Neurotherapeutic potential of erythropoietin after ischemic injury

 of the central nervous system
Florian Simon, Nicolaos Floros, Wiebke Ibing, Hubert Schelzig, Artis Knapsis

Neural Regeneration Research 2019 14(8):1309-1312

Erythropoietin (EPO) is one of the most successful biopharmaceuticals in history and is used for treating anemia of different origins. However, it became clear that EPO could also work in a neuroprotective, antiapoptotic, antioxidative, angiogenetic and neurotropic way. It causes stimulation of cells to delay cell apoptosis, especially in the central nervous system. In rodent models of focal cerebral ischemia, EPO showed an impressive reduction of infarct size by 30% and improvement of neurobehavioral outcome by nearly 40%. A large animal model dealing with ischemia and reperfusion of the spinal cord showed that EPO could reduce the risk of spinal cord injury significantly. In addition, some clinical studies tested whether EPO works in real live clinical settings. One of the most promising studies showed the innocuousness and improvements in follow-up, outcome scales and in infarct size, of EPO-use in humans suffering from ischemic stroke. Another study ended unfortunately in a negative outcome and an increased overall death rate in the EPO group. The most possible reason was the involvement of patients undergoing simultaneously systemic thrombolysis with recombinant tissue plasminogen activator. An experimental study on rats demonstrated that administration of EPO might exacerbate tissue plasminogen activator-induced brain hemorrhage without reducing the ischemic brain damage. This case shows clearly how useful animal models can be to check negative side effects of a treatment before going into clinical trials. Other groups looked in human trials at the effects of EPO on the outcome after ischemic stroke, relation to circulating endothelial progenitor cells, aneurysmal subarachnoid hemorrhage, traumatic brain injury, hemoglobin transfusion thresholds and elective first-time coronary artery bypass surgery. Most of the results were positive, but are based mostly on small group sizes. However, some of the most neglected facts when focusing on experimental setups of ischemia of the central nervous system are issues like age and comorbidities. It might be extremely worthy to consider these points for future projects, because EPO might influence all these factors. 

Hypertension and sleep duration and water intake

Association between hypertension and sleep duration and water intake in Indian young adults
Umeshwar Pandey, Tanu Midha, Yashwant Kumar Rao

Journal of Clinical and Preventive Cardiology 2019 8(2):50-55

Context: The prevalence of hypertension is on the rise in developing countries like India. Physiological parameters such as sleep duration and water intake may be associated with hypertension in young adults. Aims: The aim is to study the association between hypertension and day and nighttime sleep duration and water intake among young adults. Setting and Design: The study was a cross-sectional study, conducted among 596 students of Government Medical College, Kannauj, aged between 17 and 22 years. Materials and Methods: Participants were classified using the diagnostic criteria of the American Heart Association. Data were recorded on a pre-designed and pretested questionnaire. Data analysis was performed using SPSS 22.0. Receiver operator characteristic curve analysis and multiple logistic regression analysis were applied. Results: The prevalence of hypertension was 34.9%, 35.9% among boys, and 33.5% among girls, respectively. Less water intake and shorter sleep duration at nighttime were found to be independent predictors of hypertension. Cutoff of sleep duration at nighttime for predicting hypertension was ≤7.6 h among boys and ≤7.1 h among girls. The sensitivity and specificity of the cutoff for sleep duration at night time in boys was 79.3% and 74.2%, respectively, and that in girls was 81.5% and 75.6%, respectively. The cutoff for water intake for predicting hypertension was ≤2.1 L for boys and ≤1.5 L for girls, respectively. The sensitivity and specificity of the cutoff for water intake in boys was 74.8% and 70.3%, and in girls was 78.3% and 71.5%, respectively. Conclusions: Young adults with longer duration of sleep during night time and more water intake had a lesser risk of hypertension. 

Ankle–brachial pressure index/carotid intima-media thickness ratio in predicting presence and severity of coronary artery disease

Utility of ankle–brachial pressure index/carotid intima-media thickness ratio in predicting presence and severity of coronary artery disease: A study from major center in Northeastern India
Farhin Iqbal, Amol Vasantrao Patil, Jogesh Chandra Barkataki

Journal of Clinical and Preventive Cardiology 2019 8(2):44-49

Background: Studies have shown that carotid intima-media thickness (CIMT) and ankle–brachial pressure index (ABI) can be used as surrogate markers of coronary artery disease (CAD). However, whether studying the ratio of ABI and CIMT has any added value in predicting CAD when compared to either of them alone, has not been studied. Aims: The aim of the study is to compare CIMT and ABI as surrogate markers for the presence and extent of CAD and to investigate whether studying the ratio of ABI and CIMT has any incremental value in predicting CAD than either of them. Methods: We prospectively enrolled 235 stable, non-ACS patients who underwent CIMT and ABI measurements followed by diagnostic coronary angiography. Results: The mean age of the study population was 56.32 ± 10.14 years. CIMT was significantly higher in the CAD group compared to non-CAD group (0.91 ± 0.22 vs. 0.66 ± 0.15, P ≤ 0.0001). ABI was significantly lower in the CAD group compared to non-CAD group (1.07 ± 0.19 vs. 1.18 ± 0.14, P ≤ 0.0001). At an optimal cutoff value of ≥0.75 mm, CIMT showed better predictive values (sensitivity and specificity –72.3% and 79%, respectively) compared to ABI ≤0.9 (sensitivity and specificity – 21.53% and 96.19%, respectively). CIMT was the strongest independent predictor of CAD (P < 0.0001) followed by ABI (P = 0.006) by multiple regression. ABI/CIMT ratio of ≤1.55 had better predictive value (sensitivity and specificity –75.4% and 78.1%, respectively) and stronger correlation with CAD severity (R = 0.42), than either of them. Conclusion: CIMT is a better surrogate marker of CAD compared to ABI. Studying ABI/CIMT ratio has an incremental value in predicting CAD. 

