Pulmonary Veno-occlusive Disease

Nrf2 Mediates Effect of Resveratrol in Ischemia-reperfusion Injury

Ischemia-Reperfusion Injury (IRI) is a paradoxical phenomenon where removing the source of injury can cause additional damage. Ischemia reduces ATP production and intracellular pH, reducing oxidative reactions, increasing lactic acid release, and activating anaerobic metabolism. Reperfusion restores aerobic respiration and increases ROS production, leading to malfunction of transmembrane transport, activation of proteases, DNA dissolution, and protein denaturation, leading to apoptotic cell death. Nrf2 is a transcription factor that regulates cellular inflammation and oxidative responses. It is activated by oxidants and electrophiles and enhances detoxifying enzyme expression, maintaining redox homeostasis. It also activates ARE, which activates several ARE-regulated genes that favor cell survival by exhibiting resistance to oxidants and electrophiles. Nrf2 regulates the antioxidant defense system by producing phase II and antioxidant defense enzymes, including HO-1, NQO-1, gglutamylcysteine synthetase, and rate-limiting enzymes for glutathione synthesis. Nrf2 protects mitochondria from damage and supports mitochondrial function in stress conditions. Resveratrol is a stilbene-based compound with a wide variety of health benefits for humans, including antioxidant, anticarcinogenic, antitumor, and estrogenic/antiestrogenic. Resveratrol protects against IRI through several signaling pathways, including the Nrf2/ARE pathway. Here, we review the studies that investigated the mechanisms of resveratrol protection against IRI through modulation of the Nrf2 signaling pathway.

Group 5 Pulmonary Hypertension: Multiple Systemic Diseases, Multiple Mechanisms of Pulmonary Hypertension, and Multiple Management Challenges

Group 5 pulmonary hypertension (PH) with unclear and/or multifactorial mechanisms includes a wide variety of conditions associated with PH, and the mechanisms by which PH develops vary dramatically depending on the underlying condition. Indeed, in many group 5 conditions, such as sarcoidosis, multiple distinct drivers of PH are present concurrently in a single patient, with the predominant factor depending on the predisposing disease phenotype. For this reason, thorough diagnostic evaluation to most accurately phenotype every patient with group 5 PH is essential. Treatment of these patients should begin by fully characterizing and optimizing the management of their underlying disease, often in conjunction with disease experts. Initial targets of PH treatment include identifying and correcting factors that worsen PH, such as volume overload and hypoxemia, as well as a complete PH evaluation, searching for other undiagnosed causes of PH (e.g., congenital heart disease or chronic thromboembolic disease). Data to guide treatment with therapies specific to pulmonary arterial hypertension (PAH) are inadequate for any specific recommendations, and adverse effects in group 5 patients are common. If these therapies are considered, evaluation by a multidisciplinary team that includes a PH specialist is recommended. Factors in the selection of PAH therapies should include consideration of the dominant physiologic features of the underlying disease, the severity of hemodynamic and right ventricular abnormalities, the risk of adverse drug effects, and any known contraindications to PAH-specific medications based on the underlying condition. Vigilant monitoring following initiation of PAH-specific therapy is critical, as the clinical effects are hard to predict, and untoward events, such as uncovering pulmonary veno-occlusive disease, may occur. Collaborative care by a multidisciplinary team of experts is key to the management of this challenging patient population.

Pulmonary Arterial Hypertension (PAH) Group 1 (Part A): Overview, Classification, Clinical Subsets, and Workup

Pulmonary hypertension is a rare, progressive disease characterized by increased pulmonary arterial pressure and right ventricular failure due to pulmonary vascular remodeling. The disease definition and management have evolved over time. The 6th WSPH now defines it as a mean pulmonary arterial pressure >20mmHg, while recent ESC/ERS guidelines recommend lowering the threshold for pulmonary vascular resistance to 2WU.

Understanding of the disease has improved through registries, classifying it into five distinct groups with similar histology, pathophysiology, and therapeutic approaches. These groups include PAH, with heritable and idiopathic causes, as well as various clinical subsets involving connective tissue disease, HIV, portopulmonary hypertension, congenital heart disease, and schistosomiasis. Long-term responders to calcium channel blockers, PAH with venous/capillaries involvement, and persistent PH of newborns are categorized under Group 1, now re-classified as IPAH.

A comprehensive workup for suspected patients includes various tests like electrocardiogram, pulmonary function testing, autoimmune workup, HIV testing, echocardiogram, right heart catheterization, and cardiopulmonary exercise testing.

This review emphasizes the disease's definition and epidemiology, delving into each subset and providing updated workup guidelines. The subsequent article will focus on risk stratification and treatment strategies.

Pathobiology of Pulmonary Arterial Hypertension

Pulmonary Arterial Hypertension (PAH) is a progressive disease associated with occlusive pulmonary arterial remodeling of vessels < 500 μm for which there is no cure. Even in the era of PAH-specific combination therapies, aberrant lung pathology and progressive right ventricular (RV) dysfunction occur, culminating in a median survival of 6.2 years, according to the latest data in the treatment era. While better than a median survival from symptom onset of 2.8 years prior to PAH-specific therapies, it is still poor. Thus, there is an urgent need to move the opportunities forward for meaningful treatment strategies. Clearly, a better understanding of the highly complex pathobiology of PAH is needed if we are to achieve new and novel treatment strategies. This is especially so if we are to pursue a more personalized treatment approach to PAH in light of the multitude of pathobiological abnormalities described in PAH, which likely culminate in a final common pathway for PAH development.

In this State-of-the-Art review, we provide comprehensive insights into the complex pathobiology of PAH to provide understanding and insights for the practicing clinician. We review the pathology of PAH and the cells involved and their impact in driving pathological abnormalities (pulmonary artery endothelial cells, smooth muscle cells, fibroblasts and pericytes) as well as the role of the extracellular matrix. Inflammation and immune dysfunction are considered important drivers of PAH and are comprehensively discussed. Another pathway relates to TGFβ/ bone morphogenic protein (BMP) imbalance, which is highlighted, as well as a new novel agent, sotatercept that impacts this imbalance. Genetic factors underlying heritable PAH (HPAH) are addressed, as well as epigenetic influences. Other important pathways highlighted include growth factor signaling, ion channels/channelopathy, hypoxia signaling pathways, and altered metabolism and mitochondrial dysfunction. We also address the “estrogen paradox”, whereby PAH is more common in women but more severe in men. The basis for drug-induced PAH is discussed, including the new methamphetamine epidemic. We briefly provide insights into DNA damage and senescence factors in pathobiology and highlight commonalities between PAH and cancer pathobiology. Furthermore, we provide concluding insights for the treating physician. In conclusion, we need to pose the right questions to motivate novel and effective treatment strategies for the management of PAH based on pathobiological principles and understanding.

Pulmonary Hypertension Related to Left Heart Disease (PH-LHD)

Pulmonary Hypertension secondary to left heart disease (PH-LHD) is the most common form of pulmonary hypertension (PH) and is a frequent complication of heart failure. It is associated with increased morbidity and mortality. The definitions of both PH and PH-LHD have changed over time and now generally follow those established by the 6th World Symposium on Pulmonary Hypertension (WSPH) in 2018 and the most recent European Society of Cardiology (ESC) guidelines in 2022. A systematic approach including clinical history and noninvasive testing is required to properly diagnose PH-LHD, and accurate hemodynamics by right heart catheterization, sometimes involving provocative testing, are often needed to diagnose PH-LHD but are essential to further subclassify PH-LHD into either isolated post-capillary pulmonary hypertension (Ipc-PH) versus combined pre and post-capillary pulmonary hypertension (Cpc-PH). This distinction is important as it guides therapeutic decisions and carries prognostic implications. Cpc-PH, in particular, shares some histo-pathologic and hemodynamic characteristics with pulmonary arterial hypertension (PAH) and, hence, the rationale for the potential use of pulmonary vasodilator therapy. To date, however, there is no strong evidence to support PAH-specific medications for Cpc- PH, and the mainstay of treatment for PH-LHD remains to treat the underlying cause of LHD. Further research is warranted to refine therapeutic approaches, improve long-term outcomes, and explore novel treatment modalities to alleviate the burden of PH in this patient population.

Invasive Fungal Infections in the Paediatric Intensive Care Unit: A Hong Kong Study

Introduction: Invasive fungal infections (IFI) cause significant mortality and morbidity in the Paediatric Intensive Care Unit (PICU). Early recognition and prompt treatment of invasive fungal infections are important. This article reviewed the mortality and morbidity of IFIs in the PICU of Hong Kong Children’s Hospital.

Methods: A retrospective review of all PICU admissions from April 2019 to May 2021 was performed. The following data were retrieved: age, gender, diagnosis, comorbidity, clinical manifestation, type of fungus, duration of stay at PICU, absolute neutrophil count, use of immunosuppressive therapy, presence of central venous catheter and use of total parental nutrition. The primary outcomes were the incidence and mortality of IFIs among PICU patients. The secondary outcomes were risk factors for developing IFI in PICU and clinical course of IFIs. Numerical variables were compared between groups by Mann-Whitney U test and categorical variables by Fisher’s exact test.

Results: There were 692 PICU admissions over the study period from April 2019 to May 2021. The crude mortality was 3% (n=24 death cases) in the PICU. Fourteen patients (2%) fulfilling the criteria for IFIs were identified using hospital electronic record system and according to PICU documentation. Eight of these 14 patients (57%) had hematological malignancy, 2 (17%) had solid tumours and 4 had non-oncological conditions. Eight (57%) patients were neutropenic with absolute neutrophil count less than 1x 109 at diagnosis of IFI. Ten (71%) had received immunosuppressive therapy including steroid, cyclosporin A, Mycophenolate mofetil (MMF), Sirolimus or tacrolimus. 12 (86%) had had central venous catheter. Eight (57%) were on parenteral nutrition. IFIs due to Rhizopus or Aspergillus infection (5/14), or in post-haematopoietic stem cell transplant patients (5/14) were associated with non-survival (p = 0.031).

Conclusion: All patients with IFIs managed in the PICU had haemato-oncology diseases or were recipients of stem cell transplantation. IFIs with Rhizopus or Aspergillus as a group were associated with high mortality in the PICU. Awareness of this pathology with prompt diagnosis and treatment may improve the outcome of these infections and reduce the mortality.

Pharmacological Considerations during Percutaneous Treatment of Heart Failure

Heart Failure (HF) remains a global health challenge, marked by its widespread prevalence and substantial resource utilization. Although the prognosis has improved in recent decades due to the treatments implemented, it continues to generate high morbidity and mortality in the medium to long term. Interventional cardiology has emerged as a crucial player in HF management, offering a diverse array of percutaneous treatments for both acute and chronic HF. This article aimed to provide a comprehensive review of the role of percutaneous interventions in HF patients, with a primary focus on key features, clinical effectiveness, and safety outcomes. Despite the growing utilization of these interventions, there remain critical gaps in the existing body of evidence. Consequently, the need for high-quality randomized clinical trials and extensive international registries is emphasized to shed light on the specific patient populations and clinical scenarios that stand to benefit most from these innovative devices.

Epigenetics Mechanism and Therapeutic Potential of Approved Epi-drugs in Pulmonary Hypertension Disease

Epigenetics is defined as a heritable change occurring in gene expression and phenotype without altering the underlying primary DNA sequence itself. Epigenetic variation consists of DNA methylation repatterning, posttranslational modification of histone proteins, and non-coding RNAs (ncRNAs). Epigenetic modifications are deeply involved in tumorigenesis and tumor development. Epigenetic abnormalities can be therapeutically reversed, and three families of epigenetic marks, including “readers”, “writers” and “erasers”, could be modulated by epi drugs. Over the past decade, ten small-molecule epi drugs (e.g., inhibitors of DNA methyltransferases and histone deacetylases) have been approved by FDA or CFDA for the treatment of different cancers. Epigenetics therapy has been most effective in oncology and has become an attractive area in cancer treatment.

Pulmonary hypertension (PH) encompasses a set of multifactorial diseases of progressive cardiopulmonary disorder. WHO classifies PH into five groups based on similar pathophysiological mechanisms, clinical presentation, haemodynamic characteristics, therapeutic management, and underlying etiology. Since PH shows many similarities with cancer, such as proliferation, resistance to apoptosis, and dysregulation of tumor suppressor genes, the current epigenetics therapeutic strategies used in cancer might be considered for the treatment of PH. The role of epigenetics in the setting of PH is a fast-growing field of research. In this review, we have summarized the up-to-date articles on the role of epigenetic mechanisms in the context of PH. The aim of this review is to provide a comprehensive insight from the epigenetics perspective and introduce the potential role of approved epi drugs in PH treatment.

Veno-occlusive Priapism, An Undesirable Outcome of Warfarin Therapy: A Case Report

Background: Priapism is one of the urological emergencies requiring prompt medical or surgical intervention. The clinical diagnosis is made with adjunct cavernosal blood gas analysis and colour doppler ultrasound to determine the underlying aetiology; ischaemic or non-ischaemic, and the majority are veno-occlusive in origin (ischaemic). The occurrence of warfarin-induced priapism complicated with penile necrosis is a rare occurrence, and many cases are related to protein C deficiency.

Case Presentation: We report a case of warfarin therapy initiation following a thromboembolic event as a sequela of COVID-19 infection, subsequently developed veno-occlusive priapism complicated with penile gangrene despite being in an overwarfarinized state. The penis was non-salvageable following the gangrenous event, even with prior cavernosal blood aspiration. Thrombophilia panel screening, which includes Protein C activity was done where the protein C activity was low, measuring 23%. Unfortunately, he succumbed to death due to severe cardiorespiratory complications before this blood result was ready.

Discussion: Prompt diagnosis and treatment of priapism is needed to prevent loss of penile function. Priapism as a sequela of anticoagulant therapy should be suspected in a patient with recent anticoagulant initiation. Thus, immediate treatment can be administered to correct the underlying coagulation disorder.

Conclusion: The development of veno-occlusive priapism and penile gangrene in a patient on warfarin therapy raises a concern about protein C deficiency.

Significance of Beta-Blocker in Patients with Hypertensive Left Ventricular Hypertrophy and Myocardial Ischemia

Background: Arterial Hypertension (HTN) is a key risk factor for left ventricular hypertrophy (LVH) and a cause of ischemic heart disease (IHD). The association between myocardial ischemia and HTN LVH is strong because myocardial ischemia can occur in HTN LVH even in the absence of significant stenoses of epicardial coronary arteries.

Objective: To analyze pathophysiological characteristics/co-morbidities precipitating myocardial ischemia in patients with HTN LVH and provide a rationale for recommending beta-blockers (BBs) to prevent/treat ischemia in LVH.

Methods: We searched PubMed, SCOPUS, PubMed, Elsevier, Springer Verlag, and Google Scholar for review articles and guidelines on hypertension from 01/01/2000 until 01/05/2022. The search was limited to publications written in English.

Results: HTN LVH worsens ischemia in coronary artery disease (CAD) patients. Even without obstructive CAD, several pathophysiological mechanisms in HTN LVH can lead to myocardial ischemia. In the same guidelines that recommend BBs for patients with HTN and CAD, we could not find a single recommendation for BBs in patients with HTN LVH but without proven CAD. There are several reasons for the proposal of using some BBs to control ischemia in patients with HTN and LVH (even in the absence of obstructive CAD).

Conclusion: Some BBs ought to be considered to prevent/treat ischemia in patients with HTN LVH (even in the absence of obstructive CAD). Furthermore, LVH and ischemic events are important causes of ventricular tachycardia, ventricular fibrillation, and sudden cardiac death; these events are another reason for recommending certain BBs for HTN LVH.

