Superior Vena Cava Syndrome

Clinical Value of Deep Vein Thrombosis Density on Lower-Extremity CT Venography: Prediction of Pulmonary Thromboembolism

Aim: Diagnosis of pulmonary thromboembolism (PTE) can be delayed if the signs and symptoms of patients are nonspecific.

Introduction: To assess the clinical value of deep vein thrombosis (DVT) density on computed tomography (CT) venography for predicting PTE.

Methods: From 2016 to 2021, patients with DVT diagnosed on lower-extremity CT venography were included. Of these patients, those without PTE were classified into ‘DVT-only group’ and those with PTE were classified into the ‘DVT with PTE group’. The DVT Hounsfield unit (HU) density was measured by drawing free-hand region-of-interests within the thrombus at the most proximal filling defect level. The risk factors associated with PTE were identified by using multivariate logistic regression analysis. A receiver operating characteristic (ROC) analysis was used to evaluate the value of DVT density for predicting the risk of PTE.

Results and Discussion: This study included 177 patients with a mean age of 41.7 ± 10.3 years (DVT-only group: 105 patients; DVT with PTE group: 72 patients). DVT density was significantly higher in DVT with the PTE group than DVT-only group (66.8HU ± 8.7 vs. 57.9HU ± 11.1, p < 0.001). The ROC analysis revealed that the area under the curve (AUC), sensitivity, and specificity for predicting the risk of PTE were 0.737, 72.2%, and 66.7%, respectively, at a DVT density cutoff of 63.0 HU. On univariate and multivariate analysis, DVT density was the only significant risk factor associated with PTE.

Conclusion: Higher DVT density was a significant risk factor for PTE. In addition, DVT density could be a predictive factor for PTE.

Acute Pancreatitis Complicated by Thrombosis in the Right Brachiocephalic Veins and Superior Vena Cava: A Case Report

Background: Acute pancreatitis (AP) is one of the most common digestive emergencies, and vascular complication is one of the primary reasons for death, with splanchnic venous thrombosis being the most common. Although extra-splanchnic venous thrombosis is rare, it carries the risk of life-threatening secondary pulmonary embolism.

Case Presentation: We have, herein, reported a case of AP complicated by rare brachiocephalic vein thrombosis and superior vena cava thrombosis. A 40 years old woman was diagnosed with severe AP for abdominal pain 21 days ago. The patient received symptomatic treatment, including acid suppression, enzyme suppression, lipid-lowering, fluid infusion, anti-infection, and continuous renal replacement therapy. The patient was discharged after symptomatic relief. Recently, the patient was admitted again for middle-upper abdominal pain and discomfort. On admission, her blood platelet, DDimer, fibrin degradation products (FDP), and triglyceride levels have been found to be increased; abdominal enhanced CT showed pancreatic necrosis and an accumulation of peripancreatic necrosis and fluid, while chest enhanced CT suggested thrombosis in the right brachiocephalic vein and superior vena cava. The patient, however, improved and was discharged after anticoagulation combined with insulin and trypsin inhibitors.

Conclusion: In diagnosing and treating AP, dynamic monitoring of D-dimer levels is necessary for the timely detection of the development of thrombotic complications.

Intratesticular Vascular Architecture Seen by Ultrasound Microvascular Imaging (MicroV). Illustration of the Testis Vascular Anatomy

The testis is a richly vascularized organ supplied by low-flow thin caliber vessels that are only partially detected by traditional Doppler systems, such as color and power Doppler.

However, in the vascular representation, these techniques determine, albeit to different extents, a cut of the weak vessels due to the necessary application of wall filters that cut the disturbing frequencies responsible for artifacts generated by pulsations of the vascular walls and surrounding tissues.

These filters cut a specific range of disturbing frequencies, regardless of whether they may be generated by low-flow vessels.

Recently, a new technology, called Ultrasound Microvascular Imaging (MicroV) has been developed, which is particularly sensitive to slow flows. This new mode is based on new algorithms capable of better selecting the low frequencies according to the source of origin and cutting only the disturbing ones, saving the frequencies originating from really weak flows.

When Ultrasound microvascular imaging is used, the vascular map is more detailed and composed of macro and microvasculature, with more subdivision branches, facilitating the interpretation of the normal and, consequently, the pathological.

This review aims to describe the vascular architecture of the testis with Ultrasound Microvascular Imaging (MicroV) in healthy testis, compared to traditional color/power Doppler, related to normal anatomy.

Imaging and Histopathological Features Of Primary Thymic Neuroendocrine Tumor

Objectives: To investigate CT, MRI, and PET/CT features with histopathological findings of primary thymic neuroendocrine tumor.

Materials and Methods: All 9 cases with pathologically proven primary thymic neuroendocrine tumors were reviewed retrospectively. Among them, 7 underwent enhanced CT, 1 with MRI (enhanced) and another with PET/CT scan. Multiple characters were examined, including tumor location, contour, CT attenuation, enhancement pattern, involvement of surrounding structure and lymphadenopathy.