Neural Regeneration Research

Tandem pore TWIK-related potassium channels and neuroprotection J Antonio Lamas, Diego Fernández-Fernández Neural Regeneration Research 2019 14(8):1293-1308 TWIK-related potassium channels (TREK) belong to a subfamily of the two-pore domain potassium channels family with three members, TREK1, TREK2 and TWIK-related arachidonic acid-activated potassium channels. The two-pore domain potassium channels is the last big family of channels being discovered, therefore it is not surprising that most of the information we know about TREK channels predominantly comes from the study of heterologously expressed channels. Notwithstanding, in this review we pay special attention to the limited amount of information available on native TREK-like channels and real neurons in relation to neuroprotection. Mainly we focus on the role of free fatty acids, lysophospholipids and other neuroprotective agents like riluzole in the modulation of TREK channels, emphasizing on how important this modulation may be for the development of new therapies against neuropathic pain, depression, schizophrenia, epilepsy, ischemia and cardiac complications.

Neurotherapeutic potential of erythropoietin after ischemic injury of the central nervous system Florian Simon, Nicolaos Floros, Wiebke Ibing, Hubert Schelzig, Artis Knapsis Neural Regeneration Research 2019 14(8):1309-1312 Erythropoietin (EPO) is one of the most successful biopharmaceuticals in history and is used for treating anemia of different origins. However, it became clear that EPO could also work in a neuroprotective, antiapoptotic, antioxidative, angiogenetic and neurotropic way. It causes stimulation of cells to delay cell apoptosis, especially in the central nervous system. In rodent models of focal cerebral ischemia, EPO showed an impressive reduction of infarct size by 30% and improvement of neurobehavioral outcome by nearly 40%. A large animal model dealing with ischemia and reperfusion of the spinal cord showed that EPO could reduce the risk of spinal cord injury significantly. In addition, some clinical studies tested whether EPO works in real live clinical settings. One of the most promising studies showed the innocuousness and improvements in follow-up, outcome scales and in infarct size, of EPO-use in humans suffering from ischemic stroke. Another study ended unfortunately in a negative outcome and an increased overall death rate in the EPO group. The most possible reason was the involvement of patients undergoing simultaneously systemic thrombolysis with recombinant tissue plasminogen activator. An experimental study on rats demonstrated that administration of EPO might exacerbate tissue plasminogen activator-induced brain hemorrhage without reducing the ischemic brain damage. This case shows clearly how useful animal models can be to check negative side effects of a treatment before going into clinical trials. Other groups looked in human trials at the effects of EPO on the outcome after ischemic stroke, relation to circulating endothelial progenitor cells, aneurysmal subarachnoid hemorrhage, traumatic brain injury, hemoglobin transfusion thresholds and elective first-time coronary artery bypass surgery. Most of the results were positive, but are based mostly on small group sizes. However, some of the most neglected facts when focusing on experimental setups of ischemia of the central nervous system are issues like age and comorbidities. It might be extremely worthy to consider these points for future projects, because EPO might influence all these factors.

Dendritic shrinkage after injury: a cellular killer or a necessity for axonal regeneration? An Beckers, Lieve Moons Neural Regeneration Research 2019 14(8):1313-1316 Dendrites form an essential component of the neuronal circuit have been largely overlooked in regenerative research. Nevertheless, subtle changes in the dendritic arbors of neurons are one of the first stages of various neurodegenerative diseases, leading to dysfunctional neuronal networks and ultimately cellular death. Maintaining dendrites is therefore considered an essential neuroprotective strategy. This mini-review aims to discuss an intriguing hypothesis, which postulates that dendritic shrinkage is an important stimulant to boost axonal regeneration, and thus that preserving dendrites might not be the ideal therapeutic method to regain a full functional network upon central nervous system damage. Indeed, our study in zebrafish, a versatile animal model with robust regenerative capacity recently unraveled that dendritic retraction is evoked prior to axonal regrowth after optic nerve injury. Strikingly, inhibiting dendritic pruning upon damage perturbed axonal regeneration. This constraining effect of dendrites on axonal regrowth has sporadically been proposed in literature, as summarized in this short narrative. In addition, the review discusses a plausible underlying mechanism for the observed antagonistic axon-dendrite interplay, which is based on energy restriction inside neurons. Axonal injury indeed leads to a high local energy demand in which efficient axonal energy supply is fundamental to ensure regrowth. At the same time, axonal lesion is known to induce mitochondrial depolarization, causing energy depletion in the axonal compartment of damaged neurons. Mitochondria, however, become mostly stationary after development, which has been proposed as a potential underlying reason for the low regenerative capacity of adult mammals. Per contra, upon reduced neuronal activity, mitochondrial mobility enhances. In this view, dendritic shrinkage after axonal injury in zebrafish could result in less synaptic input and hence, a release of mitochondria within the soma-dendrite compartment that then translocate to the axonal growth cone to stimulate axonal regeneration. If this hypothesis proofs to be correct, i.e. dendritic remodeling serving as fuel for axonal regeneration, we envision a major shift in the research focus within the neuroregenerative field and in the potential uncovering of various novel therapeutic targets.

Regenerative biomarkers for Duchenne muscular dystrophy Simon Guiraud, Kay E Davies Neural Regeneration Research 2019 14(8):1317-1320 Skeletal muscle has an extraordinary capacity to regenerate after injury and trauma. The muscle repair mechanism is a complex process orchestrated by multiple steps. In neuromuscular disorders such as Duchenne muscular dystrophy (DMD), the pathological consequences of the lack of dystrophin and the loss of the dystrophin-associated protein complex are dramatic, with a progressive cascade of events, such as continual influx of inflammation, repeated cycles of degeneration and impaired regeneration. Thus, muscle regeneration is a hallmark of the disease and careful monitoring of regenerative processes with robust markers should provide useful information to the field. Since decades, several indices of regeneration such as centronucleation and fibre size have been commonly used. In the present review, we discuss the impaired regenerative process in DMD, the common and new indices of regeneration and their associated methodologies. We notably highlight the regenerative marker embryonic myosin as a robust indicator of muscle regeneration. We also describe new quantitative methodologies offering the possibility of using a panel of translational regenerative biomarkers to obtain a more complete view of the regeneration processes. Upregulation of utrophin, an autosomal and functional paralogue of dystrophin, is one of the most promising therapeutic strategies as it targets the primary cause of the disease and is applicable to all DMD patients regardless their genetic defects. As utrophin is a regeneration associated protein increased in dystrophic muscle, we discuss the correlation of utrophin levels after drug treatment with regeneration markers. The recent advances in technologies and complementary markers of muscle regeneration described in this review, provide an unprecedented opportunity to develop more robust utrophin DMD based strategies for all DMD patients.

