of pY14 as compared to the respective controls, reinforcing the occurrence of senescence in PBMNCs and the myocardium. We postulate that DAHP promotes early onset of cellular-senescence, potentially through OS-mediated cellular events in diabetic or non-diabetic models.

Forskolin attenuates doxorubicin-induced accumulation of asymmetric dimethylarginine and s-adenosylhomocysteine via methyltransferase activity in leukemic monocytes.

Doxorubicin (DOX) is an antitumor drug, associated with cardiomyopathy. Strategies to address DOX-cardiomyopathy are scarce. Here, we identify the effect of forskolin (FSK) on DOX-induced-asymmetric-dimethylarginine (ADMA) accumulation in monocytoid cells. DOX-challenge led to i) augmented cytotoxicity, reactive-oxygen-species (ROS) production and methyltransferase-enzyme-activity identified as ADMA and s-adenosylhomocysteine (SAH) accumulation (SAH-A). However, except cytotoxicity, other DOX effects were decreased by metformin and FSK. FSK, did not alter the DOX-induced cytotoxic effect, but, decreased SAH-A by >50% and a combination of three drugs restored physiological methyltransferase-enzyme-activity. Together, protective effect of FSK against DOX-induced SAH-A is associated with mitigated methyltransferase-activity, a one-of-a-kind report.

Caveolin1/protein arginine methyltransferase1/sirtuin1 axis as a potential target against endothelial dysfunction.

Endothelial dysfunction (ED), an established response to cardiovascular risk factors, is characterized by increased levels of soluble molecules secreted by endothelial cells (EC). Evidence suggest that ED is an independent predictor of cardiac events and that it is associated with a deficiency in production or bioavailability of nitric oxide (NO) and/or an imbalance in the relative contribution of endothelium-derived relaxing and contracting factors. ED can be reversed by treating cardiovascular risk factors, hence, beyond ambiguity, ED contributes to initiation and progression of atherosclerotic disease. Majority of cardiovascular risk factors act by a common pathway, oxidative stress (OS), characterized by an imbalance in bioavailability of NO and reactive oxygen species (ROS). Enhanced ROS, through several mechanisms, alters competence of EC that leads to ED, reducing its potential to maintain homeostasis and resulting in development of cardiovascular disease (CVD). Influential mechanisms that have been implicated in the development of ED include (i) presence of elevated levels of NOS inhibitor, asymmetric dimethylarginine (ADMA) due to augmented enzyme activity of protein arginine methyl transferase-1 (PRMT1); (ii) decrease in NO generation by endothelial nitric oxide synthase (eNOS) uncoupling, or by reaction of NO with free radicals and (iii) impaired post translational modification of protein (PTM) such as eNOS, caveolin-1 (cav1) and sirtuin-1 (SIRT1). However, the inter-related mechanisms that concur to developing ED is yet to be understood. The events that possibly overlay include OS-induced sequestration of SIRT1 to caveolae facilitating cav1-SIRT1 association; potential increase in lysine acetylation of enzymes such as eNOS and PRMT1 leading to enhanced ADMA formation; imbalance in acetylation-methylation ratio (AMR); diminished NO generation and ED. Here we review current literature from research showing interdependent association between cav1-PRMT1-SIRT1 to the outcomes of experimental and clinical research aiming to preserve endothelial function with gene- or pharmaco-therapy.