Results: Among 9 patients studied, 7 (77%) masses were located in the anterior superior mediastinum, 1 in the anterior superior-middle mediastinum, and 1 in the anterior and middle mediastinum. The maximum diameter (longitudinal) ranged from 4.2 to 23 cm (mean ± standard deviation, 9.5 cm ± 2.8). Four masses had irregular, 3 had lobulated, and 2 had smooth contours, while 8 masses had clear margins and 1 had an ill-defined margin. Six masses showed heterogeneous attenuation with necrotic/cystic component (n=5), calcification (n=2) and hemorrhage(n=1), and 3 showed homogeneous attenuation on the non-enhanced image. After contrast administration, 8 masses showed heterogeneous attenuation, and 1 showed homogeneous attenuation with tumor vessels visible in 4 masses. Among all, 8 masses showed strong enhancement, and 1 showed moderate enhancement in comparison to muscles in the anterior thoracic wall on enhanced images. Involvement of adjacent mediastinal structures was observed in 5 cases. Immunohistochemical analysis showed that the tumor cells were positive for CgA, Syn, CK, CD56 and EMA.

Conclusion: Primary NETs are large masses located anterior superior mediastinum, irregular in contour, showing heterogeneous attenuation with necrotic/cystic component and strong heterogeneous enhancement with tumor vessels, compressing local mediastinal structures. In addition, immunohistochemical examination is required in such a diagnosis.

Identifying Predictors for Hypoplastic Aortic Arch (HAA) in Pediatric Patients with Complex Coarctation of the Aorta (CoA)

Objective: HAA is a significant risk factor in complex CoA patients. We conducted a retrospective study to explore the relationship between HAA and other cardiovascular factors.

Methods: We analyzed 103 patients diagnosed with complex CoA using CT angiography and echocardiography. Aortic diameter was measured at six levels, and severe coarctation was defined as coarctation site to diaphragmatic level ratio (CDR) < 50%. Correlations between non-HAA and HAA groups were assessed. Univariate and multivariate logistic regression identified HAA risk factors.

Results: Among 103 children with complex CoA, 55 were in the non-HAA group and 48 in the HAA group. The incidence of PDA (56.3% vs. 32.7%, p < 0.05), severe coarctation (CDR < 50%, 81.3% vs. 34.5%, p < 0.01), and collateral arteries (39.6% vs. 0, p < 0.01) were higher in the HAA group than one in the non-HAA group. The aortic arch size was positively correlated with age and negatively correlated with severe coarctation, VSD, collateral arteries, and left heart dysfunction. Logistic regression results showed that collateral arteries were risk factors for the whole aortic arch (proximal arch OR = 11.458; p < 0.01, distal arch OR = 4.211; p < 0.05, and isthmus OR = 11.744; p < 0.01), severe coarctation (OR = 6.653; p < 0.01), and left heart dysfunction (OR = 5.149; p < 0.01) associated with isthmus hypoplasia.

Conclusion: This study highlights the prevalence of HAA in complex CoA patients and its associations with various cardiovascular factors. These insights improve diagnosis and treatment approaches.

Colour Doppler Sonography of the Ovarian Vein: Recognition and Associated Lesions

Aim: The purpose of this study was to evaluate the diagnostic value of colour Doppler sonography for ovarian veins. The clinical incidence of ovarian venous lesions is relatively low and often overlooked. The ovarian veins are located deep in the pelvis, and they are relatively elongated, which could make medical imaging more difficult. Therefore, there is limited literature on the diagnosis of ovarian venous disease. The purpose of this study was to evaluate the diagnostic value of colour Doppler sonography towards ovarian vein.

Methods: A total of 37 consecutive patients with clinically suspected ovarian venous disorders were included. All the patients underwent colour Doppler sonography. CTV was performed in 31 patients, while retrograde phlebography was performed in 6 patients. CT/phlebography was the established diagnostic criterion for ovarian vein disorders. The SPSS 22.0 program was used for statistical analysis. Sensitivity, specificity, and positive and negative predictive values for colour Doppler sonography were calculated. k-test was used to evaluate consistency between colour Doppler sonography and CT/phlebography.

Results: In the 37 patients,18 cases were positive for ovarian vein disorders and 19 cases were negative, as assessed with colour Doppler sonography. The associated lesions included ovarian vein thrombosis (7 cases), ovarian varicocele (3 cases), and ovarian venous leiomyoma (8 cases). The calculated values of sensitivity, specificity, and positive and negative predictive value were 94.4%, 94.7%, 94.4%, and 94.7%, respectively. The overall accuracy rate was 94.9%. The K level of the degree of agreement between CT/phlebography and colour Doppler sonography was 0.892.

Conclusion: Colour doppler sonography can provide sufficient imaging information. In clinical ultrasonography, attention should be paid to recognizing and detecting ovarian venous lesions.

Pulmonary Hypertension associated with Congenital Heart Disease

Pulmonary hypertension in patients with congenital heart disease is associated with significant mortality, morbidity and health services utilization. The predominant subtype of pulmonary hypertension in these patients is pulmonary arterial hypertension (PAH). PAH associated with congenital heart disease (PAH-CHD) comprises up to one-third of all PAH cases globally and is most commonly associated with anatomically simple shunt lesions. A myriad of clinical phenotypes of PAH-CHD are seen across the spectrum of shunt size, location and directionality. A conceptual framework to categorize these patients based on pathophysiology is described. Contemporary data regarding the management of the varied phenotypes are reviewed, and a novel algorithm to guide decision-making with shunt closure in patients with PAH-CHD is provided. Further data spanning the spectrum of basic, translational and clinical science are much needed to further inform the management of this highly complex and heterogeneous population.

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.