Exploring the efficacy of natural products in alleviating Alzheimer's disease Prajakta Deshpande, Neha Gogia, Amit Singh Neural Regeneration Research 2019 14(8):1321-1329 Alzheimer’s disease (hereafter AD) is a progressive neurodegenerative disorder that affects the central nervous system. There are multiple factors that cause AD, viz., accumulation of extracellular Amyloid-beta 42 plaques, intracellular hyper-phosphorylated Tau tangles, generation of reactive oxygen species due to mitochondrial dysfunction and genetic mutations. The plaques and tau tangles trigger aberrant signaling, which eventually cause cell death of the neurons. As a result, there is shrinkage of brain, cognitive defects, behavioral and psychological problems. To date, there is no direct cure for AD. Thus, scientists have been testing various strategies like screening for the small inhibitor molecule library or natural products that may block or prevent onset of AD. Historically, natural products have been used in many cultures for the treatment of various diseases. The research on natural products have gained importance as the active compounds extracted from them have medicinal values with reduced side effects, and they are bioavailable. The natural products may target the proteins or members of signaling pathways that get altered in specific diseases. Many natural products are being tested in various animal model systems for their role as a potential therapeutic target for AD, and to address questions about how these natural products can rescue AD or other neurodegenerative disorders. Some of these products are in clinical trials and results are promising because of their neuroprotective, anti-inflammatory, antioxidant, anti-amyloidogenic, anticholinesterase activities and easy availability. This review summarizes the use of animal model systems to identify natural products, which may serve as potential therapeutic targets for AD.

Involvement of insulin receptor substrates in cognitive impairment and Alzheimer's disease Daisuke Tanokashira, Wataru Fukuokaya, Akiko Taguchi Neural Regeneration Research 2019 14(8):1330-1334 Type 2 diabetes—associated with impaired insulin/insulin-like growth factor-1 (IGF1) signaling (IIS)—is a risk factor for cognitive impairment and dementia including Alzheimer’s disease (AD). The insulin receptor substrate (IRS) proteins are major components of IIS, which transmit upstream signals via the insulin receptor and/or IGF1 receptor to multiple intracellular signaling pathways, including AKT/protein kinase B and extracellular-signal-regulated kinase cascades. Of the four IRS proteins in mammals, IRS1 and IRS2 play key roles in regulating growth and survival, metabolism, and aging. Meanwhile, the roles of IRS1 and IRS2 in the central nervous system with respect to cognitive abilities remain to be clarified. In contrast to IRS2 in peripheral tissues, inactivation of neural IRS2 exerts beneficial effects, resulting in the reduction of amyloid β accumulation and premature mortality in AD mouse models. On the other hand, the increased phosphorylation of IRS1 at several serine sites is observed in the brains from patients with AD and animal models of AD or cognitive impairment induced by type 2 diabetes. However, these serine sites are also activated in a mouse model of type 2 diabetes, in which the diabetes drug metformin improves memory impairment. Because IRS1 and IRS2 signaling pathways are regulated through complex mechanisms including positive and negative feedback loops, whether the elevated phosphorylation of IRS1 at specific serine sites found in AD brains is a primary response to cognitive dysfunction remains unknown. Here, we examine the associations between IRS1/IRS2-mediated signaling in the central nervous system and cognitive decline.

Role of macrophages in peripheral nerve injury and repair Ping Liu, Jiang Peng, Gong-Hai Han, Xiao Ding, Shuai Wei, Gang Gao, Kun Huang, Feng Chang, Yu Wang Neural Regeneration Research 2019 14(8):1335-1342 Resident and inflammatory macrophages are essential effectors of the innate immune system. These cells provide innate immune defenses and regulate tissue and organ homeostasis. In addition to their roles in diseases such as cancer, obesity and osteoarthritis, they play vital roles in tissue repair and disease rehabilitation. Macrophages and other inflammatory cells are recruited to tissue injury sites where they promote changes in the microenvironment. Among the inflammatory cell types, only macrophages have both pro-inflammatory (M1) and anti-inflammatory (M2) actions, and M2 macrophages have four subtypes. The co-action of M1 and M2 subtypes can create a favorable microenvironment, releasing cytokines for damaged tissue repair. In this review, we discuss the activation of macrophages and their roles in severe peripheral nerve injury. We also describe the therapeutic potential of macrophages in nerve tissue engineering treatment and highlight approaches for enhancing M2 cell-mediated nerve repair and regeneration.

Therapeutic strategies for peripheral nerve injury: decellularized nerve conduits and Schwann cell transplantation Gong-Hai Han, Jiang Peng, Ping Liu, Xiao Ding, Shuai Wei, Sheng Lu, Yu Wang Neural Regeneration Research 2019 14(8):1343-1351 In recent years, the use of Schwann cell transplantation to repair peripheral nerve injury has attracted much attention. Animal-based studies show that the transplantation of Schwann cells in combination with nerve scaffolds promotes the repair of injured peripheral nerves. Autologous Schwann cell transplantation in humans has been reported recently. This article reviews current methods for removing the extracellular matrix and analyzes its composition and function. The development and secretory products of Schwann cells are also reviewed. The methods for the repair of peripheral nerve injuries that use myelin and Schwann cell transplantation are assessed. This survey of the literature data shows that using a decellularized nerve conduit combined with Schwann cells represents an effective strategy for the treatment of peripheral nerve injury. This analysis provides a comprehensive basis on which to make clinical decisions for the repair of peripheral nerve injury.