The Role of NF-κB in Myocardial Ischemia/Reperfusion Injury

Acute myocardial infarction (AMI) is a threat to human life and physical health worldwide. Timely reperfusion is very important to limit infarct size and protect ischemic myocardium. Unfortunately, it has also caused severer myocardial damage, which is called “myocardial ischemia/ reperfusion injury (MIRI)”. There is no effective clinical treatment for it. Over the past two decades, biological studies of NF-κB have improved the understanding of MIRI. Nuclear Factor-κB (NF-κB) is a major transcription factor associated with cardiovascular health and disease. It is involved in the release of pro-inflammatory factors and apoptosis of cardiomyocytes. Recent studies have shown that inhibition of NF-κB plays a protective role in acute hypoxia and reperfusion injury. Here we review the molecular regulation of NF-κB in MIRI, better understanding of NF-κB signaling mechanisms related to inflammation and crosstalk with endogenous small molecules. We hope this review will aid in improving therapeutic approaches to clinical diagnosing. This review provides evidence for the role of NF-κB in MIRI and supports its use as a therapeutic target.

Surgical Treatment of Pulmonary Embolism and Chronic Thromboembolic Pulmonary Hypertension

Venous thromboembolism clinically presents as deep venous thrombosis or acute pulmonary embolism and is globally recognized as the third most frequent acute cardiovascular syndrome after myocardial infarction and stroke. Although pulmonary embolism does not typically cause severe pulmonary hypertension in the acute setting, thrombus organization and fibrosis can lead to stenosis or obliteration of pulmonary arteries in a minority of patients, which in turn result in severe pulmonary hypertension and right heart failure. This disease is labeled chronic thromboembolic pulmonary hypertension and can occur after a single episode or multiple ones of pulmonary embolism. The cornerstone of pulmonary embolism treatment is medical therapy, whereas systemic thrombolytic therapy has to be considered for patients with hemodynamic instability. Given the current acceptable short-term surgical mortality, the potential of first-line surgical embolectomy as an alternative to medical thrombolysis has gained momentum as far as pulmonary embolism treatment is concerned. In contrast to pulmonary embolism, bilateral complete pulmonary endarterectomy under short deep hypothermic circulatory arrest intervals is the treatment of choice against chronic thromboembolic pulmonary hypertension, given patients’ operability. Pulmonary endarterectomy is suggested in every operable patient when the operation is offered by an experienced multidisciplinary team, including at least one experienced surgeon. Surgical embolectomy should also be limited to large institutions since it also requires an experienced heart team. This review concerns a thorough discussion regarding surgical treatment of pulmonary embolism and chronic thromboembolic pulmonary hypertension. Eligibility criteria, operation-related complications and postoperative outcomes are discussed in detail.

Relationship between Augmentation Index and Wall Thickening Fraction during Hypotension in an Animal Model of Myocardial Ischemia-Reperfusion and Heart Failure

Aims: Non-invasive indices to evaluate left ventricular changes during ischemic heart failure are needed to quantify the myocardial impairment and the effectiveness of therapeutic manoeuvres. The aims of this work were to calculate the Wall Thickening Fraction (WTF) and the Augmentation Index (AIx) and to assess the relationship between WTF and AIx using data obtained from an animal model with heart failure followed by a myocardial ischemia stage and a reperfusion stage.

Methods: Nine Corriedale sheep that had been monitored for 10 minutes during a basal stage underwent 5-minute myocardial ischemia, followed by 60-minute reperfusion. Seven of them were subjected to an induced heart failure through an overdose of halothane, two of which were treated with intra-aortic counterpulsation during the reperfusion stage. The remaining two animals were monitored during their ischemia-reperfusion stage.

Results: Data obtained in the 5 animals suffering from heart failure followed by myocardial ischemia showed that: a) heart failure induction determined decrease in cardiac output, cardiac index and systolic and diastolic aortic pressure (AoP) with respect to their basal values (p<0.05), b) myocardial ischemia decreased the WTF compared with basal and induced heart failure values (p<0.05), c) during the reperfusion stage accompanied by induced heart failure, WTF increased with respect to values observed during the ischemia induction stage (p<0.05); nevertheless, basal values were not recovered after reperfusion (p<0.05). During this 60-minute stage, systolic and diastolic AoP values were lower (p<0.05) than those at the basal stage.

Conclusion: AIx and WTF values calculated from synchronically recorded values of aortic pressure and left ventricular wall thickness during the reperfusion stage in all animals (n = 9) showed a negative correlation (p<0.05). Analysed data provided evidence of a negative relationship between a left ventricular index of myocardial function and an arterial index obtained from AoP waves.

Iatrogenic Right Atrial Thrombus Complicated by Pulmonary Embolism: Management and Outcomes

Right atrial thrombus can originate from distal venous sources or can be iatrogenic, secondary to the placement of central venous catheters, atrial devices, or surgeries. One of the most common complications of Central Venous Catheters (CVCs) is thromboembolism, which can be either fixed to the right atrium or can be free-floating. Device-related Right Atrial Thrombosis (RAT) can result in catheter occlusion, vascular occlusion, infection, and pulmonary embolism. The true incidence of these complications is unknown because the diagnosis may not be considered in asymptomatic patients, and it might be missed by Transthoracic Echocardiography (TTE). In this literature review, we discuss iatrogenic etiologies of RAT that is complicated by pulmonary embolism. We highlight the importance of maintaining a high index of suspicion of iatrogenic RAT, possible complications, and its management.

The Protective of Baicalin on Myocardial Ischemia-Reperfusion Injury

Background: The aim of this study was to explore the inhibitory effect of baicalin on myocardial apoptosis induced by Ischemia-Reperfusion (I/R).

Methods: Sprague Dawley rats' heart and myocardial cells I/R model were established in vivo and vitro, then 100 mg/kg and 10 μmol/l baicalin were administrated, respectively. The experiment was randomly divided into 4 groups (n=10): Control; I/R; IR+DMEM; and I/R+baicalin groups. Postoperation, the Left Ventricular (LV) End-Diastolic Pressure (LVEDP), the maximum velocity of LV contraction (dP/dtmax) and the maximum velocity of LV diastole (dP/dtmin) were recorded by the transthoracic echocardiography; the myocardial apoptosis percentage was analyzed by Annexin VFITC/ PI and TUNEL staining, and the apoptosis gene and protein were detected by RT-PCR and western blot. Furthermore, the protein expression of the calcium-sensing receptor (CaSR) and ERK1/2 phosphorylation were observed by western blot and Fura-2-acetoxymethyl ester. Moreover, primary rats’ cardiomyocytes were cultured and ERK1/2 specific inhibitor PD98059 was added to the culture medium. The cell survival rate, vitality and apoptosis were detected by MTT, lactate dehydrogenase (LDH) and TUNEL staining assay Kit, respectively.

Results: Our present study showed that baicalin significantly improved LV hemodynamic parameters and myocardial apoptosis in myocardial I/R injury rats. Furthermore, we found that baicalin could down-regulate the protein expression of CaSR, but up-regulate the protein expression of ERK1/2. Furthermore, when the cells were pretreated with ERK1/2 inhibitor PD98059, the cells survival rate significantly decreased, but LDH activity and apoptosis significantly increased. The results indicated that the effect of baicalin on myocardial I/R injury could be inhibited by ERK1/2 inhibitor.

Conclusion: In conclusion, our data suggests that baicalin attenuates I/R-induced myocardial injury maybe through the suppression of the CaSR/ERK1/2 signaling pathway.

The Advances on the Protective Effects of Ginsenosides on Myocardial Ischemia and Ischemia-Reperfusion Injury

Ginseng is a traditional medicine with a complex chemical composition, wide bioactivity and unique pharmacological action. Many studies have confirmed that ginsenosides are the active ingredients of ginseng, and ginsenosides have always been the focus of different researchers. With the development of modern separation and analysis technology, more than 150 kinds of ginsenosides have been isolated. The ginsenosides Rb1, Rb2, Rc, Rg1 and Re account for more than 80% of total ginsenosides, and other saponins, such as Rd, Rg3 and Rh2, which are minor constituents, accounting for only a small portion of the total amount. In recent years, ginsenosides have been found to possess strong pharmacological activities, such as antioxidation, clearing of oxygen free radicals, reducing calcium overload and anti-apoptosis. Ginsenosides play a protective role in ischemia-reperfusion injury. This paper reviews the protective effects of ginsenosides on myocardial ischemia and ischemiareperfusion injury.

Cardiovascular Disease in Antiphospholipid Syndrome

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by venous, arterial or microvascular thrombosis or obstetric events in the presence of persistently positive antiphospholipid antibodies and constitutes a major cause of cardiovascular events in young people. Τhis review highlights the pathophysiology of cardiovascular complications in patients with APS and possible treatment options.

Patients with APS have endothelial dysfunction, accelerated endothelial proliferation and intimal hyperplasia, atherogenesis, platelet activation, inflammatory products secretion and coagulation-fibrinolytic dysregulation. Cardiovascular complications include accelerated atherosclerosis, acute coronary syndrome, Libman-Sacks endocarditis, cardiomyopathy and venous, arterial or intracardiac thrombi. Moreover, pulmonary hypertension and peripheral microvascular dysfunction are common findings.

Management of these patients is not well documented. The role of primary thrombosis prevention remains controversial in individuals with positive antiphospholipid antibodies. Treatment of traditional cardiovascular risk factors according to current guidelines for the prevention of cardiovascular disease in the general population is recommended for primary prevention of APS. Anticoagulation therapy with unfractionated or low-molecular-weight heparin overlapped with a vitamin K antagonist remains the mainstay of the treatment for APS patients with venous thrombosis, whereas direct oral anticoagulants are not yet recommended. Data are scarce regarding the secondary arterial thrombosis prevention and it is not clear whether dual or triple antithrombotic therapy is necessary. To date, it is recommended to follow current guidelines for the management of acute coronary syndrome in the general population. New treatment targets are promising options for patients with catastrophic APS.

Impaired Myocardial MIF/AMPK Activation Aggravates Myocardial Ischemia Reperfusion Injury in High-Fat Diet-Induced Obesity

Background: Obese patients are more sensitive to myocardial ischemia, which has been linked with high mortality rates. The following study investigates the effects of impaired macrophage Migration Inhibitory Factor (MIF)/AMP-Activated Protein Kinase (AMPK) activation on increased susceptibility to myocardial ischemia/reperfusion (I/R) in high-fat diet-induced obesity.

Methods: Male C57BL/6J mice were fed with a normal diet (10% kcal as fat, lean group) or a high-fat diet (60kcal as fat, obese group) for 12 consecutive weeks. To detect the MIF expression and AMPK activation in response to I/R in isolated hearts from lean and obese mice, myocardial samples were collected from left ventricular areas at different time points. To determine whether MIF supplementation is protective against I/R injury, recombined MIF (10 ng/mL) was applied before ischemia. Myocardial infarct size was estimated by triphenyltetrazolium staining. Western blot was used to detect myocardial MIF expression, AMPK activation and membrane glucose transporter 4 (Glut4) expression.

Results: The expression of MIF was remarkably higher in obese group compared to lean group. Ischemia increased myocardial MIF expression and phosphorylation of AMPK in lean mice, whereas it had no significant effect on obese mice. Furthermore, administration of recombinant MIF increased ischemic AMPK activation and membrane Glut4 expression in both lean and obese mice, while it reduced the infarct size in lean mice only.

Conclusion: An impaired MIF/AMPK activation response and consequent reduced membrane Glut4 expression may play an important role in increasing myocardial susceptibility to I/R in obesity.

Connexin43 and Myocardial Ischemia-Reperfusion Injury

Background: Recently, the treatment and prevention of ischemic cardiomyopathy is one of the emerging research topics in the cardiovascular field. Gap junction is the basic structure of cardiac electrophysiology. Connexin is the basic unit of gap junctions. Connexin43(CX43) is the most abundant member of Cx family in the heart, the normal expression of Cx43 is important for heart development, electrically coupled cardiomyocytes activities and coordination of myocardial function. The connection between Cx43 and myocardial ischemia/reperfusion or reperfusion injury has become the focus of current research.

Methods: We undertook a structured search of bibliographic database for peer-reviewed research literature using a focused review question and inclusion/exclusion criteria. The quality of retrieved papers was appraised using standard tools. The characteristics of screened papers were described, and a deductive qualitative content analysis methodology was applied to analyze the interventions and findings of included studies using a conceptual framework.

Results: Twenty-one papers were included in the review, eight papers outlined the relationship of Cx43 and reperfusion arrhythmias. Eight papers pointed out the effect on the infarct size of Cx43.

Conclusion: The findings of this review confirm that Cx43 is the most abundant member of Cx family in the heart and is vital for myocardial protection during ischemia/reperfusion process and for ischemia/reperfusion injury. Many of its mechanism are still not very clear and require future research in the future.

Role of Redox Homeostasis and Inflammation in the Pathogenesis of Pulmonary Arterial Hypertension

This review addresses pulmonary arterial hypertension (PAH), an incurable disease, which determines high morbidity and mortality. Definition of the disease, its characteristics, classification, and epidemiology are discussed. A difficulty in the diagnosis of PAH due to the lack of symptoms specificity is highlighted. Echocardiographic analysis and electrocardiogram of patients help in the diagnosis and in the follow up of the disease. Nevertheless, right ventricle (RV) catheterization constitutes the gold standard for diagnosing PAH. Oxidative stress and inflammation, in an interactive manner, play a major role in the development of pulmonary vascular remodeling and consequent increase of pulmonary pressure. The latter results in an increase in RV afterload, culminating with RV hypertrophy, which may progress to failure. Both clinical and experimental studies have shown increased oxidative stress and inflammation, not only in lungs and pulmonary vasculature but also in RV. The use of experimental models, such as the monocrotaline-induced PAH, has helped in the understanding of the pathophysiology of PAH, as well as in the development of new therapeutic strategies. In addition to the traditional therapeutics, the use of therapeutic interventions capable of modulating oxidative stress and inflammation may offer newer strategies in the prevention as well as management of this disease.

Cardioprotective Utility of Urocortin in Myocardial Ischemia- Reperfusion Injury: Where do We Stand?

Background: There has been a constant pursuit for development of newer therapies which can contribute to the relatively nascent field of cardioprotection in the setting of myocardial ischemiareperfusion injury. One novel cardioprotective agent among others, that has shown promising results in the limited number of research studies undertaken till now, is Urocortin. Urocortins are peptides belonging to the Corticotropin-Releasing Hormone family.

Results: Acting through a variety of downstream mechanisms, urocortin has been shown to alter cellular metabolism and modulate the mechanism of cell death occurring as a result of ischemia-reperfusion injury. New evidence continues to accumulate in support of urocortin’s beneficial role in cytoprotection.

Conclusion: We present here an updated review largely focused on the various mechanisms through which urocortin alters cellular metabolism, and discuss the clinical potential of urocortin’s cardioprotective ability in myocardial ischemia-reperfusion injury.

New Pharmacological Approaches to the Prevention of Myocardial Ischemia- Reperfusion Injury

Background: Early reperfusion of the blocked vessel is critical to restore the blood flow to the ischemic myocardium to salvage myocardial tissue and improve clinical outcome. This reperfusion strategy after a period of ischemia, however, may elicit further myocardial damage named myocardial reperfusion injury. The manifestations of reperfusion injury include arrhythmias, myocardial stunning and micro-vascular dysfunction, in addition to significant cardiomyocyte death. It is suggested that an overproduction of reactive oxygen species, intracellular calcium overload and inflammatory cell infiltration are the most important features of myocardial ischemia-reperfusion injury.