The Right Ventricle in Pulmonary Arterial Hypertension: An Organ at the “Heart of the Problem”

Pulmonary Arterial Hypertension (PAH) is a progressive disease with no cure. A major determinant of outcome is the function of the right ventricle (RV). Unfortunately, progressive RV dysfunction and failure can occur despite PAH-specific therapies. While initial adaptive hypertrophic changes occur to maintain cardiac output and preserve contractile function and reserve, maladaptive changes occur in the RV muscle that contribute to RV systolic and diastolic dysfunction and failure. These include impaired angiogenesis / decreased capillary density with ischemia, fibrosis, cardiomyocyte apoptosis and impaired autophagy, inflammation, enhanced oxidative stress, altered metabolism, etc. Of note, there are no therapies currently approved that offset these changes and treatment of RV dysfunction is largely supportive only. Further patients often do not qualify for bilateral lung transplantation because of co-morbidities such as renal impairment. Thus, a dire unmet need exists regarding the management of RV dysfunction and failure in patients with PAH. In this State-of-the-Art review, we comprehensively outline the unique features of the RV compared to the left ventricle (LV) under normal circumstances and highlight the unique challenges faced by the RV when confronted with increased afterload as occurs in PAH. We provide detailed insights into the basis for the adaptive hypertrophic phase as well as detailed commentary into the pathophysiology of the maladapted dysfunctional state as well as the pathobiological aberrations occurring in the RV muscle that underlines the progressive dysfunction and failure that commonly ensues. We also review comprehensively the evaluation of RV function using all currently employed imaging, hemodynamic and other modalities and provide a balanced outline of strengths and limitations of such approaches with the treating clinician in mind. We outline the current approaches, albeit limited to chronic multi-modal management of RV dysfunction and failure. We further outline new possible approaches to treatment that include novel pharmacologic approaches, possible use of cellular/stem cell therapies and mechanical approaches. This review is directed to the treating clinician to provide comprehensive insights regarding the RV in patients with PAH.

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.

Risk Prediction Models and Novel Prognostic Factors for Heart Failure with Preserved Ejection Fraction: A Systematic and Comprehensive Review

Background: Patients with heart failure with preserved ejection fraction (HFpEF) have large individual differences, unclear risk stratification, and imperfect treatment plans. Risk prediction models are helpful for the dynamic assessment of patients' prognostic risk and early intensive therapy of high-risk patients. The purpose of this study is to systematically summarize the existing risk prediction models and novel prognostic factors for HFpEF, to provide a reference for the construction of convenient and efficient HFpEF risk prediction models.

Methods: Studies on risk prediction models and prognostic factors for HFpEF were systematically searched in relevant databases including PubMed and Embase. The retrieval time was from inception to February 1, 2023. The Quality in Prognosis Studies (QUIPS) tool was used to assess the risk of bias in included studies. The predictive value of risk prediction models for end outcomes was evaluated by sensitivity, specificity, the area under the curve, C-statistic, C-index, etc. In the literature screening process, potential novel prognostic factors with high value were explored.

Results: A total of 21 eligible HFpEF risk prediction models and 22 relevant studies were included. Except for 2 studies with a high risk of bias and 2 studies with a moderate risk of bias, other studies that proposed risk prediction models had a low risk of bias overall. Potential novel prognostic factors for HFpEF were classified and described in terms of demographic characteristics (age, sex, and race), lifestyle (physical activity, body mass index, weight change, and smoking history), laboratory tests (biomarkers), physical inspection (blood pressure, electrocardiogram, imaging examination), and comorbidities.

Conclusion: It is of great significance to explore the potential novel prognostic factors of HFpEF and build a more convenient and efficient risk prediction model for improving the overall prognosis of patients. This review can provide a substantial reference for further research.

Doege-Potter Syndrome; A Case of Solitary Fibrous Pleura Tumor Associated with Severe Hypoglycemia: A Case Report in Internal Medicine

Background: Doege-Potter syndrome is a rare paraneoplastic entity that is often diagnosed incidentally during the work-up of hypoglycemia of unclear etiology. It is characterized by a non-islet cell tumor hypoglycemia mostly associated with solitary fibrous tumors. These uncommon tumors have been reported in <5% of solitary fibrous tumors. Although not unique in its kind, this case is extremely important as this syndrome often conceals unrecognized tumors that can be surgically resolved.

Case Presentation: We present the case of a 59-year-old non-diabetic man with a 2-month history of severe and recurrent fasting hypoglycaemia presenting with severe dyspnea and sweating. Further workup revealed low insulin, C-peptide, and IGF-1 levels and a large right in-trathoracic solitary fibrous tumor. Unfortunately, bioassays for IGF-2 were unavailable at our hos-pital. Nevertheless, as hypoglycemia completely resolved after resection of the mass, Doege-Potter syndrome was highly suspected.

Conclusion: Doege-Potter syndrome is a complication of rare tumors. If hy-poglycemia is unexplained, this syndrome should always be suspected, and the presence of un-known masses should be investigated.

Anesthetic Management of a Child with Adrenocortical Virilizing Tumour Excision

Introduction: A multidisciplinary team that includes an endocrinologist, radiologist, anesthesiologist, and surgeon is a prerequisite for adrenal gland surgeries. The prime indications for adrenal gland surgery can include both hormonal and non-hormonal secreting tumors. Adrenal hormone secreting tumors usually present to the anesthesiologist with a unique set of challenges that require a good preoperative evaluation and hemodynamic control, corrections of all electrolytes and metabolic imbalances, a carefully planned anesthetic strategy, detailed knowledge about the specific diseases, maintaining of postoperative adrenal function, and finally a good collaboration with other involved colleagues. This review will mainly focus on endocrine issues and anesthetic management during the resection of a hormone secreting adrenal gland tumor.