Role and prospects of regenerative biomaterials in the repair of spinal cord injury Shuo Liu, Yuan-Yuan Xie, Bin Wang Neural Regeneration Research 2019 14(8):1352-1363 Axonal junction defects and an inhibitory environment after spinal cord injury seriously hinder the regeneration of damaged tissues and neuronal functions. At the site of spinal cord injury, regenerative biomaterials can fill cavities, deliver curative drugs, and provide adsorption sites for transplanted or host cells. Some regenerative biomaterials can also inhibit apoptosis, inflammation and glial scar formation, or further promote neurogenesis, axonal growth and angiogenesis. This review summarized a variety of biomaterial scaffolds made of natural, synthetic, and combined materials applied to spinal cord injury repair. Although these biomaterial scaffolds have shown a certain therapeutic effect in spinal cord injury repair, there are still many problems to be resolved, such as product standards and material safety and effectiveness.

The "Brain Stress Timing" phenomenon and other misinterpretations of randomized clinical trial on aneurysmal subarachnoid hemorrhage Rafael Martinez-Perez, Natalia Rayo, Agustín Montivero, Jorge Marcelo Mura Neural Regeneration Research 2019 14(8):1364-1366 Clipping and coiling are currently the two alternatives in treatment of ruptured cerebral aneurysms. In spite of some meritorious analysis, further discussion is helpful to understand the actual state of art. Retreatment and rebleeding rates clearly favors clipping, although short-term functional outcome seems to be beneficial for clipping, while this different is not such if we perform the comparison at a longer follow up. Long-term follow ups and cost analysis are mandatory to have a clear view of the current picture in treatment of subarachnoid hemorrhage. Treatment strategy should be made by a multi-disciplinary team in accredited centers with proficient experience in both techniques.

Clinical and Preventive Cardiology

Editor's page April 2019 Ravi R Kasliwal Journal of Clinical and Preventive Cardiology 2019 8(2):43-43

Utility of ankle–brachial pressure index/carotid intima-media thickness ratio in predicting presence and severity of coronary artery disease: A study from major center in Northeastern India Farhin Iqbal, Amol Vasantrao Patil, Jogesh Chandra Barkataki Journal of Clinical and Preventive Cardiology 2019 8(2):44-49 Background: Studies have shown that carotid intima-media thickness (CIMT) and ankle–brachial pressure index (ABI) can be used as surrogate markers of coronary artery disease (CAD). However, whether studying the ratio of ABI and CIMT has any added value in predicting CAD when compared to either of them alone, has not been studied. Aims: The aim of the study is to compare CIMT and ABI as surrogate markers for the presence and extent of CAD and to investigate whether studying the ratio of ABI and CIMT has any incremental value in predicting CAD than either of them. Methods: We prospectively enrolled 235 stable, non-ACS patients who underwent CIMT and ABI measurements followed by diagnostic coronary angiography. Results: The mean age of the study population was 56.32 ± 10.14 years. CIMT was significantly higher in the CAD group compared to non-CAD group (0.91 ± 0.22 vs. 0.66 ± 0.15, P ≤ 0.0001). ABI was significantly lower in the CAD group compared to non-CAD group (1.07 ± 0.19 vs. 1.18 ± 0.14, P ≤ 0.0001). At an optimal cutoff value of ≥0.75 mm, CIMT showed better predictive values (sensitivity and specificity –72.3% and 79%, respectively) compared to ABI ≤0.9 (sensitivity and specificity – 21.53% and 96.19%, respectively). CIMT was the strongest independent predictor of CAD (P < 0.0001) followed by ABI (P = 0.006) by multiple regression. ABI/CIMT ratio of ≤1.55 had better predictive value (sensitivity and specificity –75.4% and 78.1%, respectively) and stronger correlation with CAD severity (R = 0.42), than either of them. Conclusion: CIMT is a better surrogate marker of CAD compared to ABI. Studying ABI/CIMT ratio has an incremental value in predicting CAD.

Association between hypertension and sleep duration and water intake in Indian young adults Umeshwar Pandey, Tanu Midha, Yashwant Kumar Rao Journal of Clinical and Preventive Cardiology 2019 8(2):50-55 Context: The prevalence of hypertension is on the rise in developing countries like India. Physiological parameters such as sleep duration and water intake may be associated with hypertension in young adults. Aims: The aim is to study the association between hypertension and day and nighttime sleep duration and water intake among young adults. Setting and Design: The study was a cross-sectional study, conducted among 596 students of Government Medical College, Kannauj, aged between 17 and 22 years. Materials and Methods: Participants were classified using the diagnostic criteria of the American Heart Association. Data were recorded on a pre-designed and pretested questionnaire. Data analysis was performed using SPSS 22.0. Receiver operator characteristic curve analysis and multiple logistic regression analysis were applied. Results: The prevalence of hypertension was 34.9%, 35.9% among boys, and 33.5% among girls, respectively. Less water intake and shorter sleep duration at nighttime were found to be independent predictors of hypertension. Cutoff of sleep duration at nighttime for predicting hypertension was ≤7.6 h among boys and ≤7.1 h among girls. The sensitivity and specificity of the cutoff for sleep duration at night time in boys was 79.3% and 74.2%, respectively, and that in girls was 81.5% and 75.6%, respectively. The cutoff for water intake for predicting hypertension was ≤2.1 L for boys and ≤1.5 L for girls, respectively. The sensitivity and specificity of the cutoff for water intake in boys was 74.8% and 70.3%, and in girls was 78.3% and 71.5%, respectively. Conclusions: Young adults with longer duration of sleep during night time and more water intake had a lesser risk of hypertension.