Objective: In this review, various pharmacological interventions to treat myocardial reperfusion injury including the antioxidant flavonols, hydrogen sulfide, adenosine, opioids, incretin-based therapies and cyclosporin A which targets the mitochondrial permeability transition pore are discussed.

Conclusion: The processes involved in reperfusion injury might provide targets for improved outcomes after myocardial infarction but thus far that aim has not been met in the clinic.

Mechanism-Based Inhibitors from Phytomedicine: Risks of Hepatotoxicity and their Potential Hepatotoxic Substructures

Background: The adverse drug reactions and poisoning events associated with the use of herbal medicines, especially the potential damaging effects of them on the liver organs, have increasingly been reported worldwide. Some herbal ingredients in medicinal plants carry the risk of herb-induced liver injury with a severe or potentially lethal clinical course, but the hepatotoxicity mechanisms and risk factors of them are not well characterized until now. Xenobiotics are converted by cytochrome P450 enzymes into highly reactive metabolites that covalently bind to the catalytic site of the enzyme itself, subsequently causing mechanism-based inhibition (MBI). Compared to reversible inhibition, MBI more frequently results in unfavorable acute and/or immune system-mediated idiosyncratic toxicities and drug/herb-drug interactions (DDI/HDIs).

Methods: We searched PubMed databases (1980-2015) for articles published in the English language to identify publications on mechanism-based inhibitors from phytomedicine and herbal ingredients hepatotoxicity.

Results: 43 mechanism-based inhibitors from phytomedicine were summarized. Twelve of these inhibitors could cause hepatotoxicity, whereas the rest have no related reports. Among them, six hepatotoxic mechanism-based inhibitors are proven to induce hepatotoxicity via their reactive metabolites (RMs). The possible mechanism for this hepatotoxicity is that RMs react with cellular components such as proteins, DNA, and membranes, resulting in ROS overproduction, respiratory chain dysfunction, and cell stress. Moreover, the amine and furan heterocycle groups might be the most potential substructures in mechanism-based inhibitors which can cause hepatotoxicity.

Conclusion: These results suggest that when mechanism-based inhibitors from phytomedicine containing amine or furan heterocycle substructures are used alone or with other drugs, in vivo hepatotoxicity screening or its clinical implications for herb-drug interactions are needed to attention.

Recent Advancements in Diagnosis and Therapy of Liver Cirrhosis

Cirrhosis is a diffuse pathophysiological state of the liver considered to be the final stage of various liver injuries, characterized by chronic necroinflammatory and fibrogenetic processes, with subsequent conversion of normal liver architecture into structurally abnormal nodules, dense fibrotic septa, concomitant parenchymal exaustment and collapse of the liver tissue. Alcoholic liver disease and chronic infections due to HBV and/or HCV constitute the main causes of liver cirrhosis worldwide. During a lag time of 15 to 30 years, chronic liver diseases can lead to liver cirrhosis and its complications. Active hepatic inflammation plays a pivotal role in the inflammation- necrosis-regeneration process, which eventually leads to liver cirrhosis and hepatocellular carcinoma. Prognosis of liver cirrhosis is highly variable and influenced by several variables, such as etiology, severity of liver disease, presence of complications and comorbidities. In advanced cirrhosis, survival decreases to one or two years. Correct advanced diagnosis and selected treatment with different molecules may help in understanding mechanisms of fibrogenesis, the driving forces of cirrhosis’s pathogenesis, and the scrupulous approach to more effective therapeutic procedures. Prevention of fibrosis with further deterioration of liver function through specific treatments is always required, through the removal of the underlying causes of liver disease. Advanced liver disease, with subsequent complications, requires targeted treatment. Therefore, the aim of this review is to assess the diagnosis and treatment of liver cirrhosis on the pathophysiological bases, searching for relevant studies published in English using the PubMed database from 2011 to the present.

Prognostic Significance of Asymptomatic Myocardial Ischemia in Women vs. Men

Background: Silent myocardial ischemia is a recognized but suboptimally studied condition in patients with and without known coronary artery disease. Limited work has focused on the association between silent myocardial ischemia and future prognosis however the majority of these analyses have focused mostly on male cohorts. As signs and symptoms of myocardial ischemia are known to be different in women, it is important to discuss and highlight any differences in association between silent myocardial ischemia and adverse cardiovascular outcomes based on gender. Methods: The aim of this review is to summarize the current literature available discussing silent myocardial ischemia and potential gender differences. We searched English language studies on PUBMED and the Cochrane Database of Systematic Reviews from the database start dates to November 2015. Conclusion: As data on the presence of silent myocardial ischemia in women is limited, whether a differential association based on gender between this condition and cardiovascular prognosis remains unknown. Future studies should target women especially those without epicardial coronary disease and suspected coronary microvascular dysfunction.

Novel Strategies in the Treatment of Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a pathophysiological condition characterized by increased pulmonary vascular resistance (PVR), initially due to abnormal pulmonary vasoconstriction in response to endothelial injury. Recent studies confirmed the key role of endothelin (ET)-1 in the vasoconstriction and remodeling of pulmonary microcirculation during PAH. In responders patients, classical treatments for PAH are prostanoids, phosphodiesterase (PDE)-5 inhibitors and endothelin receptor antagonists (ERAs), which target prostaglandin I2, nitric oxide and endothelin pathways, respectively. Randomised, placebo-controlled trials have shown that ERAs improves haemodynamic parameters of the pulmonary circulation, functional capacity and clinical outcome in patients affected by PAH. Here, we will review the definition, classification and pathophysiology of PH. Furthermore, we will provide an up-to-date overview of currently recommended diagnostic and therapeutic work-up in PAH.

Epigenetic Modulation: A Promising Avenue to Advance Hematopoietic Stem Cell-Based Therapy for Severe Autoimmune Disorders

Severe autoimmune disorders, such as certain serious forms of multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus, lead to poor prognosis for patients and can be fatal. Traditional immunosuppression therapies are rarely curative but only temporarily relieve patients from the flares. Arising “epigenetic” medications may enhance specificity but limitations still exist for their applications to severe autoimmune disorders due to the medications targeting differentiated immune cells. Hematopoietic stem cell-based therapy represents a different therapeutic strategy, which aims to reconstitute the functionality of the whole immune system. Such a re-constitutive approach has demonstrated long-lasting clinical benefits. Currently, hematopoietic stem cell transplantation remains a challenging and risky procedure, but recent scientific discoveries indicate that targeting epigenetics in hematopoietic stem cells bears promise to improve both the success rate and safety profile of hematopoietic stem cell-based therapy for treating severe autoimmune disorders.

Histopathology of Connective Tissue Disease-Associated Pleuropulmonary Disease

Pulmonary complications associated with autoimmune connective tissue disease (CTD) are common causes of clinical interstitial lung disease (ILD). Pleural manifestations are dominated by inflammation and varying amounts of diffuse fibrosis. In the lung, a wide spectrum of histologic injury patterns are encountered in every anatomic location including small airway disease most commonly in the form of chronic bronchiolitis, vascular changes, and interstitial lung disease ranging from diffuse alveolar damage to advanced pulmonary fibrosis. The most common interstitial pattern, seen in nearly all of the different CTDs, is a cellular and variably fibrotic ILD referred to as nonspecific interstitial pneumonia (NSIP). Each of the major CTDs has particular manifestations more commonly manifested, but the histopathologic changes found in these CTDs are often not specific and a definitive diagnosis usually requires detailed clinical, serologic, and pathologic correlation as well as close patient follow-up.

microRNAs: Promising Biomarkers and Therapeutic Targets of Acute Myocardial Ischemia

microRNAs (miRNAs), small non-coding RNA molecules that act as negative regulators of gene expression, are involved in a wide range of biological functions and control several cellular processes. This review illustrates miRNA regulation and function in tissue response to acute ischemia, focusing on miRNA role in acute myocardial infarction and describing a subset of miRNAs de-regulated upon cardiac ischemia. These miRNAs may represent “master ischemic” miRNAs, playing a pathogenetic role in one of the different components of tissue response to ischemia. Moreover, circulating miRNAs correlated to myocardial infarction and examples of miRNA involvement in ischemic diseases different from cardiac ischemia are also discussed. The identification of specific miRNAs as key regulators of cell biology has opened new clinical avenues, and may allow new diagnostic and/or prognostic tools development, as much as innovative therapeutic strategies. Two paradigmatic reports, in which miRNAs have been targeted to improve cardiac function in pre-clinical models of myocardial infarction, are described in detail and confirmed the efficacy of these strategies.

Molecular Pathophysiology of Priapism: Emerging Targets

Priapism is an erectile disorder involving uncontrolled, prolonged penile erection without sexual purpose, which can lead to erectile dysfunction. Ischemic priapism, the most common of the variants, occurs with high prevalence in patients with sickle cell disease. Despite the potentially devastating complications of this condition, management of recurrent priapism episodes historically has commonly involved reactive treatments rather than preventative strategies. Recently, increasing elucidation of the complex molecular mechanisms underlying this disorder, principally involving dysregulation of nitric oxide signaling, has allowed for greater insights and exploration into potential therapeutic targets. In this review, we discuss the multiple molecular regulatory pathways implicated in the pathophysiology of priapism. We also identify the roles and mechanisms of molecular effectors in providing the basis for potential future therapies.

Penile Rehabilitation After Radical Prostatectomy

Erectile dysfunction (ED) is the main and most frequent side effect after radical prostatectomy. Also, ED is the primary impact factor for quality of life after radical prostatectomy. ED post radical prostatectomy is mainly due to lesions in the neurovascular bundles which can occur by partial or total sectioning, by stretching (the most common), or by thermal lesion of the nervous fibers, leading to a condition called “neuropraxia”. The term penile rehabilitation (PR) after prostatectomy has been defined as any intervention with the intent of reestablishing preoperative erectile function and includes the isolated or combined use of phosphodiesterase 5 inhibitors (PDE5i), intracavernous injection, vacuum erectile device therapy, and use of intraurethral drugs. The use of intracavernous drugs, of intraurethral prostaglandin and the use of vacuum therapy have a poorly defined role regarding postoperative penile rehabilitation and must be better investigated through further studies. The use of PDE5i as PR is strongly supported by experimental research, but most clinical trials found controversial results.

Pulmonary Hypertension in the Perioperative Period-Focus on Current and Emerging Therapies

Patients with pulmonary hypertension continue to present for both cardiac and non-cardiac surgery in greater numbers worldwide, and are usually managed by cardiothoracic anesthesiologists. These specialists have traditionally used intravenous therapy in the operating room to manipulate hemodynamics (cardiac output systemic and pulmonary vascular resistance), to effectively manage these high risk patients. General anesthesia involves the administration of both intravenous and inhaled drug therapy to achieve the desired goals, i.e. analgesia, amnesia, muscle relaxation and blockade of autonomic activity. Anesthesiologists are the experts in the use and titration of drugs that are administered through the inhaled route. However, this method of drug delivery presents many challenges, notably timing, dosage accuracy, rapid titratability and consistency of drug delivery. In patients with severe pulmonary hypertension, arguably the most rapid method of treating acutely reactive pulmonary vasculature would involve drugs that directly act upon the pulmonary endothelium. In the perioperative period, pulmonary hypertension and right ventricular failure are high predictors of morbidity and mortality and present significant challenges to the anesthesiologist. In this article, we will focus on the current status of intravenous and inhaled therapy of these conditions, including concerned recent patents.

Extrahepatic Targets and Cellular Reactivity of Drug Metabolites

Biotransformation is one of the key elements of chemically induced toxicity. Although organisms have an intrinsic tendency to diminish the harm posed by chemical exposure with or without structural modification and excretion of the agents (detoxification), this is not always the case; toxification may also occur. The liver has evolved to be the center of biotransformation from the anatomical, physiological and biochemical points of view; it is located alongside the stomach and intestine, it receives more than 25% of the cardiac output and it contains, in general, the richest quantity but also variety of drug metabolizing enzymes. That is why many orally taken drug-induced toxic effects are seen in the liver. Nevertheless, non-hepatic tissues in the organism are also subjected to toxic insult. Although several instances have suggested transport of liver-bioactivated reactive metabolites to the target tissue is responsible, such as monocrotaline-associated lung toxicity, tetraethyl lead- and n-hexane-associated nervous system toxicity and 2-methoxyethanol-associated testis toxicity, etc. [1], the vast majority of data show local bioactivation in the target tissue is responsible for the extrahepatic toxic outcome. The impact of extrahepatic bioactivation and toxicity of drugs can also be seen in cases of drug attrition due to unacceptable toxicity; adverse cardiovascular effects were the foremost reason for drug withdrawals between 1993 and 2006 [2]. On the other hand, the parent drug and/or its stable metabolite( s) may also cause adverse effects such as inhibition of transporters, occlusion of bile secretion (cholestasis) and accumulation in organelles such as mitochondria, causing steatosis in liver and possibly in other organs. However, this review attempts to summarize only extrahepatic bioactivation of drugs/chemicals and their effects at the cellular and tissue level. Specifically, it focuses on the two most perfused organs, lung and heart tissue, as well as thyroid, blood, brain, and skin. Clozapine, a still-in-use drug with severe off-target toxicities (agranulocytosis and cardiovascular toxicity), is investigated in depth and various drugs are reviewed with a special emphasize on the other mentioned organs.

Emerging Therapy Options in Heparin-Induced Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a life and limb-threatening thrombotic complication of heparin, which is the result of platelet activation by anti-PF4/heparin antibodies. With lepirudin and danaparoid no longer available in the US, treatment options are limited to argatroban, fondaparinux (off-label use) and bivalirudin (for patients undergoing percutaneous coronary intervention). Both argatroban and bivalirudin are parenteral drugs and require close monitoring and hospitalization. Fondaparinux is contraindicated in patients with significant renal impairment and is associated with a small risk of HIT. Anticoagulants approved for thromboprophylaxis and management of thromboembolic conditions such as rivaroxaban, dabigatran, and apixaban have fixed oral dose, rapid onset of action and does not require monitoring. These novel agents do not interact with anti-PF4/heparin antibody and offer attractive therapy options for HIT. Their utility in HIT has been supported by a few clinical reports, however, larger studies are needed before they can be utilized in clinical practice. Therapeutic plasma exchange has been utilized with some success in patients with HIT, who need heparin reexposure for cardiac surgery but their safety and efficacy needs further exploration. 2-O, 3-O desulfated heparin, which lacks any anticoagulant effect, has been shown to reduce the development of HIT in murine models. Finally, novel targets based on the molecular pathogenesis of HIT are being studied for therapeutic drug development. We hope that the availability of novel therapies in the future will expand the options available for the management of HIT.

ECMO for Refractory Hypoxia; Current State of the Art and Future Directions

Refractory hypoxia in adult respiratory distress syndrome remains a highly lethal process. Low tidal volume ventilation maneuvers have improved outcomes. In severe Acute Respiratory Distress Syndrome (ARDS), the mortality remains high. Veno-Venous Extracorporeal Membranous Oxygenation (VV ECMO) has been employed to treat this very sick group of patients. The proper selection of patients for VV ECMO as well as proper critical care management while on ECMO remains the key to improved outcomes. This review article details the current state of the art therapy for VV ECMO for refractory hypoxia, and describes controversies and future directions.