Case Presentation: This is a case report of a 1.5-year-old boy weighing 13.5 kg who was admitted to our hospital with complaints of an increase in height and weight more than appropriate for age, macroglossia, facial oedema, abnormally enlarged genitals and development of pubic hair for 6 months. On examination along with signs of precocious puberty, he had presented raised blood pressure for which he was started on medication.

Results: On ultrasonography, a 6*4 cm mass was seen in the right supra renal fossa which was confirmed on the CECT scan. He underwent surgery for the excision of the tumor mass under general anesthesia with a regional blockade (epidural). The histopathological report of the tumor specimen revealed Adrenocortical Carcinoma. The child required post-operative steroid treatment and subsequently was started on chemotherapy as well.

Conclusion: The perioperative medical management of active Adreno Cortical Carcinomas is complex enough, but anesthesia causes even more substantial changes in physiology. Treatment with steroids helps to maintain hemodynamics to a great extent.

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.

Focusing the Controversies in Budd-Chiari Syndrome Management

Budd-Chiari Syndrome (BCS) is characterized by significant clinical and pathophysiological aspects that seem to allow a sharp differentiation between a variant in the West from one in the East.

The aim of this paper is to focus on the main issues and controversies about the management of BCS in the West. The study discusses different treatment options and how research is trying to solve controversies about debated topics, such as the timing of treatment. In fact, guidelines regarding management of BCS suggest a step-wise strategy starting with medical therapy, arriving at revascularization or TIPS as the second step, and culminating to liver transplant as rescue therapy.

However, long-term outcome is frequently dismal on sole medical therapy. In fact, it is a matter of debate whether further intervention should be suggested only when hemodynamic consequences of portal hypertension are evident. However, as recently hypothesized, chronic micro-vascular ischemia due to impaired venous hepatic outflow could trigger liver fibrosis, resulting in portal hypertension and progressive liver failure. Consequently, liver congestion relief through treatment might be useful as a preventive tool. Recently, early TIPS proved to improve BCS outcome. A direct comparison of early intervention versus step-wise strategy would seem advisable. Furthermore, further studies should address whether non-invasive tools could predict which patients benefit from early intervention.

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.

Genitourinary Tract Tumors in Children: An Update

Background: Genitourinary tract tumors in children are less common than in adults. Most of these tumors have different genetic backgrounds, clinical presentation, and oncologic behavior than their adult counterpart. As a result of low prevalence in children, some of the treatment approaches and recommendations are based on treatment experience in adult patients. However, thanks to scientific and technological development, survival rates have risen considerably.

Objective: This paper presents a review of the principal features of the tumors involving the genitourinary tract in children and an update in genetic background, diagnosis, and treatment.

Methods: A narrative review was performed on published literature about genitourinary tract tumors in pediatric patients. Papers presented in English and Spanish literature were reviewed. PubMed, Science Direct, and SciELO databases were used to collect information and present this article.

Results: Kidney tumors are the most common type of genitourinary tumors in children. Among those, Wilms tumor represents the majority of cases and shows the successful work of clinical trial groups studying this tumor type. Other tumors involving the genitourinary tract in children include Rhabdomyosarcoma, Transitional cell carcinoma, Testicular, and Adrenal tumors.

Conclusion: Genitourinary tract tumors in children represent significant morbidity and economic burden, so awareness in early diagnosis represents improvement in treatment, clinical, and oncological outcomes.

Association of Large Vessel Aneurysm/Pseudo-Aneurysm/Aortitis and Deep Vein Thrombosis in Patients with Behçet’s Disease: A Case Report

Background: Behçet’s disease (BD) is a complex vasculitis with some vascular manifestations including venous thrombosis, arterial thrombosis/aneurysm/pseudoaneurysm, and co-associated venous thrombosis and arterial lesions. We present two patients with Behçet’s disease came with progressive both arterial and venous involvement.

Case Presentation: The first patient was a young man with recurrent oral aphthosis and skin folliculitis and referred with complaint of new abdominal pain and 2 months severe headache. He had not referred to a physician due to COVID-19 pandemic until that time. In addition, he gradually developed a lower extremity edema and eventually was diagnosed with BD complicated with brain sagittal sinus vein thrombosis, abdominal aortic aneurysms and aortitis and deep vein thrombosis (DVT) of femoral vein. The second patient was a young woman with previous history of uveitis, DVT and recurrent oral and genital aphthosis presented with a large inguinal mass due to large iliac artery pseudoaneurysm impending to rupture, and after the operation, due to poor follow-up, developed a new femoral DVT.

Conclusion: It seems the same inflammatory process is responsible for arterial and venous involvement in patients with BD, so it should be considered that involvement in one side (venous/arterial) can be a risk factor for the other side (venous/arterial) and early immunosuppressive treatment should always be considered to improve the prognosis.

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.

Totally Implantable Venous Access Port Systems: Implant Depth-based Complications in Breast Cancer Therapy - A Comparative Study

Background: Totally implantable venous access port system (TIVAPS) is widely used in breast cancer therapy; TIVAPS has several associated complications depending on the depth of implantation in breast cancer (BC) patients during continuous infusional chemotherapy regimens. The purpose of this study is to find out the optimal depth of TIVAPS implantation to reduce the incidence of complications during infusional chemotherapy.