Clinical presentation and 2-year mortality outcomes in acute heart failure in a tertiary care hospital in South India: A retrospective cohort study Vengatesh Munusamy, Luxitaa Goenka, Masum Sharma, Thilagavathi Ramamoorthy, Durga Jha, S Solaipriya, VE Dhandapani, Melvin George Journal of Clinical and Preventive Cardiology 2019 8(2):56-63 Background: Heart failure (HF) is one of the leading causes of mortality and morbidity worldwide. We sought to describe the clinical epidemiology of HF from a representative sample in a tertiary care setting and to evaluate the factors which could increase the mortality risk in the study patients. Methods: This retrospective cohort study was carried out among patients who had been admitted with a diagnosis of acute HF from 2013 to 2017. Demographic data, history, laboratory investigations, data on medication clinical variables, and in-hospital outcomes were obtained from the patient's hospital records. The patients were assessed through the telephonic interview for mortality outcomes. Data were analyzed using SPSS software version 16.0 (SPSS Inc., Chicago, IL) and all values of P < 0.05 was considered as statistically significant. Results: A total of 355 acute heart failure (AHF) patients were included in the study with a mean age of 57.78 ± 12.78 years. The most common etiologies among the study patients were ischemic heart disease (58%) and Dilated Cardiomyopathy (24.79%). The in-hospital and 2-year mortality was found to be 104 (29.3%) and 179 (50.4%), respectively. The 2-year mortality was significantly higher in patients with ischemic HF than that of nonischemic HF (119 [57.8%] vs. 58 [39.5%], P = 0.003). Multivariate Cox proportional hazard analysis demonstrated that elderly age, the presence of diastolic dysfunction and higher levels of total leukocyte count (TLC) were independent predictors of mortality. Conclusion: The mortality rate in AHF is higher among ischemic HF than nonischemic HF. The major factors contributing to the 2-year mortality rate among AHF were elderly age, diastolic dysfunction, and high-TLC.

Stress echocardiography in aortic stenosis Nitin Burkule Journal of Clinical and Preventive Cardiology 2019 8(2):64-70 In apparently asymptomatic severe aortic stenosis (AS) group, stress echocardiography objectively identifies symptomatic, high-risk AS patients requiring early aortic valve replacement (AVR). The low-flow, low-gradient AS is well-characterized clinical entity with distinct diagnostic, management, and clinical outcome challenges. A comprehensive two-dimensional transthoracic echocardiography (2D echo) and Doppler and low-dose dobutamine stress echocardiography are of paramount importance for accurate diagnosis and timely decision of AVR. However, clinicians and imaging experts should be aware of the pitfalls and inaccuracies inherent in 2D echo/Doppler measurements and the effects of pathophysiological factors which impact the stroke volume and transvalvular gradient measurements. In appropriate clinical situations, clinicians should take additional help of cardiac computational tomography, cardiac magnetic resonance imaging, and biomarkers.

QT interval – Its measurement and clinical significance Sita Ram Mittal Journal of Clinical and Preventive Cardiology 2019 8(2):71-79 QT interval extends from the beginning of QRS complex to the end of T wave. Thus, it includes the duration of ventricular depolarization (QRS) and repolarization (J point to end of T wave). It corresponds to the duration of cellular action potential. “long-” and “short”-QT intervals are considered as risk markers for cardiac arrhythmias and sudden death. In the last decade, there have been significant advances in our understanding about measurement and significance of QT interval. We have made an attempt to review the literature to find the limitations and queries surrounding the present status of measurement of QT interval and its significance as a risk marker for cardiac arrhythmias and sudden death.

Republication- Indian academy of echocardiography guidelines and manual for performance of stress echocardiography in coronary artery disease Nitin Burkule, Manish Bansal Journal of Clinical and Preventive Cardiology 2019 8(2):80-112 Stress echocardiography is one of the most useful non-invasive diagnostic modalities for detection and evaluation of coronary artery disease (CAD). It is also very useful for assessment of cardiac response to hemodynamic stress in a variety of other cardiac and non-cardiac disorders. Given its cost-effectiveness, stress echocardiography is particularly suited for Indian scenario where the incidence of CAD is rising at an alarming rate and the astronomical expenditure required for its management is borne largely by the patients themselves. However, despite its unequivocal diagnostic value, stress echocardiography remains underutilized, particularly in India, due to the lack of adequate exposure and training in this modality. Unfortunately, while there is extensive literature available to document diagnostic accuracy of stress echocardiography, there are very few texts that actually describe how to perform stress echocardiography in real life. This Indian Academy of Echocardiography guideline document aims to fill this very void. This is a comprehensive 'how to do' document prepared with the objective of providing detailed description of the steps involved in performance and interpretation of stress echocardiography so that there is increased adoption of this important and clinically useful diagnostic modality in daily clinical practice. However, while stress echocardiography has several clinical applications, the present document is restricted to its main application, which is evaluation of CAD. Republished with permission from: Dr. Satish Govind, Editor-in-chief (Journal of the Indian Academy of Echocardiography & Cardiovascular Imaging).

Pharmacognosy Reviews

A comprehensive review on eugenol's antimicrobial properties and industry applications: A transformation from ethnomedicine to industry Kit-Kay Mak, Masnah Banu Kamal, Sunday Buru Ayuba, Raghavendra Sakirolla, Yew-Beng Kang, Kavitha Mohandas, Madhu Katyayani Balijepalli, Sazali Hamzah Ahmad, Mallikarjuna Rao Pichika Pharmacognosy Reviews 2019 13(25):1-9 Eugenol and eugenol-containing plants are used in ethno and modern medicine for various biological activities including antimicrobial activity. This review article provides an insightful transformation of eugenol from being an ethnomedicine to being a food protectant in the food industry. Scientific publications on the antimicrobial activity of eugenol and its respective advancements were collected from scientific databases such as Scopus, PubMed, and Google Scholar published between 1995 and June 2018. The eugenol has shown significant broad-spectrum antimicrobial activities against Gram-positive, Gram-negative, fungi, and virus. The eugenol has also shown synergistic effects with conventional antimicrobials. Formulations, such as micro- and nanoemulsions, nanocapsules, and nanoparticles, are prepared to improve the aqueous solubility and efficacy of eugenol. Eugenol is used as a food protectant in storing plants, grains, fruits, and livestock. This review covers eugenol's antimicrobial activities, formulations to improve aqueous solubility, and applications in the food industry. Extensive scientific investigations validated the ethnomedicinal uses of eugenol as an antimicrobial agent. Its activity on multidrug-resistant pathogens should further be explored to identify the molecular mechanisms and synergistic/antagonistic effects with conventional antimicrobials. There were no studies on investigating eugenol's potential in in vivo infectious animal models. This is the first review on eugenol that details the antimicrobial potential of eugenol and its possible applications as a protectant in the food industry.