Myocardial Ischemia/Reperfusion Injury: Potential of TRPV1 Agonists as Cardioprotective Agents

Myocardial Ischemia/Reperfusion (I/R) induced injury has widespread detrimental effects partially negating the benefits obtained from early revascularization in Acute Myocardial Infarction. Various complex mechanisms contribute to I/R injury and different agents targeting those specific mechanisms are being studied. Despite continued research and widespread interest, none of them have become incorporated into everyday practice. The TRPV1 (transient receptor potential vanilloid 1) channel is a non selective cation channel predominantly expressed in sensory neurons with the nerve fibers innervating the heart and blood vessels. Multiple studies have demonstrated the importance of the activation of TRPV1 and subsequent release of sensory neurotransmitters in cardioprotection. This review focuses on the role of TRPV1 in prevention of cardiac I/R injury, the work that has been done so far and future implications for TRPV1 agonists as cardioprotective agents.

Primary Antiphospholipid Syndrome and Pulmonary Hypertension

Primary antiphospholipid syndrome (APS) is a disease characterized by the presence of autoantibodies reacting with proteins bound to phospholipids, leading to thrombosis and gestation abnormalities. Prothrombotic states and impaired clot dissolution are believed to contribute to the occurrence of chronic thromboembolic pulmonary hypertension (CTEPH) in APS. Whether preventive anticoagulation therapy in patients with antiphospholipid autoantibodies without a history of thrombosis reduces the risk of thrombosis is currently unclear. The diagnosis and treatment of CTEPH in APS is similar to CTEPH complicated by other predisposing conditions, with surgical treatment being the most effective. However, not every patient with CTEPH is suitable for pulmonary thromboendartarectomy and such individuals may benefit from pharmacotherapy of pulmonary hypertension, given the presence of pulmonary microvascular abnormalities similar to those in idiopathic pulmonary hypertension. Anticoagulation therapy is the mainstay of management because of the high risk of recurrent embolization and local in-situ thrombosis.

Transactivation of ErbB Receptors by Leptin in the Cardiovascular System: Mechanisms, Consequences and Target for Therapy

Many experimental and clinical studies have demonstrated that elevated leptin concentration in patients with obesity/metabolic syndrome contributes to the pathogenesis of cardiovascular disorders including arterial hypertension, atherosclerosis, restenosis after coronary angioplasty and myocardial hypertrophy. Receptor tyrosine kinases belonging to the ErbB family, especially ErbB1 (epidermal growth factor receptor) and ErbB2 are abundantly expressed in the blood vessels and the heart. EGFR is activated not only by its multiple peptide ligands but also by many other factors including angiotensin II, endothelin-1, norepinephrine, thrombin and prorenin; the phenomenon referred to as “transactivation”. Augmented EGFR signaling contributes to abnormalities of vascular tone and renal sodium handling as well as vascular remodeling and myocardial hypertrophy through various intracellular mechanisms, in particular extracellular signal-regulated kinases (ERK) and phosphoinositide 3-kinase (PI3K). Recent experimental studies indicate that chronically elevated leptin transactivates the EGFR through the mechanisms requiring reactive oxygen species and cytosolic tyrosine kinase, c-Src. In addition, hyperleptinemia increases ErbB2 activity in the arterial wall. Stimulation of EGFR and ErbB2 downstream signaling pathways such as ERK and PI3K in the vascular wall and the kidney may contribute to the increase in vascular tone, enhanced tubular sodium reabsorption as well as vascular and renal lesions in hyperleptinemic obese subjects.

Current Diagnostic Investigation in Pulmonary Hypertension

Pulmonary hypertension refers to pathological elevation of the pulmonary arterial pressure and can be seen in a variety of clinical conditions. It is progressive and ultimately fatal if untreated. Timely recognition and accurate diagnosis are therefore paramount in providing effective management to patients so as to prevent, reduce or stabilise irreversible damage to the pulmonary vasculature, which ultimately causes right heart failure. PH is often not considered or misdiagnosed and a median time of 14 months from the onset of symptoms to diagnosis has been reported. As well as an awareness of the condition it is imperative that physicians know how to correctly interpret a range of investigations that are necessary in reaching the diagnosis.

Pharmacologic Treatment of Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a rare, incurable disease characterized by adverse remodeling of the pulmonary vasculature, leading to increased pulmonary arterial pressures and right ventricular failure. Contemporary pharmacotherapy targets 3 distinct molecular pathways that are abnormal in PAH: deficient production of nitric oxide and prostacyclin, and over production of endothelin. Risk assessment is critical in guiding therapeutic decision making and in disease surveillance following treatment initiation. Patients with more advanced disease are best treated with continuous infusion therapy, while those less symptomatic patients may respond to oral or inhaled therapies. Combination therapy is being increasingly utilized in patients who fail to achieve treatment goals.

Radiological Diagnosis of Renal Thrombosis in Children

Renal thrombosis has multiple potential causes and a variety of imaging techniques can be used to make the diagnosis. Hypercoagulable states, ranging from hereditary thrombophilia to dehydration, may result in thrombosis in previously healthy renal veins. Abnormal vasculature, including a spectrum of primary vascular disorders, such as stenosis or vasculitis, may result in arterial or venous thrombosis. Traumatic injury to the vascular pedicle or dissection may also cause thrombosis.

Renal vein thrombosis is an uncommon but potentially serious condition that may result in acute complications such as pulmonary embolus and acute renal failure, or may lead to chronic kidney disease and hypertension. Until relatively recently, RVT could only be confidently confirmed or excluded with selective renal venography, however ultrasound is now the imaging method of choice for neonatal and pediatric RVT [1-4]. A spectrum of grey-scale, and Doppler imaging features has been described for the acute and late phases of the condition. Some authors have reported specific sonographic features that might predict poor outcome and renal atrophy [4, 5].

Magnetic resonance imaging provides accurate diagnostic evaluation of renal vasculature, particularly in the assessment of renal masses, but is typically reserved for those cases where the Doppler findings are inconclusive. In general, computed tomography (CT) diagnostic yield is comparable to magnetic resonance imaging (MRI). The requirement for IV contrast and significant radiation dose should be balanced against the potential need for general anaesthesia as well as institutional availability and expertise.

Treatment of Pulmonary Edema by ENaC Activators/Stimulators

Lungs contain a particular amount of fluid that is crucial for proper lung function. This fluid content is tightly controlled within certain limits. Fluid accumulation in the alveolar airspace impairs gas exchange and represents a lifethreatening condition referred to as pulmonary edema. Ion transport processes by pulmonary epithelia represent a mechanism, responsible for fluid absorption from the airspace. Thus, it is obvious to consider ion transport processes as target for therapeutic interventions in pulmonary edema. The principle mechanism responsible for fluid absorption from the airspace is: Na⁺ diffuses through luminal Na⁺ channels into epithelial cells and is extruded by Na⁺/K⁺-ATPases at the basolateral side. This process generates an osmotic gradient that represents the driving force for fluid absorption. The rate of Na⁺ absorption is limited by the number/activity of Na+ channels in the luminal membrane of alveolar epithelial cells. Although different Na+ channels have been identified, the epithelial Na+ channel (ENaC) is a major player that participates in Na⁺-driven fluid absorption and thus a suitable target for the treatment of pulmonary edema.

This article reviews cellular mechanisms by which ENaC activity can be increased in alveolar epithelia (lectins, proteases, β-adrenoceptors, mineralo-/glucocorticoid-receptors). These mechanisms are involved in regulating ENaC-dependent fluid absorption under physiological conditions. Additionally, pre-clinical as well as some preliminary clinical studies revealed that “ENaC-activators/stimulators” (β2-adrenoceptor agonists and mineralo-/glucocorticoid-receptor agonists) could be beneficial for therapeutic interventions in patients with pulmonary edema. However, the outcome of subsequently performed multicenter clinical trials with “ENaC-activators/stimulators” for treatment of patients with pulmonary edema was disappointing.

Immunotherapy in Invasive Fungal Infection - Focus on Invasive Aspergillosis

Despite the availability of new antifungal compounds, morbidity and mortality of invasive aspergillosis are still unacceptably high, in particular in immunocompromised patients such as patients with hematological malignancies or allogeneic hematopoietic stem cell or solid organ transplant recipients. Over the last decades, our knowledge of the immunopathogenesis of invasive aspergillosis has greatly advanced. This, in turn, provided critical information to augment host immunity against fungal pathogens. Potential approaches for enhancing the host immune system in the combat against Aspergillus include the administration of effector and regulatory cells (e.g., granulocytes, antigen-specific T cells, natural killer cells, dendritic cells) as well as the administration of recombinant cytokines, interferons and growth factors (e.g., interferon-γ,granulocyte- and granulocyte-macrophage colony stimulating factor) and various vaccination strategies. Although promising results are reported on in vitro data and animal studies, current data are too limited to allow solid conclusions on the risk and the benefit of these strategies in the clinical setting. Therefore, the real challenge in the future is to perform appropriately designed and powered clinical trials. These require international, multi-center collaboration, but may ultimately improve the outcome in immunocompromised patients suffering from invasive aspergillosis.

Current and Experimental Antibody-Based Therapeutics: Insights, Breakthroughs, Setbacks and Future Directions

The premise of targeted therapy was born from an intimate understanding of the unique biological pathways and endpoints which are implicated in the development of different disease states and conditions. In addition, the identification of the most appropriate drugs to use for targeted drug therapy has aided in growing interest of the pharmaceutical industry to allocate more resources to monoclonal antibody (mAb) therapeutics. This being the case, it is important to understand antibody based therapeutics, some of the currently Food and Drug Administration (FDA)-approved mAbs in different disease states, as well as the future direction of mAb therapies. In this article, we will provide a critical overview, and discuss a selection of antibody based therapeutics, including their bioengineered structural and functional elements. Furthermore, a segment of the currently FDA-approved mAb antibody therapies, those in research, or in investigation for disease states and conditions ranging from autoimmune disease, inflammatory response, immunosuppression, cancer, including antibody-drug conjugates, immunotherapy, and exciting prospects for antiplatelet and antithrombotic monoclonal antibody therapeutics will be reviewed. Finally, we will discuss our predictions and aspirations for the future directions of mAb-based therapeutic interventions.

Advances in Drug Safety

The operating room offers a unique setting where anesthetics, preoperative medications, patient comorbidities, and surgery all merge. Anesthesiologists are responsible for combining these concerns into a dependable and safe approach. From formulation to administration, enhancements in nearly every aspect of a given drug have improved the ability of anesthesiologists to accomplish this. Some of these methodologies, including novel anesthetics and analgesics, drug delivery and administration including infusion pumps, antithrombotics, and a reappraisal of previous medications are highlighted in this review.

While these advancements are significant, patients and healthcare systems globally are rightfully demanding safer application of drugs at every level. On May 1, 2012, a report issued by the Institute of Medicine advised the United States Food and Drug Administration to undertake a much more rigorous patient-centered effort to evaluate a drug’s safety over its entire life-cycle. This recommendation is in agreement with the objectives of the Anesthesia Patient Safety Foundation. With these mutual goals shared by many stakeholders and their continued efforts, the future of the estimated 200 million global surgeries to be undertaken this year hopefully provides a safer experience while under anesthesia.

Transcatheter Embolization Therapy in Liver Cancer

Embolization procedure is commonly used in interventional oncology. Transarterial chemoembolization (TACE) has been shown to provide a survival benefit for liver cancer patients. TACE combines targeted chemotherapy with the effect of ischemic necrosis induced by arterial embolization. Recently, there have been efforts to improve the delivery of chemotherapeutic agents to tumors, leading to the development of drug-eluting particles. To avoid the limitation of external beam irradiation due to the radiosensitive nature of normal hepatic tissue, minimally invasive transarterial radioembolization (TARE) technique has been developed, and proven to be safer in advanced liver cancers. This review describes the basic procedure of transarterial chemoembolization, properties and efficacy of some chemoembolization agents and radioembolization agents which are commercially available and/or currently under clinical evaluation. The key clinical trials of transcatheter arterial therapy for liver cancer and the recent patents relevant to cancer chemoembolization are also summarized.

PDE5 Inhibitor Treatment Options for Urologic and Non-Urologic Indications: 2012 Update

Phosphodiesterase (PDE) enzymes are widely distributed throughout the body, having numerous effects and functions. The use of on demand PDE5 inhibitors (-Is) for the treatment of erectile dysfunction (ED) has recently obtained approval for chronic daily dosing for the same indication. There are published data supporting the use of PDE5-Is for the treatment of lower urinary tract symptoms (LUTS) caused by benign prostatic hyperplasia (BPH). Additional reports suggest benefit by these agents in patients with chronic heart failure, pulmonary hypertension, essential hypertension, and for the treatment of ischemia. Various central nervous system disorders have been described as targets by PDE5-Is. Sildenafil may have a potential therapeutic indication as a cognitive enhancer in age-related cerebral conditions. There is preclinical evidence for further investigation of the use of PDE5A -Is to improve recovery of cerebral function in humans after stroke by enhancing angiogenesis, neurogenesis and improving neurologic function. Sildenafil delays intestinal ulceration by an increase in the secretion of mucus/fluid and a decrease in hypermotility, and has a protective effect in reducing gastric damage. Larger scale, well designed clinical trials are needed to ascertain the safety, efficacy and cost-effectiveness of PDE5-Is in the future treatment of both urologic and non-urologic diseases. In this review, potential applications of PDE5-Is on urologic, cardiovascular, gastrointestinal, and central nervous system disorders will be updated.

Nonstandard Drugs and Feasible New Interventions for Autoimmune Hepatitis: Part I

Nonstandard drugs that target critical pathogenic pathways or immune regulatory mechanisms constitute the next generation of treatments for autoimmune hepatitis. Mycophenolate mofetil impairs the proliferation of lymphocytes, decreases autoantibody production, and induces apoptosis of activated immunocytes. Patients treated for azathioprine intolerance improve more frequently than patients treated for refractory liver disease (54% versus 10%), and mycophenolate mofetil is emerging as a rescue therapy for this population. Complete corticosteroid withdrawal is possible in 40% of patients treated with mycophenolate mofetil, and the frequency of side effects ranges from 3-34%. Budesonide in combination with azathioprine has normalized liver tests more frequently (47% versus 18%) and with fewer side effects (28% versus 53%) than standard therapy after 6 months. Budesonide is emerging as a frontline treatment in non-cirrhotic patients with uncomplicated disease or contraindications to conventional corticosteroids. Cyclosporine and tacrolimus are effective salvage agents for steroid-refractory disease, but side effects have been common and occasionally serious. The 6- thioguanine nucleotides and rapamycin are feasible treatments for autoimmune hepatitis, but 6-thioguanine has major obstacles to overcome, especially the risk of liver toxicity or nodular regenerative hyperplasia. The nonstandard drug therapies emerging for autoimmune hepatitis reflect the need to supplement or supplant current treatment regimens. None has been licensed for use in autoimmune hepatitis, and their applications have been based on results from small singlecenter experiences.

Continuous Renal Replacement Therapy in Children Post-Hematopoietic Stem Cell Transplantation: The Present and the Future

Allogeneic hematopoietic stem cell transplantation (HSCT) use has expanded markedly to treat different disorders like hematologic malignancies, immunodeficiency, and inborn errors of metabolism. However, it is commonly associated with complications that limit the benefit of this therapy. Acute renal failure occurs commonly after HSCT and results in increased risk of mortality. In many instances, children post-HSCT develop acute renal insufficiency in the context of other organ failure, necessitating intensive care unit admission for management. Recently, continuous renal replacement therapy (CRRT) has emerged as the favored modality of renal replacement therapy in the care of critically ill children who are hemodynamically unstable. Currently, CRRT is being utilized more often in the care of critically ill post- HSCT children to treat renal failure or to prevent fluid overload (FO). FO>20% has been shown in many studies to be an independent risk of mortality in critically ill children and therefore, many clinicians will initiate this therapy due to FO even without overt renal failure. CRRT may be beneficial in disease processes as acute lung injury due to removal of fluid. CRRT results in improved oxygenation in post-HSCT children with acute lung injury and this improvement is sustained for at least 48 hours after initiation of this therapy. Survival in post-HSCT children requiring this therapy ranges from 17% to 45%, however, long term survival is still poor. This review will discuss current practice of CRRT in children post-HSCT, as well as future directions.