Methods: This study reviewed the depth of TIVAPS implantation in the internal jugular vein in 1282 breast cancer patients over a ten-year period (2009-2019), and associated complications. We segregated the patients as 5 groups: ‘Group A (depth < 4 mm), Group B (depth of 4-8 mm), Group C (depth of 8-12 mm), and Group D (depth of 12-16 mm), and Group E (depth of > 16 mm)’. Consequently, the ‘internal complications’ such as infection, venous thrombotic syndrome, catheter folding & migration, extravasation, whereas the ‘external complications’ viz., inflammation, local hematoma, local cutaneous reactions, and port exteriorization were significantly analyzed during TIVAPS implantation at different depths in BC patients.

Results: Overall incidence of ‘internal complications’ such as infections (8.6%, 2/23 cases), venous thrombotic syndrome (7.69%, 1/13 cases), catheter folding & migration (8.3%, 1/12 cases), and extravasation (8.3%, 1/12 cases) was comparatively lesser in Group C (8-12 mm) (p<0.01) than the Group A, Group B, Group D, and Group E respectively. Mainly, the external complications such as inflammation in Group C (8-12 mm) (pp< 0.01) was lesser (6.8%, 3/44 cases) than Group A, Group B, Group D, Group E. On the similar note, the local hematoma, and local cutaneous reaction, and port exteriorization were observed as ‘5% (1/20 cases), 4.2% (2/47 cases), and (3.2%, 1/31 cases)’ in Group C patients (p<0.01), which were comparatively lesser than the other groups.

Conclusion: Subcutaneous implantation of TIVAPS at a depth of 8-12 mm could be preferred due to the lowest incidence of internal and external complications compared to the incidence of these complications in other groups; this depth could be referred to as the safe and convenient implantation depth for the effective delivery of chemotherapy regimen in BC patients without difficulty in transcutaneous access to the port.

Management of Acute Aluminum Phosphide Poisoning: Has Anything Changed?

Due to its easy availability, rapid and severe toxicity, and no specific antidote, aluminum phosphide has emerged as a lethal toxin, commonly used for suicidal intent in agricultural communities. Despite various advances in medicine, this compound’s toxicity is poorly understood, and it still has a very high case fatality rate with no definitive treatment options available. This review aims to understand the mechanism of toxicity, clinical toxidrome of acute aluminum phosphide poisoning, and the available therapeutic options, including recent advances. A literature review was performed searching PubMed, EMBASE Ovid, and Cochrane Library, using the following search items: (“aluminum phosphide poisoning” OR “aluminum phosphide poisoning toxicity” OR “aluminum phosphide ingestion”) AND (“management” OR “therapy” OR “treatment”). Selected articles were discussed amongst all the authors to shape this review. High case fatality rate and lack of any specific antidote are persisting challenges. Therapeutic measures need to be implemented from all fronts – reducing easy access to the poison, developing less toxic alternatives for use as a pesticide, and more studies directed at developing an effective reversal agent for phosphine. The advent of promising agents like glucose-insulin-potassium infusion and lipid emulsion is a new ray of hope in the complete recovery in this fatal poisoning. The need of the hour is to find an agent that rapidly and effectively reverses aluminum phosphide's toxic effects. Large multicenter controlled trials are required to establish the role of glucose-insulin-potassium and lipid emulsion.

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.

Imaging Features of Thoracic Manifestations of Behçet’s Disease: Beyond Pulmonary Artery Involvement

Background: Behçet’s disease is a chronic multisystemic vasculitis affecting vessels of different sizes in various organs. Thoracic manifestations of the disease show a wide spectrum involving a variety of anatomic structures within the chest. However, pulmonary artery involvement is a typical manifestation of the disease that contributes significantly to mortality in patients. The study aimed to analyze CT features of thoracic manifestations, particularly pulmonary artery involvement, and to quantitatively assess bronchial arteries in Behçet’s disease.

Methods: Patients with Behçet’s disease who underwent CT scans for suspected thoracic involvement between 2010 and 2018 were included. CT findings of 52 patients were retrospectively analyzed for thoracic manifestations of the disease. Bronchial arteries were assessed regarding diameter in patients with/without pulmonary artery involvement. The pulmonary symptoms were noted.

Results: Of the 52 patients, 67% had thoracic manifestations including pulmonary artery involvement, parenchymal changes, superior vena cava thrombosis, and intracardiac thrombus. Pulmonary artery involvement was observed in 50% of the cohort. Peripheral pulmonary arteries (77%) were the most commonly affected branches, followed by lobar (42%) and central (35%) pulmonary arteries. Other thoracic findings were significantly correlated with pulmonary artery involvement (p<0.05). Compared to patients without pulmonary artery involvement, those with pulmonary artery involvement had a higher bronchial artery diameter (p<0.05) and occurrence rate of dilated bronchial arteries.

Conclusion: Involvement of peripheral pulmonary arteries is frequently encountered in Behçet’s disease and it can resemble pulmonary nodules. Dilated bronchial arteries, which can be observed in cases of pulmonary artery involvement, should be considered in patients with hemoptysis.