Can medicinal properties of watercress be relevant to human health? A systematic review based on preclinical study in vivo Mirna Clemente, Marilis Dallarmi Miguel, Karina Bettega Felipe, Gislene Mari Fujiwara, Luiz Claudio Fernandes, Joseane de Fatima Gaspari Dias, Sandra Maria Warumby Zenin, Beatriz Cristina Konopatzki Hirota, Obdulio Gomes Miguel Pharmacognosy Reviews 2019 13(25):10-15 Nasturtium officinale (Watercress) is a perennial dicotyledonous herbaceous plant and a member of the Brassicaceae family. The leaves of this plant are used as a home remedy as expectorant and hypoglycemic. They can also be used in the treatment of hyperlipidemia, hypertension, as well as many other chronic diseases. This finding supports the idea of watercress being a health promoter. In addition, this study intends to provide recommendations for future research. This systematic review was performed by Science Direct, MEDLINE, Cochrane, and Scopus from July 2017 to August 2018. A total of 14 preclinical studies with watercress were selected by the inclusion and exclusion criteria, 13 were with rats and mice and 1 fish. The search terms used were “bioactive compounds,” “Nasturtium,” “preclinical study,” and “systematic review.” For the quality of the individual studies, we adopted the risk of bias. The results of the selected articles with Nasturtium in animals showed positive effects on the improvement of the immune system, hypoglycemic hypercholesterolemia, and anti-inflammatory activity, sex hormones synthesis, the preventive effect on the renal stone formation, and others. Since Nasturtium is widely used for therapeutic and nontherapeutic purposes that trigger its significant value, a new approach is necessary. Different combinations and the numerous medicinal properties of its extract juice and leaves, whether administrated orally or topically, demand further studies about other useful and unknown properties of this multipurpose plant. Finally, it is suggested by our reviewers that more studies with animals to be applied to human health, should be investigated of bioactive compounds from watercress.

Mangifera and Impatiens from Sumatra: Phylogenetic positions and their modes of action as anticancer agents Agustina Dwi Retno Nurcahyanti Pharmacognosy Reviews 2019 13(25):16-23 Cancer has become a growing health threat due to the emergence of multidrug resistance and the increasing diversity of cancer cells. The continuous investigation into the development of anticancer agents and treatments is crucial because the current treatments can cause adverse side effects and are often ineffective. Anticancer derived medicinal plants are a potential source of treatment. However, the abundance of medicinal plant species can cause several problems, like the adulteration. The author aims to demonstrate DNA Barcoding technique as a tool to perform phylogenetic positions of Mangifera and Impatiens species grown in Sumatra. The phylogenetic positions of the plants are supported by the review on the active secondary metabolites from Mangifera and Impatiens. The current study is based on unpublished work on DNA Barcoding technique, an established modern technique to identify the phylogenetic position and also adulteration in medicinal plants. The review on the active secondary metabolites including the mechanism of action as anticancer is based on pertinent papers that were retrieved using relevant keywords in PubMed and Science Direct. Work using DNA Barcoding technique confirmed that Mangifera and Impatiens from Sumatra are closely related to Momordica foetida and Impatiens balsamina from other areas, indicating that they may share the same anticancer traits with those species. The mechanism of action of Mangifera and Impatiens includes inhibition of the cell cycle, cytotoxicity activity, apoptosis and leading to cell death, and anti-angiogenesis activity. Further research on both species is needed to identify their relevant chemical components to potentially develop anticancer drugs, either as a single compound or as a drug combination with minimal side effects and also to determine possible adverse reactions.

The beneficial properties of virgin coconut oil in management of atopic dermatitis Yik-Ling Chew Pharmacognosy Reviews 2019 13(25):24-27 Atopic dermatitis (AD) is a chronic, inflammatory skin disease that is characterized by intense pruritus and eczematous lesions. It is an increasingly pruritic inflammatory skin disorder which can affect both children and adults. Natural products offer great hope in the identification of bioactive lead compounds and their development into topical cream or ointment in managing skin diseases which are associated with inflammatory response. One of the most popular natural products which have been vastly used in managing AD is virgin coconut oil (VCO). VCO is extracted from the fresh and mature kernel of the coconut (Cocos nucifera L.) through wet and dry methods, without altering the valuable phytochemicals and physiochemical properties of the oil. It possesses numerous health benefits from the retained physiochemical properties from its triglycerides and medium chain fatty acids. The use of VCO in the management of AD is one of the topical therapies which have been proven to have good therapeutic effects and it is safe for topical applications. Studies have been proven that VCO exhibits antioxidant, anti-inflammatory, antibacterial, wound healing, and moisturizing properties which were extremely important in the management of AD.

The potential of xanthones as a therapeutic option in macrophage-associated inflammatory diseases Ida May Jen Ng, Caroline Lin Lin Chua Pharmacognosy Reviews 2019 13(25):28-33 Xanthones are well known for their significant biological activities and can be found in many herbal medicines. These compounds have the ability to regulate various inflammatory activities and signaling pathways in immune cells, especially macrophages. Macrophages are innate immune cells that can either fuel or dampen an inflammatory response depending on their activation states and play an active role in the development of inflammatory diseases such as atherosclerosis, arthritis, cancer, and diabetes. Many traditional medicines used as a remedy for these diseases contain xanthones, and their bioactivities may be partially attributed to their ability in regulating macrophage responses. In this review, we discuss the in vitro and in vivo findings on the effects of xanthones on different macrophage immune functions including nitric oxide and cytokine production, migration, polarization, and phagocytosis. Their specific modes of action are highlighted whenever known. We also discuss the potential and challenges in using xanthones as a therapeutic option in various inflammatory diseases. It is hoped that this review can pave the way for future research that focuses on developing xanthones as specific macrophage-targeted therapeutics.