Contemporary Overview on Clinical Trials and Future Prospects of Hepato-protective Herbal Medicines

Till date the synthetic hepato-protective agents used in clinical practices are therapeutically non-promising and may itself lead to hepatotoxicity. Herbal medicines and their bioactives are considered to be relatively safe and have been used in the treatment of liver diseases for a long time. The 21st century has seen a paradigm shift towards therapeutic standardization of herbal drugs in hepatic disorders by evidence-based randomized controlled clinical trials to support their clinical efficacy. Even so, the specific hepato-protective clinical trial protocols for herbal medicines are not established till now. So, the efficacy of herbal medicines needs to be evaluated through rigorously designed multicentre clinical studies. In this review, we have enlightened the clinically evaluated hepatoprotective herbals and herbal formulations with respect to their status in different trial stages. Moreover, the problems and their strategic solutions during the development of clinical trial protocol for hepatoprotective herbal medicine are also addressed.

Mixed Connective Tissue Disease (MCTD) – A Coming of Age

In Mixed Connective Tissue Disease (MCTD), features of various connective tissue disorders such as systemic lupus erythematosus (SLE), progressive systemic sclerosis (PSSc), dermatomyositis/polymyositis (DM/PM), and occasionally Sjogren’s syndrome and rheumatoid arthritis (RA) can coexist and overlap. The picture is marked by the presence of high titer anti-U1 ribonucleoprotein (RNP) antibodies. Over the last 30 years since first described a lot of controversial studies have been published regarding the nature, the severity or the very existence of the condition. MCTD is not a benign condition easily responsive to treatment or without major complication as previously believed and every effort should be made from the start to identify the type and extent of organ involvement. Overall the mortality is not as high as in SLE but pulmonary hypertension and its cardiac complications are the major cause of death in MCTD and the patients should be monitored closely for its development and progression. This is a review of the clinical aspects and an update of the management of the main morbidities of MCTD.

Interactions between Phytochemicals from Traditional Chinese Medicines and Human Cytochrome P450 Enzymes

Traditional Chinese medicine (TCM) formulas with fixed combinations rely on \"sovereign, minister, assistant and guide\" and fuzzy mathematical quantitative law, leading to greater challenges for the identification of active ingredients. Transformation and metabolic studies involving the Phase I drug-metabolizing enzyme cytochrome P450 (CYP) might potentially solve some of these challenges. The pharmacological effects can not be attributed to one active ingredient in TCMs, but integrated effects resulting from the combined actions of multiple ingredients. However, it is only after long-term administration that most ingredients exert their actions, which can result in prolonged exposure to herbs in vivo. Therefore, interactions between herbal compounds and CYPs appear to be inevitable. Yet unlike Western drugs, experimental determination of the absorption and disposition properties is not commonly carried out for TCMs. Moreover, the use of TCM as injections is an innovation aimed to improve efficiency in extensive clinical use in Mainland China. Therefore, in recent years, cases of adverse drug reactions (ADR) mainly concerning allergic reactions involving TCMs such as ShenMai injection and QingKaiLing injection have been reported, which have attracted attention with regard to the legal responsibilities for TCM approval. The lack of information on the ADME characteristics, especially the metabolic stability and interaction potential between CYPs and herbs, increases ADR occurrence due to TCMs. In this article, we review the most common herbs used in TCM prescriptions and fixed combinations of their usable frequency, and summarize the current understanding of the ability of phytochemical ingredients to act as substrates, inhibitors or inducers of human CYP enzymes, through which the key role of CYP enzymes on the herb disposition and toxicity is highlighted. The potential interaction between herbal phytochemicals and CYP enzymes dominates the target exposure, which further helps to elucidate the herbal pharmacological basis, assess the individual toxic risk of herbal remedies and gain mechanistic insight into herb–drug interactions (HDIs).

Role of Cytokines in the Pathophysiology of Acute Graft-Versus-Host Disease (GVHD)– Are Serum/Plasma Cytokines Potential Biomarkers for Diagnosis of Acute GVHD Following Allogeneic Hematopoietic Cell Transplantation (Allo-HCT)?

Due to the advent of less-toxic reduced intensity conditioning regimens (RIT), allogeneic hematopoietic cell transplantation (allo-HCT) is currently widely used to treat chemotherapy-resistant hematological diseases, particularly in older patients,which are the fastest growing group of patients receiving allo-HCT. However, graft-versus-host disease (GVHD) is still the major complication after allo-HCT, causing immune deficiency, infection, organ damage, and occasionally patient death. Mortality from GVHD is in part attributed to the difficulty in making accurate diagnosis and determining the optimal timing for appropriate treatment. The diagnosis of acute GVHD is dependent on clinical features and is sometimes indistinguishable from other causes and requires invasive procedures. Therefore, non-invasive, diagnostic and predictive monitoring tools, such as plasma/serum biomarkers, are needed. Determination of the roles of cytokines in the physiopathology of acute GVHD has provided an explanation for many preclinical and clinical observations. However, measurement of a single cytokine lacks specificity for GVHD diagnosis. Therefore, comprehensive assessment of plasma/serum cytokine concentrations is required to identify a panel of biomarkers with good specificity and sensitivity for GVHD. In this review, we summarize the roles of individual cytokines in the pathophysiology of acute GVHD and discuss the possibility of cytokines as biomarkers of acute GVHD after allo-HCT.

Pain Management in Hematological Patients with Major Organ Dysfunctions and Comorbid Illnesses

Background: Organ dysfunctions and medical complications, such as renal failure, liver impairment, coagulation disorders, cardiovascular and respiratory illnesses, may hamper an adequate pain management in haematological patients.

Aim: To summarize current knowledge on pain management in hematological patients presenting major organ dysfunctions and comorbidity. We also attempted to provide recommendations to optimize analgesia and to minimize side effects in the setting of medically compromised and frail haematological patients.

Methods: A systematic search of the literature, using relevant key words, was conducted in PubMed.

Results and conclusions: Pain in hematological patients is a common symptom and is often multi-factorial. Most pharmacotherapeutic measures, including causal therapies, analgesics and adjuvant agents routinely applied in pain management, may also be used in the setting of clinical frailty and medical comorbidities; however, comprehensive clinical and functional patient’s evaluations and a careful consideration of expected benefits and potential adverse events are required.

Microvascular Diseases: Is A New Era Coming?

The microvascular bed is an anatomical entity which comprises myriads of small arterioles, capillaries and venules. Microvessels and surrounding tissue metabolism are tightly coupled; consequently they are equipped with many, very specific and fine-tuned mechanisms allowing permanent, precise regulation of nutrient delivery. The review thoroughly describes the structure and physiology of arterioles and capillaries as well as the specialized means to investigate them. Microcirculation has been largely neglected for decades, mainly because of lack of technical possibilities for visualization and quantitation. However the past years have completely renewed the scientific interest, due to the combination of the availability of new techniques in human research and the recognition that the microcirculation is autonomically and causally involved in diseases previously thought to be essentially a question of macrocirculation. Today we start to see that microangiopathy is not only a consequence of large vessel diseases but can be the source of many pathologies in both cardiovascular and metabolic disorders, the best example –developed here- being the cardiometabolic syndrome or prediabetes. With very few exceptions, pentoxifylline and the antidiabetic metformin, no specific treatments have been developed for treating disorders at the microcirculatory level. Metformin has unique, intrinsic actions specifically at the level of terminal arterioles, which are completely independent of its antidiabetic effect. Other drugs are shortly described which have revealed a potential interest in this field. Our review aims at showing that microcirculation is entering a new era, starting with rapidly increasing knowledge of its intimate functioning and worth specific pharmacological developments.

Systemic Sclerosis-Related Pulmonary Hypertension: Unique Characteristics and Future Treatment Targets

Pulmonary arterial hypertension (PAH) is a severe vascular complication of connective tissue diseases. In the context of systemic sclerosis (SSc), PAH is a devastating disease with a dramatic impact on prognosis and survival. Despite advances in early diagnosis and the development of new targeted treatments, SSc-related pulmonary arterial hypertension (SScPAH) represents the leading cause of death in SSc patients with reported poorer response in therapy and worse prognosis compared with idiopathic PAH. Recent findings indicate that factors accounting for these differences may include cardiac involvement, pronounced autoimmune and inflammatory response and pulmonary venous vasculature remodeling. Deeper understanding of the underlying pathogenic mechanisms of pulmonary vascular disorders in SScPAH may lead to novel therapeutic strategies which are currently under investigation and may improve the outcome of these patients, for whom our therapeutic armamentarium is not effective enough. In this article we attempt to critically analyze the factors contributing to the unique phenotype of SScPAH focusing on future challenges for the design of novel targeted treatments which may alter the natural history of the disease.

Testosterone as Potential Effective Therapy in Treatment of Obesity in Men with Testosterone Deficiency: A Review

Objective: Obesity negatively affects human health. Limiting food intake, while producing some weight loss, results in reduction of lean body mass. Combined with moderate exercise it produces significant weight loss, maintains lean body mass and improves insulin sensitivity, but appears difficult to adhere to. Bariatric surgery is clinically effective for severely obese individuals compared with non-surgical interventions, but has limitations. Clinical and pre-clinical studies have implicated a role for testosterone (T) in the patho-physiology of obesity.

Methods: Evidence Acquisition and Synthesis: A literature search in PubMed on the role of T in counteracting obesity and its complications.

Results: Obesity per se impairs testicular T biosynthesis. Furthermore, lower-than-normal T levels increase accumulation of fat depots, particularly abdominal (visceral) fat. This fat distribution is associated with development of metabolic syndrome (MetS) and its sequels, namely type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). T treatment reverses fat accumulation with significant improvement in lean body mass, insulin sensitivity and biochemical profiles of cardiovascular risk. The contribution of T to combating obesity in hypogonadal men remains largely unknown to medical professionals managing patients with obesity and metabolic syndrome. Many physicians associate T treatment in men with risks for prostate malignancy and CVD. These beliefs are not supported by recent insights.

Conclusion: While overall treatment of obesity is unsuccessful, T treatment of hypogonadal men may be effective, also because it improves mood, energy, reduces fatigue and may motivate men to adhere to diet and exercise regimens designed to combat obesity.

Pulmonary Hypertension: Clinical Presentation, Diagnosis, Treatment,and Dana Point World Symposium Highlights

Pulmonary arterial hypertension (PAH) is a progressive, debilitating, and potentially fatal disease. Symptoms of PAH are non-specific and may include dyspnea, fatigue, chest discomfort, pre-syncope/syncope, palpitations, lower extremity swelling, non-specific gastro-intestinal symptoms, weight loss, and cyanosis. Pulmonologists are increasingly involved in the care of these patients, whether at the initial presentation and diagnosis, medication titration, or for symptom relief and management of complications. The pulmonologist and intensivist also frequently care for patients that are at an increased risk of developing PAH, such as patients with cirrhosis, hypoxic lung disease, scleroderma, sickle cell disease, and HIV to name a few. An echocardiogram, although often inaccurate in estimating the right-sided heart pressures, is the best screening tool for PAH. A right heart catheterization is the gold standard for diagnosing PAH. Supplemental therapies may include oxygen, diuretics, and anticoagulation. In addition to the limited role of calciumchannel blockers, PAH-specific therapies fall into one of 3 families for now: Phospho-diesterase-5 inhibitors, endothelin receptor antagonists, and prostacyclins. The current estimated 2 year survival of PAH patients now exceeds 90%, compared to a historical median survival of 2-3 years.

Pulmonary Hypertension: Current Therapy and Future Prospects

Pulmonary hypertension (PH) is a sequel of a variety of cardiovascular and systemic diseases. Heterozygous mutation of BMPRII, a member of the TGFβ superfamily is the commonest genetic defect so far identified in PH. Recent advances have contributed a great deal to the understanding of the disease; however, the actual mechanism/s is not yet clear. Endothelial damage is the key underlying feature of PH. The main effects are loss of vascular relaxation response, increased cell proliferation and impaired apoptosis, matrix deposition, obstruction in the small pulmonary arteries, right ventricular hypertrophy; and eventually leading to right heart failure and death. The diagnosis of PH is often made late because of the insidious onset of symptoms, therefore the treatment poses a daunting challenge. Furthermore, depending on the underlying pathology, not all patients respond equally to same therapeutic agents. Current therapy includes a group of drugs mainly involved in improving vascular relaxation (cAMP and cGMP mechanisms) and endothelin receptor blockers alone or in combination. Newer drugs such as guanylate cyclase activators, PDGF blocker, RhoA/Rho kinase blockers have shown encouraging results in animal studies and in a few clinical cases of PH. Other drugs and signaling pathways such as nitrite, PPARγ, ACE2, ghrelin etc. are under investigation. Studies with gene therapy are being actively pursued. This review summarizes the available therapy and the future prospects.

Strategies on the Development of Small Molecule Anticancer Drugs for Targeted Therapy

The main challenges currently encountered in chemotherapy are the lack of tumor selectivity and drug resistance. The design of novel cytostatic drugs has become the state-of-the-art technology in terms of targeted tumor therapy. This review illustrates the mechanisms and the advantages of representative chemotherapeutic agents, and presents an updated summary of the various drug design strategies developed by modern medicinal chemists during the most recent tumor targeting research which include rational design for overcoming drug resistance, the combi-targeting strategy, the prodrug approach, and tumor specific transporter based drug design. The concept of transporter related tumor targeting strategies for small molecule anticancer drug design discussed in this review may be amenable to predictable drug discovery for targeted therapy.

Impact of Pulmonary Vascular Resistances in Heart Transplantation for Congenital Heart Disease

Congenital heart disease is one of the major diagnoses in pediatric heart transplantation recipients of all age groups. Assessment of pulmonary vascular resistance in these patients prior to transplantation is crucial to determine their candidacy, however, it is frequently inaccurate because of their abnormal anatomy and physiology. This problem places them at significant risk for pulmonary hypertension and right ventricular failure post transplantation. The pathophysiology of pulmonary vascular disease in children with congenital heart disease depends on their pulmonary blood flow patterns, systemic ventricle function, as well as semilunar valves and atrioventricular valves structure and function. In our review we analyze the pathophysiology of pulmonary vascular disease in children with congenital heart disease and end-stage heart failure, and outline the state of the art pre-transplantation medical and surgical management to achieve reverse remodeling of the pulmonary vasculature by using pulmonary vasodilators and mechanical circulatory support.

Peripartum Cardiomyopathy: An Intensivist's Perspective

Peripartum cardiomyopathy (PPCMP) is a relatively rare form of dilated cardiomyopathy with unknown etiology. A generally accepted definition comprises the following criteria: 1) cardiac failure occurring in the last month of pregnancy or within 5 months after delivery; 2) absence of an alternative cause for the cardiomyopathy; 3) absence of heart disease before the last month of pregnancy and 4) demonstrated left ventricular dysfunction.