Aortic Dissection: A Review of the Pathophysiology, Management and Prospective Advances

Aortic dissection is an emergent medical condition, generally affecting the elderly, characterized by a separation of the aortic wall layers and subsequent creation of a pseudolumen that may compress the true aortic lumen. Predisposing factors mediate their risk by either increasing tension on the wall or by causing structural degeneration. They include hypertension, atherosclerosis, and a number of connective tissue diseases. If it goes undetected, aortic dissection carries a significant mortality risk; therefore, a high degree of clinical suspicion and a prompt diagnosis are required to maximize survival chances. Imaging methods, most commonly a CT scan, are essential for diagnosis; however, several studies have also investigated the effect of several biomarkers to aid in the detection of the condition. The choice of intervention varies depending on the type of dissection, with open surgical repair remaining of choice in those with type. In dissections, however, the role of conventional open surgery has considerably diminished in complicated type B dissections, with endovascular repair, a much less invasive technique, proving to be more effective. In uncomplicated type B dissections, where medical choice reigned supreme as the optimal intervention, endovascular repair is being explored as a viable option which may reduce long- term mortality outcomes, although the ideal intervention in this situation is far from settled.

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.

Hypothetical Role of Growth Factors to Reduce Intervertebral Disc Degeneration Significantly through Trained Biological Transformations

Background: Given the evidence of little or no therapeutic benefit of injection-based growth factor therapies, it has been proposed that a naturally triggered uninterrupted blood circulation of the growth factors would be superior.

Objective: We seek to stimulate discussions and more research about the possibility of using the already available growth factors found in the prostate gland and endometrium by starting novel educable physiology, known as biological transformations controlled by the mind.

Methods: We summarized the stretch-gated ion channel mechanism of the cell membrane and offer several practical methods that can be applied by anyone, in order to stimulate and enhance the blood circulation of the growth factors from the seminal fluid to sites throughout the body. This study describes, in detail, the practical application of our earlier published studies about biological transformations.

Results: A previously reported single-patient case study has been extended, adding more from his personal experiences to continually improve this novel physiological training and extending the ideas from our earlier findings in detail.

Conclusion: The biological transformation findings demonstrate the need for additional research to establish the benefits of these natural therapies to repair and rejuvenate tissues affected by various chronic diseases or aging processes.

A Review of Selected Adult Congenital Heart Diseases Encountered in Daily Practice

The advancement in corrective surgical procedures and anaesthesia technology has resulted in the increased survival of patients with Congenital Heart Diseases (CHD). Most of the surviving CHD patients have successfully reached adulthood and those surviving adults now outnumber the infants born with the CHD. Unfortunately, the surviving adults with CHD do not get proper care due to either inconsistent follow-up or not getting care from a specialist in the field of CHD. It is imperative for general practicing clinicians to be aware of the congenital diseases as well as the current clinical recommendations. This manuscript reviews some of the common congenital diseases seen in adults such as cardiac shunts, left heart obstructive lesions, and aortopathies.

Conduction Disorders: The Value of Surface ECG

Purpose of Review: The purpose of the current mini-review is to describe the importance of surface ECG for the diagnosis of conduction disorder.

Methods: The MEDLINE/PubMed database was used, with the keywords "ECG" and "conduction disorders"; over the past 10 years. Other documents were included because of their relevance.

Main Findings: Data on the anatomy and function of the cardiac electrical system have been described. Conduction disorders including sinus node dysfunction, atrioventricular blocks, intraventricular conduction disorders are exposed as to their epidemiology, etiology, presentation, anatomical site of impaired conduction of the electrical stimulus. The importance of ECG in patients with a cardiac implantable electronic device was also discussed, in addition to future perspectives.

Conclusion: Surface ECG allows the diagnosis of atrioventricular and intraventricular conduction disorder and its anatomical block site most of the time, without the need for invasive tests such as electrophysiological study. Dysfunctions of cardiac implantable electronic devices can be diagnosed by ECG, as well as the prediction of response to cardiac resynchronization therapy.

Advancements in Treatment Options of Women Infertility

Infertility is defined as the inability to conceive a pregnancy after one year or more of unprotected sexual intercourse, among the women at the risk of conceiving a pregnancy. In addition to the age factor, it is known to be associated with pathological and genetic conditions that contribute to its early onset. Polycystic ovarian syndrome (PCOS), endometriosis, fibroids, and blockade in fallopian tubes are certain common pathological causes of female infertility. Researches are focused to eradicate the primary cause of infertility to achieve healthy fertile ground for fertilization. Depending on the cause, therapeutic options include medicines (chemical, herbal and Chinese), hormonal stimulation, surgery, assistive reproductive technology, and tissue engineering. To the extent of research, biotechnology has played a significant role to answer the problem. This review discusses advancements in these therapeutic fields to treat women-associated infertility.

Human Ascariasis: An Updated Review

Background: Ascaris lumbricoides is the most common helminthic infection. More than 1.2 billion people have ascariasis worldwide.

Objective: This article aimed to provide an update on the evaluation, diagnosis, and treatment of ascariasis.

Methods: A PubMed search was conducted in February 2020 in Clinical Queries using the key terms “ascariasis” OR “Ascaris lumbricoides”. The search strategy included meta-analyses, randomized controlled trials, clinical trials, observational studies, and reviews published within the past 10 years. The search was restricted to English literature. The information retrieved from the above search was used in the compilation of the present article. Patents were searched using the key term “ascariasis” OR “Ascaris lumbricoides” in www.freepatentsonline.com.