Medical Research

Family planning in India: The way forward Poonam Muttreja, Sanghamitra Singh Indian Journal of Medical Research 2018 148(7):1-9 Given the magnitude of the family planning programme in India, there is a need to strengthen the coordination of all its aspects, focusing on planning, programmes, monitoring, training and procurement. The quality of care in family planning must be a major focus area to ensure the success of family planning programmes. Despite serious efforts and progress, India has yet to achieve its family planning goals. Furthermore, there is a need for greater male participation both as enablers and beneficiaries and also address the sexual and reproductive needs of the youth. It is imperative for the government to ensure the prioritization of family planning in the national development agenda. Family planning is crucial for the achievement of the sustainable development goals, and subsequent efforts need to be made to improve access and strengthen quality of family planning services.

Infertility & assisted reproduction: A historical & modern scientific perspective Radhey Shyam Sharma, Richa Saxena, Rajeev Singh Indian Journal of Medical Research 2018 148(7):10-14 Infertility has always been considered as a social stigma and has often been treated as socially, mentally and physically damaging experience for the childless women rather than man. Fatherhood was more a social rather than biological concept, thereby making childlessness a legitimate ground for divorce and a matter of disgrace for women. Every country has its own set of customs and traditional beliefs for the relief of childlessness. While introducing a second wife was one way to overcome the predicament of childlessness, divorce was also an available choice. There were several myths that contemplated the human concerns and their needs during ancient times. It is evident that types of the infertility and their treatment in the modern era have some historical background and different representations in the ancient civilizations. The present review discusses the historical and modern perspectives of infertility and assisted reproduction and their importance in different cultures.

Mid-life fertility: Challenges & policy planning Umesh N Jindal Indian Journal of Medical Research 2018 148(7):15-26 This review highlights the challenges, priority areas of research and planning, strategies for regulation of services and the need to develop guidelines and laws for fertility treatments during mid-life. The success rate of all treatments is poor in advanced age women because of declining ovarian reserve and natural fertility. There is often a need of third-party involvement which has its own ethical, legal and medical issues. Welfare of children born to older women and early death of parents are important concerns. Most of the new techniques such as the pre-implantation genetic diagnosis, oocyte augmentation, use of stem cells or artificial gametes, ovarian tissue preservation and ovarian transplantation are directed to improve, preserve or replace the declining ovarian reserve. These techniques are costly and have limited availability, safety and efficacy data. Continued research and policies are required to keep pace with these techniques. The other important issues include the patients' personal autonomy and right of self-determination, welfare of offspring, public vs. private funding for research and development of new technologies vs. indiscriminate use of unproven technology. It is important that mid-life fertility is recognized as a distinct area of human reproduction requiring special considerations.

Socio-economic correlates of bereavement among women - Examining the differentials on social axes Sanghmitra S Acharya Indian Journal of Medical Research 2018 148(7):27-37 Death, disease and disaster can inflict anyone, anywhere and at any time. While occurrence of such an event could be absolved of any selective strike, the outcome reflects otherwise. Historical deprivations experienced by certain populations have caused more bereavement and sorrow to them than those who have experienced lesser or no deprivation. Therefore, the process which shapes the factors to yield such a result is important and needs to be understood for any policy suggestions and programmatic inputs. Loss of pregnancy and newborn inflicts sorrow and bereavement across space, time and social labyrinth. The degree of bereavement is likely to reduce with time, but space and social context govern the response to it. Therefore, factors contributing to the differentials vary in their demographic, social and economic characteristics. The loss of pregnancy and newborn remains inadequately addressed. Family and community play a significant role in coping. While the developed countries have institutional structure to address coping with the loss, the South Asian countries rely heavily on the family and the community for such support. The present review examines these trajectories across social groups.

Stem cells survive oncotherapy & can regenerate non-functional gonads: A paradigm shift for oncofertility Deepa Bhartiya Indian Journal of Medical Research 2018 148(7):38-49 A large proportion of patients who survive cancer are rendered infertile as an unwanted side effect of oncotherapy. Currently accepted approaches for fertility preservation involve banking eggs/sperm/embryos or ovarian/testicular tissue before oncotherapy for future use. Such approaches are invasive, expensive, technically challenging and depend on assisted reproductive technologies (ART). Establishing a gonadal tissue bank (for cancer patients) is also fraught with ethical, legal and safety issues. Most importantly, patients who find it difficult to meet expenses towards cancer treatment will find it difficult to meet expenses towards gonadal tissue banking and ART to achieve parenthood later on. In this review an alternative strategy to regenerate non-functional gonads in cancer survivors by targeting endogenous stem cells that survive oncotherapy is discussed. A novel population of pluripotent stem cells termed very small embryonic-like stem cells (VSELs), developmentally equivalent to late migratory primordial germ cells, exists in adult gonads and survives oncotherapy due to their quiescent nature. However, the stem-cell niche gets compromised by oncotherapy. Transplanting niche cells (Sertoli or mesenchymal cells) can regenerate the non-functional gonads. This approach is safe, has resulted in the birth of fertile offspring in mice and could restore gonadal function early in life to support proper growth and later serve as a source of gametes. This newly emerging understanding on stem cells biology can obviate the need to bank gonadal tissue and fertility may also be restored in existing cancer survivors who were earlier deprived of gonadal tissue banking before oncotherapy.