From an intensivists perspective, the diagnosis of PPCMP should always be considered when triaging a woman with peripartum respiratory or hemodynamic distress. Timely diagnosis is crucial to enable prompt initiation of the proper management in order to minimize the risk for serious maternal and neonatal sequelae. Goal-directed echocardiography should be utilized as early as possible, preferably already in the emergency department, to demonstrate or rule out PPCMP. Only then, appropriate supportive measures such as appropriate medical therapy, intra-aortic balloon counter pulsation (IABP), extracorporeal membrane oxygenation (ECMO) or assist device support can be initiated.

Approaches to the Management of Acute Kidney Injury in Children

Acute kidney injury (AKI) causes increased morbidity in critically ill children and damage to the kidney, a central mediator of homeostasis in the body, affects survival. The incidence of AKI in pediatrics is significant and despite alarming data, therapeutic interventions have failed to affect a meaningful difference in outcomes. In this review, we will discuss the epidemiology of AKI in pediatrics, treatment strategies attempted to date, experimental therapies targeting molecular patterns associated with AKI, and highlight the needed direction of AKI research and management. Prospective trials in pediatrics are needed to test the validity of diagnostic tools, to identify the point of most efficacious intervention, and to underscore the therapies that can be effective in the different downstream effects of AKI. In this review, we will discuss recent patents and advancements in diagnosis, management, and prevention.

C-type Natriuretic Peptide (CNP): Cardiovascular Roles and Potential as a Therapeutic Target

Natriuretic peptides play a fundamental role in cardiovascular homeostasis by modulation of fluid and electrolyte balance and vascular tone. C-type natriuretic peptide (CNP) represents the paracrine element of the natriuretic peptide axis which complements the endocrine actions of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). CNP is produced by the endothelium and the heart and appears to play a prominent role in vascular and cardiac function, both physiologically and pathologically. This provides a rationale for the therapeutic potential of pharmacological interventions targeted to CNP signalling. This article provides an overview of the biology and pharmacology of CNP, with emphasis on the cardiovascular system, and discusses pathologies in which drugs designed to manipulate CNP signalling maybe of clinical benefit.

Vascular Toxicity of Chemotherapeutic Agents

Cancer chemotherapy is not free of undesirable side effects. With respect to the cardiovascular system, cardiotoxicity is a well-described and potentially lethal side effect of certain chemotherapeutic agents, such as anthracyclines. However, in the last few years, several clinical studies have taken into account the fact that some non-anthracycline chemotherapy treated-patients also have a significantly increased risk of cardiovascular events. The exact mechanism of this toxicity is not known, and several possibilities, including vascular autonomic neuropathy and vascular damage, have been proposed. The aim of the present review was to collate information on the clinical and experimental evidence regarding vascular toxicity for each of the different groups of chemotherapeutic agents. The mechanisms proposed to underlie this toxicity are also discussed.

Thromboembolic Complications in Malignant Haematological Disorders

It is well known that solid cancers are associated with thromboembolic complications, but recent studies have shown that the incidence of thrombosis may be as high (or even higher) in patients with malignant haematological disorders. However, this may be obscured by the significant morbidity and mortality due to other complications of haematological malignancies, such as bleeding and infections. The vast majority of patients with haematological neoplasias also have clinically silent haemostatic abnormalities, but some may show clinical manifestations, including venous thromboembolism, pulmonary embolism, disseminated intravascular coagulation and life-threatening thrombohaemorrhagic syndrome in acute leukaemias. The pathogenesis of thromboembolic disease in haematological malignancies is complex and multifactorial: tumour cell-derived procoagulant, fibrinolytic or proteolytic factors and inflammatory cytokines affect clotting activation, and chemotherapy and anti-angiogenic drugs increase thrombotic risk in patients with lymphoma, acute leukaemia and multiple myeloma. Infectious complications are another important factor: endotoxins from gramnegative bacteria induce the release of tissue factor (TF), tumour necrosis factor (TNF) and interleukin-1b (IL-1b), and gram-positive organisms can release bacterial mucopolysaccharides that directly activate factor XII. Leukaemic patients may be affected by other prothrombotic factors, including hyperleukocytosis, increased TF expression and activation, and the prothrombotic properties of therapeutic agents such as all-trans retinoic acid and L-asparaginase, which can induce thrombosis involving multiple organs. The very high risk of haemorrhage in these patients warrants prospective randomised trials evaluating optimal anti-thrombotic prophylaxis and treatment.

Thrombotic Microangiopathy and Occult Neoplasia

Thrombotic thrombocytopenic purpura (TTP), which is typically characterized by fever and central nervous system manifestations and hemolytic uremic syndrome (HUS), in which renal failure is a prominent feature are the most common thrombotic microangiopathies (TMAs). TTP is usually associated with a severe deficiency of ADAMTS13 [a metalloproteinase involved in the degradation of von Willebrand factor (vWF) multimers], causing excessive accumulation of ultra-large vWF multimers and platelet aggregation with organ failure. By contrast, patients with HUS or other TMAs usually display a normal or at least detectable ADAMTS13 activity.

A TMA may be occasionally developed in association with HELLP (haemolysis, elevated liver enzymes, and low platelet count) syndrome, infections, cancer and bone marrow transplantation. In cancer patients, TMA may be related to chemotherapeutic regimens or the malignant disease itself. Occasionally, TMA is the first manifestation of an occult cancer, and in large series approximately 3% of patients who were originally diagnosed with TTP, were in fact harboring an occult malignancy. The pathogenesis of cancer-associated TMAs is not completely elucidated, but probably the most important factor is endothelial damage.

However, cancer-associated TMAs show some distinct features that should promptly lead to complementary investigations for an underlying malignancy.

Weakness, cough and dyspnoea, fever, weight loss, bone and abdominal pain are the most common presenting symptoms. Generally, biochemistry reveals markedly increased LDH levels, increased alkaline phosphatase and the blood smear shows erythromyelemia. Bone marrow biopsy is a valuable tool in order to establishing malignant seeding. Treatment of the underlying neoplasia is the mainstay of therapy and there is no role for plasmapheresis or plasma infusions.

Drug-Induced Thromboembolic Events in Patients with Malignancy

Patients with malignancies are often in a hypercoagulable status. The pathogenetic mechanisms of thrombotic events in malignancy are multifaceted and consist of release or expression of procoagulants by cancer cells, but also appearance of procoagulant action by normal host cells. Most importantly, current therapeutic modalities for cancer such as high dose chemotherapy and surgery represent a significant additional risk for serious or even fatal thromboembolic events. There is a wide spectrum of clinical manifestations of these events which encompass Trousseau's syndrome, deep venous thrombosis, marantic endocarditis, disseminated intravascular coagulation, thrombotic microangiopathy and arterial thrombosis. Cancer chemotherapy is most commonly associated with deep vein thrombosis but intracranial sinus vein thromboses and thrombotic microangiopathy may also occur. Our purpose is to review the relevant literature linked to the effect of chemotherapy and other cancer-related interventions on thromboembolic incidents.

Exploring the Potential of NO-Independent Stimulators and Activators of Soluble Guanylate Cyclase for the Medical Treatment of Erectile Dysfunction

Nitric oxide (NO)-sensitive soluble guanylyl cyclase (sGC) is the receptor that catalyzes the formation of the intracellular messenger cyclic guanosine monophosphate (cGMP). Binding of the physiological activator, NO, to the reduced heme moiety of sGC increases the conversion of guanosine triphosphate (GTP) to cyclic GMP (cGMP) and engages crucial effector systems such as protein kinases, phosphodiesterases, and ion channels. The development of compounds that activate sGC independent of NO release has therapeutic implications. Recent studies have demonstrated the potential use of heme-dependent sGC stimulators (e.g. YC-1, BAY 41- 2272, BAY 41-8543, BAY 63-2521, CFM-1571 and A-350619) and heme-independent sGC activators (e.g. BAY 58-2667, HMR-1766, S-3448, A-778935) in the treatment of cardiovascular diseases. Erectile dysfunction (ED) affects millions of men. Phosphodiesterase (PDE)-5 inhibitors, producing an NO-dependent increase in intracellular cGMP concentration, have been a successful approach in the treatment of ED. However, > 30% of men with ED do not respond to PDE-5 inhibitor therapy, implying that endogenous NO production may be impaired to such an extent that inhibition of cGMP degradation produces no significant therapeutic advantage. Endogenous NO released from nitrergic nerves in the corpora cavernosa is significantly decreased in various conditions (e.g. diabetes, aging, and hypertension) and has reduced activation of the NO-sGC-cGMP pathway. It is conceivable that sGC stimulators and/or activators may be more effective than PDE5 inhibitors in the treatment of ED in such circumstances by improving NO-sGC-cGMP signaling and erectile function. This novel drug therapy approach for the treatment of ED shows promise.

Pulmonary Arterial Hypertension

The last 10 years have seen significant advances in the understanding of the pathophysiology and treatment of pulmonary arterial hypertension (PAH). This has included new insights into the genetics, cell-signalling pathways and pathological changes seen in the small pulmonary arteries as well as the introduction of new treatments which have improved prognosis. The classification of pulmonary hypertension (PH) has also been changed several times, most recently in 2003. It now divides forms of PH into 5 broad groups according to their pathophysiology and response to treatment. This review focuses primarily on the advances that have been made in the comprehension and treatment of Group 1 (PAH); however reference is also made to other groups within the classification. Pharmacologic treatment now includes calcium-channel blockers, endothelin antagonists, prostanoids, phosphodiesterase type 5 inhibitors, anticoagulants and diuretics. There are 2 recent sets of guidelines directing treatment, one published by the American College of Chest Physicians in 2007 and the most recent published by the National Pulmonary Hypertension Centres of the UK and Ireland in 2008. The recent advances in understanding of the underlying cellular mechanisms have also opened the doorway to new potential therapies such as stem cell transplantation and the targeting of platelet-derived factors and apoptosis.

Treatment and Outcome of Pulmonary Arterial Hypertension in HIVInfected Patients: A Review of the Literature

Pulmonary arterial hypertension (PAH) is a life-threatening complication of HIV infection. The prevalence of HIV-associated PAH (HIV-PAH) seems not to be changed over time, regardless of the introduction of highly active antiretroviral therapy (HAART). HIV-PAH treatment is similar to that for all PAH conditions and includes lifestyle modifications, general treatments, and disease-specific treatments. We reviewed the cases of HIV-PAH reported in the Literature in order to evaluate the role of HAART and specific PAH therapy in the prognosis and outcome of HIV-PAH. The research was performed through the PubMed database, by using the following key words: human immunodeficiency virus, AIDS, pulmonary hypertension, antiretroviral, and treatment. The outcome was reported as survival at the end of the observation period of each study. We found 509 patients with HIV-PAH described in the literature to date. At the end of follow-up period, survival rates were 55% and 22% among patients treated or not with antiretroviral therapy (ART), respectively (p = 0.02). Moreover, survival rates at the end of follow-up were 76% and 32% among patients treated or not with specific therapy for PAH (PAH-ST), respectively (p < 0.0000001). Survival rates were 69% and 38% among patients treated or not with ART and PAH-ST, respectively (p = 0.02). Specific therapy for PAH should be strongly recommended in patients with HIV-PAH. The role of the HAART in influencing the outcome of HIV-PAH is controversial, even if some evidences seem to indicate a beneficial effect in the clinical course of the disease.

Effect of β-Blockers on Perioperative Myocardial Ischemia in Patients Undergoing Noncardiac Surgery

Background: Myocardial ischemia remains a major cause of morbidity in patients undergoing noncardiac surgery. The purpose of the paper was to review the evidence of the use of perioperative β-blockers for the reduction of myocardial ischemia in patients having noncardiac surgery. Method: Pubmed was searched for articles that included β-blockers and perioperative myocardial ischemia. Randomized controlled trials that assessed the effect of β-blockers on myocardial ischemia in patients undergoing noncardiac surgery were included in this review and a meta-analysis was performed. Results: Sixteen randomized controlled trials including 2230 patients were included. The study methodologies and results were summarized and meta-analysis performed. Ten trials used β-blockers in the postoperative period; 954 patients received β-blockers and 924 patients were in the control group. Of the six trials that used β-blocker for premedication, there were 207 patients in the β-blocker and 145 patients in the control group. For the cohort when β-blockers were used postoperatively, myocardial ischemia was reduced significantly with the use of β-blockers (OR 0.42; 95% CI 0.27-0.65; P=0.0001; I2=0%). A similar beneficial effect was observed in trials that used β-blocker for premedication (OR 0.16; 95% CI 0.07-0.35; P < 0.00001; I2=40%). Conclusion: The meta-analysis shows that the use of β-blockers, both as premedication and postoperatively, in noncardiac surgery is associated with a significant reduction in perioperative myocardial ischemia.

Toll-Like Receptors and Myocardial Ischemia/Reperfusion, Inflammation, and Injury

Cardiac ischemia/reperfusion (I/R) injury occurs in several important clinical contexts including percutaneous coronary interventions for acute myocardial ischemia, cardiac surgery in the setting of cardiopulmonary bypass, and cardiac transplantation. While the pathogenesis of I/R injury in these settings is multifactorial, it is clear that activation of the innate immune system and the resultant inflammatory response are important components of I/R injury. Toll-like receptor 4 (TLR4), originally identified as the sensor for bacterial lipopolysaccharide (LPS), has also been shown to serve as a sensor for endogenous molecules released from damaged or ischemic tissues. Accordingly, recent findings have demonstrated that TLR4 not only plays a central role as a mediator of cardiac dysfunction in sepsis, but also serves as a key mediator of myocardial injury and inflammation in the setting of I/R. Furthermore, TLR4 may play a role in the development of atherosclerotic lesions. Other studies have implicated TLR4 in the adverse remodeling that may occur after ischemic myocardial injury. This emerging body of literature, which is reviewed here, has provided new insight into the early molecular events that mediate myocardial injury and dysfunction in the setting of I/R injury.

Cellular Therapy of Lysosomal Storage Disorders: Current Status and Future Prospects

Lysosomal storage disorders (LSD) arise from genetic deficiency of a lysosomal enzyme (or its transport) and from subsequent accumulation of the enzyme substrates. Haemopoietic Stem Cell Transplant (HSCT) therapy for LSD corrects disease through cross correction of enzyme deficiency in recipient cells by enzyme secreted from engrafted, donor blood cells. The process of such transplant, its efficacy and its inherent risks are central in defining its current place in therapy. Two decades of HSCT have seen dramatically improving results as well as an improved understanding of the factors that affect outcome in both the short and long term. With improving survival figures transplant might become a viable treatment for patients that were traditionally excluded from transplant because of perceived risk. Some LSD respond better to HSCT than others and even within a responding disease some organs respond better than others. We develop the concept of delivered enzyme following cellular and other therapies of LSDs, including pharmacological enzyme replacement therapy (ERT). Delivered enzyme must be sufficient to achieve a correctable threshold that is both tissue and disease specific. Therapies of LSDs in the future will be more effective as they improve enzyme delivery to tissues and do so more safely and with reduced long term toxicities.

Heart Disease in Patients with HIV/AIDS-An Emerging Clinical Problem

HIV/AIDS (Human immunodeficiency virus/ Acquired immuno deficiency syndrome) is a growing global problem, in terms of its incidence and mortality. Patients with HIV/AIDS are living much longer with HAART (Highly active antiretroviral therapy) therapy so much so that HIV/AIDS has now become a part of the chronic disease burden, like hypertension and diabetes. Patients with HIV/AIDS and symptoms suggestive of cardiac disease represent a diagnostic and therapeutic challenge in clinical practice; Cardiologists are more frequently encountering this problem. An algorithmic, anatomic approach to diagnosis, localizing disease to the endocardium, myocardium and pericardium can be useful. An intimate knowledge of opportunistic infections affecting the heart, effects of HAART therapy and therapy for opportunistic infections on the heart is needed to be able to formulate a differential diagnosis. Effects of HAART therapy, especially protease inhibitors on lipid and glucose metabolism, and their influence on progression to premature vascular disease require consideration. Treatment of cardiac disease, in HIV/AIDS patients can vary from non-HIV patients, based on drug interactions, differences in responsiveness, and other factors; and this area requires further research.