Results: Ascaris lumbricoides is transmitted through the ingestion of embryonated eggs from fecal- contaminated material. Ascariasis has high endemicity in tropical and subtropical areas. Predisposing factors include poverty, poor sanitation, inadequate sewage disposal, and poor personal hygiene. The prevalence is greatest in children younger than 5 years of age. The majority of patients with intestinal ascariasis are asymptomatic. For those with symptoms, anorexia, nausea, bloating, abdominal discomfort, recurrent abdominal pain, abdominal distension, and intermittent diarrhea are not uncommon. Other clinical manifestations vary widely, depending on the underlying complications. Complications include Löeffler syndrome, intestinal obstruction, biliary colic, recurrent pyogenic cholangitis, cholecystitis, acalculous cholecystitis, obstructive jaundice, cholelithiasis, pancreatitis, and malnutrition. The diagnosis is best established by microscopic examination of fecal smears or following concentration techniques for the characteristic ova. Patients with A. lumbricoides infection warrant anthelminthic treatment, even if they are asymptomatic, to prevent complications from migration of the parasite. Albendazole and mebendazole are the drugs of choice for children and nonpregnant individuals with ascariasis. Pregnant women with ascariasis should be treated with pyrantel pamoate. Recent patents related to the management of ascariasis are also discussed.

Conclusion: The average cure rate with anthelminthic treatment is over 95%. Unfortunately, most treated patients in endemic areas become re-infected within months. Health education, personal hygiene, improved sanitary conditions, proper disposal of human excreta, and discontinuing the use of human fecal matter as a fertilizer are effective long-term preventive measures. Targeting deworming treatment and mass anthelminthic treatment should be considered in regions where A. lumbricoides is prevalent.

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.

Management of Patients with Heart Failure: Focus on New Pharmaceutical and Device Options

Hospitalization rates and survival of patients with Heart Failure (HF) have improved. However, 5-year mortality rates remain high and the prevalence of the disease is rising likely due to aging of the population and advances in diagnosis and treatment of other acute and chronic cardiovascular diseases. Over the past three decades the therapeutic armamentarium of heart failure has improved substantially with development of medications targeting neuro-hormonal activation and devices preventing sudden cardiac death and improving cardiac synchrony. Recently, inhibition of angiotensin receptors and neprilysin as well as sinoatrial pacemaker modulating f-current, have been found safe and effective strategies that improve HF hospitalization rates and/or mortality. Antidiabetic agents inhibiting sodium-glucose co-transporters 2, result in natriuresis and osmotic diuresis and may further improve HF related outcomes. Furthermore, emerging therapies such as cardiac myosin activators, soluble guanylate cyclase stimulators and non-steroidal mineralocorticoid receptor antagonists are undergoing investigation in phase II and III studies of HF patients. Finally, rapid evolution of in the management of advanced HF has occurred with the application of second and third generation continuous flow left ventricular assist devices in clinical practice. Ongoing clinical studies will validate the safety and efficacy of emerging therapeutic strategies in HF population underrepresented in previous clinical trials.

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.

A Long Time History of a Mediastinal Fibrosis with Triple Vascular Stenosis

Mediastinal fibrosis is a rare disease of diverse etiologies, but sometimes idiopathic. Its evolution is progressive and its complications depend on the structures it compresses. Vascular compressions may lead to superior vena cava syndrome, and pulmonary hypertension. Surgery and endovascular treatment may be effective, but often need to be repeated. Systemic treatments, including corticosteroids, have variable responses.

We present an original case of mediastinal fibrosis, compressing the superior vena cava, the right pulmonary artery, and upper right pulmonary vein. For a 6 year follow up, the patient did not present pulmonary hypertension but only superior vena cava syndrome which was effectively treated by endovascular stenting. Systemic corticosteroids were not very effective for the improvement of symptoms. Later, the patient was treated with chemotherapy and immunosuppressive drugs for acute myeloid leukaemia. His respiratory, cardiovascular and imaging exams revealed stability which led us to reflect on the possible impact of the immunosuppressive therapy on the evolution of this mediastinal fibrosis.

Neonatal Systemic Thrombosis: An Updated Overview

Thromboembolic disease is a complex disorder with a multifactorial aetiology and a severe outcome. In newborns and children it may be missed or diagnosed late, thus worsening the prognosis. The neonatal disease is different from the disorder affecting older children and adults. However, scant epidemiological data and few randomised clinical trials regarding paediatric patients are available, and treatment recommendations are largely based on adult guidelines. Younger patients then have several decades over which they will suffer from the complications of thrombosis and risk of a new thrombotic episode. Current knowledge about neonatal thromboembolic disease and its prevention is reviewed here along with maternal, foetal, neonatal, pharmacological, environmental, lifestyle and occupational contributing factors. Additional data are urgently needed to improve diagnostic and therapeutic strategies and patient outcomes.

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.

Dyspnea in Cancer Patients: A Well-Known and Neglected Symptom

Background: Dyspnea is a very common and well-known symptom in patients with advanced cancer, but it is often neglected by physicians. Moreover, despite the high frequency of dyspnea, few controlled studies have been conducted on cancer patients. In most cases, this ‘awareness of breathing with difficulty' and its severity can only be judged by the patient. Moderate or severe dyspnea is described in 20-80% of patients with advanced cancer and breathlessness is considered a prognostic factor for shorter survival, either alone or associated with other parameters.

Methods: I reviewed the literature and guidelines on the topic with the aims to focus on what is known and on future pathways to follow for the diagnosis and treatment of dyspnea.