Dendritic cell engineering for selective targeting of female reproductive tract cancers Arpit Bhargava, Rupesh Kumar Srivastava, Dinesh Kumar Mishra, Rajnarayan R Tiwari, Radhey Shyam Sharma, Pradyumna Kumar Mishra Indian Journal of Medical Research 2018 148(7):50-63 Female reproductive tract cancers (FRCs) are considered as one of the most frequently occurring malignancies and a foremost cause of death among women. The late-stage diagnosis and limited clinical effectiveness of currently available mainstay therapies, primarily due to the developed drug resistance properties of tumour cells, further increase disease severity. In the past decade, dendritic cell (DC)-based immunotherapy has shown remarkable success and appeared as a feasible therapeutic alternative to treat several malignancies, including FRCs. Importantly, the clinical efficacy of this therapy is shown to be restricted by the established immunosuppressive tumour microenvironment. However, combining nanoengineered approaches can significantly assist DCs to overcome this tumour-induced immune tolerance. The prolonged release of nanoencapsulated tumour antigens helps improve the ability of DC-based therapeutics to selectively target and remove residual tumour cells. Incorporation of surface ligands and co-adjuvants may further aid DC targeting (in vivo) to overcome the issues associated with the short DC lifespan, immunosuppression and imprecise uptake. We herein briefly discuss the necessity and progress of DC-based therapeutics in FRCs. The review also sheds lights on the future challenges to design and develop clinically effective nanoparticles-DC combinations that can induce efficient anti-tumour immune responses and prolong patients' survival.

Postpartum uterine infection & ovarian dysfunction Sunita Dahiya, Suman Kumari, Payal Rani, Suneel Kumar Onteru, Dheer Singh Indian Journal of Medical Research 2018 148(7):64-70 Postpartum uterine infections such as metritis, endometritis and mastitis have been considered as underlying causes for ovarian dysfunction in mammals. Almost all mammals, particularly dairy animals are susceptible to postpartum uterine infections, resulting in impaired fertility and economic loss. One of the factors for low fertility in females is ovarian dysfunction, which is exhibited as impaired growth and function of ovarian follicles by the postpartum infection. Immune system of mammals provides a host defence mechanism against pathogenic microbes through the recognition of pathogen-associated molecular patterns (PAMPs) and forming inflammasomes. Like immune cells, ovarian granulosa cells also exhibit a similar pattern of cytokine gene expressions on exposure to PAMPs. Genome-wide transcriptomic approaches explored the molecular mechanisms underlying the immune function of buffalo granulosa cells during endotoxin exposure. Understanding the molecular mechanism of ovarian dysfunction due to uterine infection would be helpful to implement various strategies to handle the adverse effects of postpartum uterine disease on fertility by developing potential therapeutics. Therefore, this article focuses on key factors that are responsible for postpartum infection and particularly summarizes the molecular mechanism of infection underlying the ovarian dysfunction in dairy animals.

Female genital tuberculosis: Revisited Jai Bhagwan Sharma, Eshani Sharma, Sangeeta Sharma, Sona Dharmendra Indian Journal of Medical Research 2018 148(7):71-83 Female genital tuberculosis (FGTB) is caused by Mycobacterium tuberculosis (rarely Mycobacterium bovis and/or atypical mycobacteria) being usually secondary to TB of the lungs or other organs with infection reaching through haematogenous, lymphatic route or direct spread from abdominal TB. In FGTB, fallopian tubes are affected in 90 per cent women, whereas uterine endometrium is affected in 70 per cent and ovaries in about 25 per cent women. It causes menstrual dysfunction and infertility through the damage of genital organs. Some cases may be asymptomatic. Diagnosis is often made from proper history taking, meticulous clinical examination and judicious use of investigations, especially endometrial aspirate (or biopsy) and endoscopy. Treatment is through multi-drug antitubercular treatment for adequate time period (rifampicin, isoniazid, pyrazinamide, ethambutol daily for 60 days followed by rifampicin, isoniazid, ethambutol daily for 120 days). Treatment is given for 18-24 months using the second-line drugs for drug-resistant (DR) cases. With the advent of increased access to rapid diagnostics and newer drugs, the management protocol is moving towards achieving universal drug sensitivity testing and treatment with injection-free regimens containing newer drugs, especially for new and previously treated DR cases.

Redox regulation & sperm function: A proteomic insight Gayatri Mohanty, Luna Samanta Indian Journal of Medical Research 2018 148(7):84-91 Infertility affects nearly 15 per cent of all couples within the reproductive age worldwide, with about 50 per cent being exhibited in the male, called male factor infertility. Successful reproduction is dependent on sperm chromatin integrity. Spermatozoa are highly specialized cells that aim to transmit the paternal genomic blueprint to the oocyte. The spermatozoon is regulated by redox mechanisms during its epididymal transit to acquire fertilizing ability. While, at physiological levels, the production of reactive oxygen species (ROS) supports the spermatozoon to acquire its fertilizing ability, at high concentrations, it affects sperm function leading to infertility. Emerging proteomic technologies provide an opportunity to address these key issues that may solve many fertility-associated problems resulting from oxidative stress (OS). This review highlights the need for an efficient therapeutic approach to male infertility with the application of high-throughput OS-mediated proteomic technology, and also addresses the question as to whether targeting these altered sperm-specific proteins may help in designing an efficient and reversible male contraceptive.

Effect of radiofrequency radiation on reproductive health Rajeev Singh, Ravindra Nath, Ajit Kumar Mathur, Radhey Shyam Sharma Indian Journal of Medical Research 2018 148(7):92-99 The development of cellular phone system has greatly increased the extent and magnitude of radiofrequency radiation (RFR) exposure. The RFR emitted from mobile phone and mobile phone base stations exerts thermal and non-thermal effects. The short-term and long-term exposure to RFR may have adverse effect on humans as well as animals. Most laboratory studies have indicated a direct link between exposure to RFR and adverse biological effects. Several in vitro studies have reported that RFR induces various types of cancer and DNA or chromosomal damage. On the other hand, some animal studies have not reported adverse effects of this radiation. The present review summarizes information available on the possible effects of RFR on the reproductive health.