Alveolar Capillary Dysplasia: A Lethal Developmental Lung Malformation

Alveolar capillary dysplasia (ACD) is a recently recognized lethal lung malformation. ACD is a rare congenital disorder of pulmonary vascular development associated with unremitting hypoxemia and respiratory failure. This paper reviews the incidence, pathophysiology and histopathology, clinical manifestations, diagnosis, and treatment of affected newborns and proposes an algorithmic approach to management of infants who present with unremitting persistent pulmonary hypertension of the newborn.

Pulmonary Arterial Hypertension in Connective Tissue Diseases

Pulmonary arterial hypertension (PAH) is characterized by progressive obliteration of the small pulmonary vasculature leading to permanently increased vascular resistance and elevated pulmonary artery pressures over 25 mmHg at rest and 30 mmHg during exercise. Elevated pressures in the pulmonary circulation result in right heart failure and premature death. Besides idiopathic PAH, it can also occur in a variety of other conditions such as connective tissue diseases. Mainly patients suffering from systemic sclerosis, systemic lupus erythematosus and rheumatoid arthritis may be affected. In these patients, PAH may occur in association with left heart disease, interstitial fibrosis or as a result of an isolated pulmonary arteriopathy. The mechanisms leading to PAH remain unknown even if a pathophysiological model includes vasoconstrictor/vasodilator imbalance, thrombogenic factors, misguided angiogenesis and pro-inflammatory factors. Symptoms and clinical presentation are very similar to idiopathic PAH but mortality was confirmed to be higher. A 2-D echoDoppler examination is considered as the first-line diagnostic tool, however the results should be confirmed by right heart catheterization. Unfortunately, despite recent major improvements in PAH treatment, no current therapy can yet cure this devastating condition. Intravenous epoprostenol therapy has been proved to improve exercise capacity and symptoms in patients with systemic sclerosis. Also the endothelin receptor antagonists (bosentan and sitaxentan), the phosphodyesterase-type-5 inhibitor (sildenafil) and subcutaneous treprostinil have shown favourable results. Despite recent advances in treatment, PAH remains essentially untreatable even if pharmacological trials seem to slow down progression of the disease improving symptoms and quality of life of these patients.

Renin Angiotensin System as a Regulator of Cell Volume. Implications to Myocardial Ischemia

It is known that long lasting changes in cell volume are incompatible with cellular functions. In the present review, I discussed the role of cell volume on gene expression and protein synthesis as well as the importance of the renin angiotensin system on the regulation of cell volume in the failing heart. Moreover, the relationship between mechanical stretch, cell volume and the renin angiotensin system as well some translational studies are also described and their relevance to the prevention or reduction of cardiac damage during myocardial ischemia is emphasized.

Current Status of Pharmacological Thrombolytic Therapy and Mechanical Thrombectomy for the Treatment of Acute Deep Venous Thrombosis

Deep venous thrombosis (DVT) is a highly prevalent clinical problem associated with significant mortality and morbidity. In the United States alone, it is estimated that DVT affects approximately 50 per 100,000 people per year. This results in > 600,000 inpatient and outpatient treatments per year and accounts for approximately 100,000 deaths from thromboembolic complications. Post-thrombotic syndrome (PTS) is associated with serious long-term physical, social and economic sequelae for patients. In this article, we attempt to perform a contemporary review of the literature pertaining to the use of thrombolytic therapy and endovascular thrombectomy in the treatment of acute DVT.

On the Sympathetic Innervation of the Human Greater Saphenous Vein: Relevance to Clinical Practice

This review focuses on sympathetic perivascular innervation of human saphenous vein. It shows the distribution of the nerves in the vein wall, including an association of the nerves with the vasa vasorum system. An account of a possible contribution of sympathetic nerves to the physiology of the saphenous vein, as well as their relevance to the outcome of coronary artery bypass surgery that uses the vein as a graft, is discussed.

Endothelial Effects of Drugs Designed to Treat Erectile Dysfunction

Erectile dysfunction (ED) and endothelial dysfunction are common in individuals with multiple cardiovascular risk factors (CRFs) and are longitudinal predictors of cardiovascular events. ED is associated with systemic endothelial cell activation/dysfunction independent from CRFs or from diffuse, unrecognized vascular damage. The pathogenesis of endothelial dysfunction and ED is intimately linked through decreased expression and activation of endothelial nitric oxide (NO) synthase and the subsequent physiologic actions of NO. Furthermore, reduced biologic activity of endotheliumderived NO links atherosclerosis to ED and underscores the role of altered endothelium in the pathogenesis of both conditions. Evidence-based data suggest that daily use of phosphodiesterase type-5 inhibitors (PDE5-i) improves endothelial and erectile functions and that this benefit is lost upon drug withdrawal. Daily PDE5-i may also improve lower tract urinary symptoms related to benign prostatic hyperplasia through a reduction of adrenergic overtone. The relevance for these drugs in the prevention of complications in internal medicine diseases, i.e. cardiovascular disease, clotting disorders and autoimmune disease is uncertain. Finally, endothelial dysfunction is present in testosterone deficiency syndromes and replacement therapy is able to revert ED and to improve endothelial function. Aim of the present review is to discuss the systemic effects of drugs designed to treat ED, such as testosterone and PDE5- i, with regard to safety, unwanted effects and efficacy in improving endothelial function; finally, a goal-oriented approach to rehabilitation using daily vs. on-demand PDE5-i in difficult patients is discussed.

Pulmonary Arterial Hypertension: Need to Treat

Pulmonary Arterial Hypertension (PAH) is defined by a persistent elevation in pulmonary artery pressure with normal left-sided pressures. It is characterized by increased pulmonary vascular resistance due to increased vascular tone and structural remodeling of pulmonary vessels. PAH is a quite rare condition, thus considering the rarity, subtle presentation, and diagnostic dilemma commonly posed by this disease, underdiagnosis and underreporting are probably widespread. In order to reach a diagnosis the use of echocardiography, right-heart catheterization and the six-minute walk test is essential. As far as therapy is concerned, the patient should be supported by oxygen, diuretics, anticoagulants, digoxin and suggest life-style changes. After diagnosing the condition ca-blockers should be administered to those who respond positively in acute vasodilation test. Other agents used, target the endothelin pathway (ET-1 blockers such as bosentan), the NO pathway (sildenafil, inhaled NO, L-arginine) and the prostacyclin pathway (prostacyclin analogues). In some cases surgical treatment is essential (atrial septestomy, pulmonary endarterectomy, lung and heart transplantation). Finally, future therapies include administration of VIP and SSRIs. The goals of evaluating pulmonary hypertension are detection, definition of severity and the nature of the hemodynamic lesion and its consequences, diagnosis of causal or associated conditions, and determination of optimal therapy.

Persistent Pulmonary Hypertension of the Newborn: Therapeutical Approach

Persistent pulmonary hypertension of the newborn (PPHN), is defined as a failure of the pulmonary vasculature to relax at birth and consequently of the normal adaptation to extra uterine life of the fetal heart/lung system, resulting in hypoxemia. This condition, occurs in about 1-2 newborns per 1000 live births and despite significant improvements in treatment it is associated with substantial infant mortality and morbidity. Over the years wider application of inhaled nitric oxide (iNO) therapy and improved ventilation strategies including surfactant, high-frequency oscillatory ventilation has led to a decrease in the need for invasive life-sustaining therapies such as extracorporeal membrane oxygenation (ECMO). Mortality rate varies from 10 to 20 % of affected newborns in developed countries, but it is much higher when PPHN is refractory to the above reported therapies or when they are not available. As a consequence, development of new therapeutic strategies for severe PPHN is crucial. In particular, recent studies seem to show that sildenafil, a phosphodiesterase inhibitor type 5 that selectively reduces pulmonary vascular resistance may be a useful therapeutic adjunct to critically ill neonates with PPHN.

Cardiac Metabolism in Myocardial Ischemia

Myocardial ischemia occurs for a mismatch between blood flow and metabolic requirements, when the rate of oxygen and metabolic substrates delivery to the myocardium is insufficient to meet the myocardial energy requirements for a given myocardial workload. During ischemia, substantial changes occur in cardiac energy metabolism, as a consequence of the reduced oxygen availability. Some of these metabolic changes are beneficial and may help the heart adapt to the ischemic condition. However, most of the changes are maladaptive and contribute to the severity of the ischemic injury leading stunned or hibernating myocardium, cell death and ultimately to contractile disfuction. Dramatic changes in cardiac metabolism and contractile function, also occur during myocardial reperfusion as a consequence of the generation of oxygen free radicals, loss of cation homeostasis, depletion of energy stores, and changes in subcellular activities. The reperfusion injury may cause in the death of cardiac myocytes that were still viable immediately before myocardial reperfusion. This form of myocardial injury, by itself can induce cardiomyocyte death and increase infarct size. During acute ischemia the relative substrate concentration is the prime factor defining preference and utilization rate. Allosteric enzyme regulation and protein phosphorylation cascades, partially controlled by hormones such as insulin, modulate the concentration effect; together they provide short-term adjustments of cardiac energy metabolism. The expression of metabolic genes is also dynamically regulated in response to developmental and (patho)physiological conditions, leading to long-term adjustments. Specific nuclear receptor transcription factors and co-activators regulate the expression of these genes. Understanding the functional role of these changes is critical for developing the concept of metabolic intervention for heart disease. The paper will review the alterations in energy metabolism that occur during acute and chronic ischemia.

Modulation of Cardiac Metabolism During Myocardial Ischemia

Metabolic modulation during myocardial ischemia is possible by the use of specific drugs, which may induce a shift from free fatty acid towards predominantly glucose utilization by the myocardium to increase ATP generation per unit oxygen consumption. Three agents (trimetazidine, ranolazine, and perhexiline) have well-documented anti-ischaemic effects. However, perhexiline, the most potent agent currently available, requires plasma-level monitoring to avoid hepatoneuro- toxicity. Besides, the long-term safety of trimetazidine and ranolazine has yet to be established. In addition to their effect in ischemia, the potential use of these drugs in chronic heart failure is gaining recognition as clinical and experimental data are showing the improvement of myocardial function following treatment with several of them, even in the absence of ischemia. Future applications for this line of treatment is promising and deserves additional research. In particular, large, randomised, controlled trials investigating the effects of these agents on mortality and hospitalization rates due to coronary artery disease are needed.

Pulmonary Hypertension in the Critically Ill

Pulmonary hypertension is not uncommonly seen in the critically ill. It may be encountered in patients with pre-existing diseases or may occur acutely without predisposing conditions. The diagnosis and management of pulmonary hypertension can be very challenging, given that critically ill patients are often concurrently haemodynamically unstable. Commonly used therapies in the Intensive Care Unit, such as fluid resuscitation, mechanical ventilation, vasopressors and inotropes may have deleterious effects in this population. We review the pathophysiology, diagnosis and current management strategies of this disease, with special emphasis on the critically ill adult population.

Monoclonal Antibodies in Clinical Oncology

Monoclonal antibodies have yet considerably modified the field of clinical oncology. The growing knowledge of key cellular pathways in tumor induction and progression, targeted therapies represent an increasing proportion of new drugs entering clinical trials. Some molecules such as trastuzumab, rituximab, alemtuzumab, cetuximab are now widely used in clinical practice. These antibodies are now tested in different indications alone or in combination with standard chemotherapy. They are also developed for the treatment of inflammatory diseases (rituximab). Numerous others antibodies are currently in pre-clinical and clinical development phases for several malignancies including renal carcinoma, melanoma, lymphomas, leukaemia, breast, ovarian and colorectal cancer. An alternative approach is to conjugate the monoclonal antibody to a toxin, a cytotoxic agent, or a radioisotope. In other cases these antibodies aim to modify the tumour microenvironnement through inhibition of angiogenesis or enhancing host immune response against cancer. If the molecule targeted by the antibodies is clearly identified, most often the precise mechanism of action of these immunoglobulins is not fully understood.They can have direct effects in inducing apoptosis or programmed cell death. They can block growth factor receptors, efficiently arresting proliferation of tumor cells. Indirect effects include recruiting cells that exert cytotoxicity, such as monocytes and macrophages (ADCC). Monoclonal antibodies also bind complement, leading to toxicity known as complement dependent cytotoxicity (CDC).The side effects associated with these new treatments were in part foreseeable depending on the affected cell or function. But new or surprising side effects emerged from clinical studies. We present an overview of the monoclonal antibodies used in clinical oncology or currently in development phases. We particularly focus on recent development including new indications, clinical trial results and specific side effects of monoclonal antibodies used in the treatment of cancer.

Potential Role of ADAMTS13 in the Progression of Alcoholic Hepatitis

Alcoholic hepatitis (AH) is a potentially life-threatening complication of alcohol abuse. The severe form of AH, severe alcoholic hepatitis (SAH), is characterized by multiorgan failure (MOF) with manifestations of acute hepatic failure and is associated with high morbidity and mortality. However, the pathogenesis of SAH in addition to AH remains to be elucidated. Recent advances showed that ADAMTS13 (a disintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13) is closely related to thrombotic thrombocytopenic purpura, a multiorgan disorder. Decreased activity of plasma ADAMTS13 (ADAMTS13:AC) leads to the accumulation of unusually large von Willebrand factor multimers (UL-VWFM) and subsequent platelet clumping and/or thrombi under high shear stress, resulting in microcirculatory disturbances. Immunological studies and in situ hybridization have indicated that ADAMTS13 is produced exclusively in hepatic stellate cells (HSCs). Plasma ADAMTS13:AC was extremely low in fatal SAH cases, and enhanced ULVWFM production with deficient ADAMTS13:AC may contribute to the progression of MOF through microcirculatory disturbances in SAH and AH. Considering that ADAMTS13 is synthesized in HSCs and its substrate, UL-VWFM, is produced in transformed vascular endothelial cells, the imbalance between ADAMTS13:AC and VWF:Ag in AH patients might also involve sinusoidal microcirculatory disturbances and subsequent liver injury. It will be necessary to clarify the mechanism of the decrease in plasma ADAMTS13:AC in association with pro-inflammatory cytokinemia, an ADAMTS13 inhibitor and the production of ADAMTS13 in HSCs. The determination of ADAMTS13:AC and its substrate will give us new insights into the pathophysiology of acute alcoholic liver injury and help to elucidate additional therapeutic strategies for this disease.

Neurocognitive Monitoring and Care During Pediatric Cardiopulmonary Bypass — Current and Future Directions

Neurologic injury in patients with congenital heart disease remains an important source of morbidity and mortality. Advances in surgical repair and perioperative management have resulted in longer life expectancies for these patients. Current practice and research must focus on identifying treatable risk factors for neurocognitive dysfunction, advancing methods for perioperative neuromonitoring, and refining treatment and care of the congenital heart patient with potential neurologic injury. Techniques for neuromonitoring and future directions will be discussed.

Pulmonary Arterial Hypertension in HIV-infected Patients

In recent years, much more insight is given to the pathogenic role of HIV and to the clinical manifestations of HIV-related pulmonary hypertension (HRPH), that currently represents one of the most severe events during the HIV disease. HRPH occurs in early and late stages of HIV infection and does not seem to be related to the degree of immune deficiency. Many of the symptoms in HRPH result from right ventricular dysfunction: the first clinical manifestation is effort intolerance and exertional dyspnoea that will progress to the point of breathlessness at rest. Echocardiography has been proved to be an extremely useful tool for the diagnosis of HRPH, and Doppler echocardiography may be used to estimate systolic pulmonary artery pressure, and to monitor the effects of therapy. Assessment of hemodynamic measures by catheterization remains, however, the best test for evaluating the response to therapy. Cardiac catheterization is mandatory to characterize the disease and exclude an underlying cardiac shunt as etiology. Vasodilators have been extensively used in the treatment of pulmonary hypertension, since vasoconstriction is a determinant characteristic of this disease. More recently, more effective therapies for pulmonary arterial hypertension have been available, including prostanoids, endothelin-receptor antagonists, and phosphodiesterase-5 inhibitors, allowing an amelioration of symptoms and a better prognosis. However, HRPH remains a progressive disease for which treatment is often unsatisfactory and there is no cure. As new efficient antiretroviral treatment will be introduced, clinicians should expect to encounter an increasing number of cases of pulmonary hypertension in HIV-infected patients in the future.

Randomised Trials of Graft Versus Host Disease Prophylaxis in Haemopoietic Stem Cell Transplantation

Allogeneic haemopoietic stem cell transplantation (HSCT) is a potentially curative option for a wide range of haematological diseases. Graft versus Host Disease (GVHD) is an inflammatory disorder in the recipient, which accounts for significant morbidity and mortality after allogeneic HSCT and directly limits the success of this procedure. Current treatment options for GVHD include intense immunosuppression, which in turn has associated side effects, an increased risk of infective complications, and a potential for increased relapse of haematological malignancy. A major benefit of allogeneic HSCT arises from reduced relapse rate of the underlying disease, which is believed to be due to the graft versus tumour or graft versus leukaemia (GVL) effect where donor immune cells recognize recipient tumour antigens. It is well established that GVL is linked to the occurrence of GVHD. Effective prophylaxis of GVHD while allowing some GVL effect is an important, yet currently elusive, therapeutic goal in HSCT. Strategies to prevent GVHD include T-cell depletion, immunosuppression, gut decontamination and appropriate donor selection. Cyclosporin (CsA) and/or methotrexate (MTX) have formed the basis of many GVHD prophylaxis strategies with no major advances on this gold standard for over twenty years. This review seeks to outline the most effective methods for the prevention of GVHD with a particular emphasis on large randomised trials. Evidence on standard regimens, appropriate dosing and emerging strategies for GVHD prophylaxis for both myeloablative and reduced intensity conditioning HSCT will be explored.

Bridging Innate Immunity and Myocardial Ischemia/Reperfusion Injury: The Search for Therapeutic Targets

Myocardial infarction necessitates new therapeutic interventions, since it still results in high morbidity and mortality worldwide. Reperfusion therapy itself results in (acceleration of) apoptosis, called myocardial ischemia/reperfusion (I/R) injury. For several decades it is known that the inflammatory response during reperfusion is the major cause of myocardial I/R injury. Therapeutic options are limited by lack of (detailed) understanding of intra- and intercellular mechanisms between inflammatory cells and cardiomyocytes. Furthermore, clinical trials generally fail to reproduce experimental successes, because essential factors are not taken into account in animal studies: risk factor for coronary artery disease, duration of ischemia and reperfusion, time of intervention. Above all, there is no specific therapeutic target for inhibiting the inflammatory response, in which cardiomyocytes are involved. The identification of Toll-like receptors (TLRs) on cardiomyocytes, has given rise to, not only new insights on the inflammatory response initiated by cardiomyocytes themselves, but also provided potential targets to reduce myocardial I/R injury. Experimental and clinical studies show that inflammatory responses are also involved in tissue repair responses. Since certain TLRs are expressed on inflammatory cells and cardiomyocytes, it ensures specific targeting of either detrimental effects or tissue repair responses in the inflammatory response during reperfusion. Which TLRs are involved in the ‘good’ and which in the ‘bad’ effects of the inflammatory response remains to be addressed. This review will discuss both experimental and clinical research on inflammatory reactions that occur after myocardial ischemia/ reperfusion (I/R). Data and conclusions concerning potential therapeutic targets in both experimental as clinical research settings will be reviewed.

Pulmonary Hypertension and Lung Transplantation

Pulmonary hypertension (PH) is a disorder with poor prognosis sustained by progressive elevation of pulmonary vascular resistance to blood flow. It is a serious condition for which treatments exist but there is no cure. The main determinants are vasoconstriction, pulmonary vascular remodelling, and in situ thrombosis associated with exuberant cellular proliferation and precapillary arterial bed obstruction. When unrecognized or untreated, PH has an unpredictable but worsening course that leads to cardiorespiratory decompensation. In the past ten years there have been significant improvements in both diagnostic and therapeutic strategies that have led to substantial changes in prognosis. However the number of subjects who over time become unresponsive to maximal medical treatment is still considerable so that surgical interventions are needed as last chance for survival. Lung transplantation (LTx) is a viable therapy for severe symptomatic PH. Even though survival after LTx has improved consistently, the recipients with an underlying diagnosis of PH seem to be affected by a greater 1-year mortality following LTx compared to recipients with other diagnoses. This article discusses the disease mechanisms and the pathophysiological processes involved in the development of PH. It provides some information on current and newer pharmacologic options, and it also considers the physiologic aspects of lung transplantation.

Low Dose Chest Computed Tomography, in Identifying Pulmonary Complications in Immunocompromised Patients After Allogeneic Hematopoietic Stem Cell Transplantation

Hematopoietic stem cell transplantation (HSCT) has been employed clinically for the therapy of a wide variety of acquired neoplastic and nonmalignant disorders. However, these immunocompromised patients remain at high risk of developing many serious and often life threatening complications. Occurring in up to 70% of allogeneic HSCT patients, respiratory complications are a leading cause of morbidity and mortality in this population. A rapid identification of the cause and institution of specific therapy is critical to achieve a good outcome. Unfortunately, early recognition and definitive diagnosis of such complications are difficult. In the presence of a modest immune response and neutropenia, the changes on a chest radiograph corresponding to early infectious and non-infectious processes are subtle, nonspecific and may not be recognized. Due to its greater sensitivity, thoracic computed tomography (CT) scan has been proposed to replace the plain chest radiograph (CXR) in the primary evaluation of immunocompromised patients. In the last five years in our institution, thoracic low dose CT (LDCT) scan has become the standard of care and has replaced the CXR in evaluating fever or respiratory symptoms in this group of patients. The published data concerning the use of LDCT scan of the chest as the primary tool for evaluation of this group of patients is limited. Our aim is to summarize the current knowledge in this matter and to add some new perspective from our experience.

Busulfan Use in Hematopoietic Stem Cell Transplantation: Pharmacology, Dose Adjustment, Safety and Efficacy in Adults and Children

Busulphan (1, 4-bis [methanesulfonyl-y] butane) is a bi-functional alkylating agent that, in combination with cyclophosphamide, has been commonly used in conditioning regimens before hematological stem cell transplantation (HSCT) for nearly 20 years. Busulfan has a very narrow therapeutic index, and acute toxicity may be related to absorption and disposition of the drug and metabolites. Precise delivery of the oral formulation is compromised by erratic gastrointestinal absorption, particularly in infants and small children. An intravenous busulfan formula was approved nearly 40 years after the approval of the oral formulation. Busulfan levels expressed as the area under the concentration-time curve (AUC) higher than 1500 μM * minute were reported to increase the risk of developing veno-occlusive disease (VOD), while low levels may result in engraftment failure or disease relapse. VOD occurs in 11-40% of patients undergoing HSCT and is associated with death in 3.3% of patients. Measurement of individual plasma busulfan levels during oral or intravenous dosing to obtain an AUC is likely to provide the necessary elements to monitor the drug disposition, ensuring efficacy and preventing toxicity of patients undergoing HSCT. It is also important to consider the busulfan drug-drug interactions and adverse drug reactions that can develop during the therapeutic process. Busulfan therapeutic drug monitoring and dose-adjustment should be performed in specialized laboratories staffed by well-trained personnel.

Recent Advances in Pulmonary Hypertension Therapy

Cardiovascular anesthesiologists have traditionally resorted to using intravenous therapy in the operating room to manipulate hemodynamics and the determinants of cardiac output and systemic vascular resistance during cardiac surgery. General anesthesia involves the administration of both intravenous and inhaled drug therapy to achieve the desired goals, i.e. analgesia, amnesia, muscle relaxation and blockade of autonomic activity. Anesthesiologists are the experts in the use and titration of drugs that are administered through the inhaled route. However, this method of drug delivery presents many challenges, notably timing, dosage accuracy, rapid titratability and consistency of drug delivery. Arguably the most rapid method of treating acute reactive pulmonary vasculature would be by drugs that directly act upon the pulmonary endothelium. In the operating room, pulmonary hypertension and right ventricular failure are high predictors of morbidity and mortality and present significant challenges to th e anesthesiologist. In this article, we will focus on advances in inhaled therapy of these conditions, including concerned recent patents. This review will focus on some of the advances in the pharmacology of inhaled drugs that are being used to treat pulmonary hypertension, right and left ventricular failure in the perioperative setting.

PAI-1 Antagonists: Predictable Indications and Unconventional Applications

At present, thrombolytic agents represent the only direct way of augmenting fibrinolytic activity in humans. While these agents are proven to be efficacious in the treatment of acute thrombotic events, they are not a viable option for long-term administration. There are numerous drugs available that indirectly to increase fibrinolytic activity by reducing plasma levels of plasminogen activator inhibitor-1 (PAI-1), including ACE inhibitors, insulin-sensitizing agents, and hormone replacement therapy in women. At present, efforts are underway to develop and test synthetic, selective PAI-1 antagonists. The potential applications of PAI-1 antagonists include thrombotic disorders (arterial and venous), amyloidosis, obesity, polycystic ovarian syndrome, and perhaps even type 2 diabetes mellitus. The availability of specific PAI-1 antagonists promises to expand the limits of understanding the role the fibrinolytic system plays in human disease and break through the current confines of therapeutic options that can effectively restore and augment the activity of the fibrinolytic system.

Plasminogen Activator Inhibitor-1 in Vascular Thrombosis

Thrombotic complications of vascular disease constitute the leading cause of morbidity and mortality in much of the developed world. Current drug therapies available to treat the thrombotic component of arterial and venous vascular complications remain limited. Novel safe and effective treatment strategies to reduce formation of occlusive thrombosis will likely have a major impact on reducing the economic burden of vascular disease on the healthcare system. Enhancing endogenous fibrinolysis by targeting plasminogen activator inhibitor-1 (PAI-1), the primary inhibitor of circulating plasminogen activators, has been shown to be effective in markedly attenuating the formation of arterial and venous occlusive thrombosis in animal models. In addition, animal and human studies of PAI-1 deficiency indicate that spontaneous bleeding complications associated with even complete PAI-1 deficiency would be rare. Patients most likely to benefit from PAI-1 inhibition would be those at high risk for vascular events where PAI-1 is elevated, such as is observed in obesity, diabetes and the metabolic syndrome. Since obesity and metabolic syndrome are now epidemic, and will likely have a major adverse impact on vascular thrombotic events, it may be time to test the clinical effectiveness of PAI-1 inhibition in a patient population at high risk for vascular thrombosis.

Metabolic Activation of Herbal and Dietary Constituents and Its Clinical and Toxicological Implications: An Update

In recent years, there has been a globally increasing application of herbal medicines and dietary supplements to treat various chronic diseases and to promote health. However, there are increasing clinical reports on the organ toxicities associated with consumption of herbal medicines. This review updates the knowledge on metabolic activation of herbal components and its clinical and toxicological implications. Like many synthetic drugs undergoing metabolic activation to form reactive metabolites which are often associated with drug toxicity, it is recognized that some herbal components may also be converted to toxic, or even mutagenetic and carcinogenic metabolites by cytochrome P450s (CYPs) and less frequently by Phase II conjugating enzymes. This is exemplified by aristolochic acids (AAs) in Aristolochia spp, which undergo reduction of the nitro group by hepatic CYP1A1/2 or peroxidases in extrahepatic tissues to generate highly reactive cyclic nitrenium ions. The latter can react with macromolecules (DNA and protein), resulting in activation of Hras oncogene and gene mutation in renal cells and finally carcinogenesis of the kidneys. Some naturally occurring flavonoids (e.g. quercetin) and alkenylbenzenes (e.g. safrole, methyleugenol and estragole) can undergo metabolic activation by sequential 1-hydroxylation and sulfation, resulting in reactive intermediates capable of forming DNA adducts and finally genotoxicity. Additional examples are pulegone present in essential oils from many mint species; and teucrin A, a diterpenoid found in germander (Teuchrium chamaedrys) used as an adjuvant to slimming dietary supplements but caused severe hepatotoxicity. Extensive pulegone metabolism generated pcresol that was a glutathione depletory, whereas the furan ring of the diterpenoids in germander was oxidized by CYP3A4 to reactive epoxide which can inactivate hepatic CYP3A and epoxide hydrolase through covalent binding. The hepatotoxic and carcinogenic species of plant pyrrolizidine alkaloids (e.g. echimidine and jacobine), namely pyrrole-type metabolites, are generated by hepatic CYP2B6 and CYP3A4. Potential mechanisms underlying the hepatotoxicity of kava have been related to intracellular glutathione depletion and/or quinone formation. Some herbal constituents (e.g. capsaicin from chili peppers, glabridin from licorice root, oleuropein in olive oil, dially sulfone in garlic, and resveratrol found in red wine) behave as mechanism-based inhibitors of various CYPs. This may provide an explanation for some reported herb-drug interactions. In addition, the inhibition of CYPs by herbal constituents may decrease the formation of toxic metabolites and thus inhibit carcinogenesis, as CYPs play an important role in procarcinogen activation. Due to the wide use and easy availability of herbal medicines, further research should be conducted to ensure the safety and quality of herbal medicine.

Measurement of Extravascular Lung Water in Critically Ill Patients

In critically ill patients, capillary leakage often occurs which in the lungs may lead to pulmonary edema by increased microvascular pressure and permeability. However, clinical assessment of the extent of pulmonary capillary leakage and pulmonary edema is difficult. Several decades ago, the transpulmonary double indicator (thermo-dye) dilution technique has been introduced for quantification of extravasastion of fluids in the lungs by determination of the extravascular lung water (EVLW). The thermo-dye is based on simultaneous central venous injection of a freely diffusible indicator (‘cold’) and a plasma-bound indicator (indocyanine green). This technique has been extensively validated in animal experiments using post-mortem gravimetry and in humans using radionuclide techniques. However, the thermo-dye dilution technique is relatively expensive and time consuming therefore assessment of EVLW is increasingly performed by single transpulmonary thermodilution, which according to animal experimental and clinical studies is sufficiently accurate for estimation of EVLW. Using EVLW to guide the management of patients with both cardiac and non-cardiac pulmonary edema (ARDS) has been shown to reduce the duration of mechanical ventilation, length of stay in the intensive care unit and potentially intensive care costs. EVLW-guided therapy also reduced mortality in those patients with congestive heart failure and ARDS. Recent clinical studies have shown that in critically ill patients EVLW correlates with the severity of lung injury and that it does have a prognostic value. Thus, monitoring EVLW can be a useful additional tool in the goaldirected therapy of critically ill patients, especially those with severe sepsis and sepsis-induced acute lung injury.