Results: There is no uniformity regarding the definition of dyspnea; consequently, there is still no general agreement about which tools are the best to use in clinical practice to detect the presence and severity of this symptom. In addition to the difficulty of assessing the symptom, a further limit concerns the management of dyspnea: a very limited number of therapies, both pharmacological and otherwise, are currently available that lead to satisfactory outcomes. Opioids such as morphine remain the cornerstone of treating dyspnea.

Conclusion: Dyspnea is a complex, multidimensional symptom that results from an interaction between factors and their causes, perception and expression. The main target of assessment and management is the intensity of dyspnea, as expressed by the patient, rather than the objective parameters of the disease. Although dyspnea is a very common symptom, debilitating and often difficult to control, especially in the terminal phase of the disease, few controlled studies have been conducted on cancer patients. Dyspnea remains a well-known but neglected symptom in advanced and terminal cancer patients. Future studies should be conducted regarding the careful assessment and management of this symptom.

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.

Transseptal Access to the Left Atrium: Tips and Tricks to Keep it Safe Derived from Single Operator Experience and Review of the Literature

Background: Transseptal puncture (TSP) remains a demanding procedural step in accessing the left atrium with inherent risks and safety concerns, mostly related to cardiac tamponade.

Objective: Based on our own experience with 249 TSP procedures and in-depth literature review, we present our results and offer several tips and tricks that may render TSP successful and safe.

Methods: This prospective study comprised 249 consecutive patients (146 men), aged 41.6±17.4 years, undergoing TSP by a single operator for ablation of a variety of arrhythmias, mostly related to left accessory pathways (n=145) or left atrial tachycardias (n=33) and more recently, atrial fibrillation (n=70). TSP was guided by fluoroscopy alone in all patients without the use of echocardiography imaging. In addition, an extensive literature review of TSP-related topics was carried out in PubMed, Scopus and Google Scholar.

Results: Among 249 patients, 33 patients were children or young adolescents (aged 7-18 years); 14 patients were undergoing a repeat procedure. Patients with a manifest accessory pathway were the youngest (mean age 33.7±15.9) and patients with atrial fibrillation the oldest (mean age 56.0±10.8 years). A successful TSP was accomplished in 247 patients (99.2%). Two (0.8%) procedures were complicated by cardiac tamponade managed successfully with pericardiocentesis or surgical drainage. Review of the literature revealed no systematic reviews and meta-analyses of TSP studies; however, several patient series have documented that fluoroscopy-guided TSP, with various modifications in the technique employed in the present series, have been effective in 95-100% of the cases with a complication rate ranging from 0.0% to 6.7%, albeit with a mortality rate of 0.018%- 0.2%. Echo imaging techniques were employed in cases with difficult TSP.

Conclusion: Employing a standardized protocol with use of fluoroscopy alone minimized serious complications to 0.8% (2 patients) among 249 consecutive patients undergoing TSP for ablation of a variety of cardiac arrhythmias. Based on this single-operator experience and review of the literature, a list of practical tips and tricks is provided for a successful and safe procedure, reserving the more expensive and patient inconveniencing echo-imaging techniques for difficult or failed cases.

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.

Is the Hepatic Factor a miRNA that Maintains the Integrity of Pulmonary Microvasculature by Inhibiting the Vascular Endothelial Growth Factor?

Background: The “hepatic factor,” a molecule or group of molecules present in the hepatic venous blood, essential for the prevention of the development of pulmonary arteriovenous malformations (PAVMs) and right-to-left shunting has been a conceptual enigma in the understanding of many related conditions.

Methods: Patients with various forms of liver diseases including acute hepatic failure, and others with normal hepatic function like hereditary hemorrhagic telangiectasia (HHT), inflammatory and parasitic disorders, cardiogenic hepatopulmonary syndrome (cHPS) and skin disorders like Dyskeratosis congenita are all known to cause PAVMs. Over a period of the last two decades our understanding of the pathogenesis of PAVMs has changed, but the mechanisms are still not clearly understood. The presence of PAVMs once considered a contraindication for liver transplantation is now a cure for PAVMs in patients with HPS.

Results: In this article the molecular mechanisms and the underlying pathogenesis of PAVMs are discussed and the role of microRNA (miRNA) in its pathogenesis is favorably argued. Identifying and preventing or treating the underlying mechanisms will significantly influence the management of a large group of patients who at present cannot be effectively treated with a very poor prognosis. Progressive polycythemia, desaturation, stroke, and infection are serious complications of PAVMs.

Conclusion: The clinical data and current understanding leads to the possible role of miRNA, which inhibits Vascular Endothelial Growth Factor (VEGF) synthesis as a pathogenic mechanism for the development of PAVMs.

Right Heart Catheterization Through Persistent Left Superior Vena Cava, an Extremely Rare Procedure and Review of Current Literature

Persistent left superior vena cava (PLSVC) is encountered occasionally during angiographic procedures. It usually coexists with right superior vena cava and drains to the right atrium through the coronary sinus, but multiple variations are described. Although PLSVC is extensively reported in the literature, there are very few articles addressing right heart catheterization in patients with isolated PLSVC. We present a patient with absent right superior vena cava and PLSVC draining to a dilated coronary sinus diagnosed during right heart catheterization in the setting of pulmonary hypertension. We were able to safely complete the procedure through the right internal jugular vein. Transthoracic echocardiography and chest CT scan were consistent with this finding. Although clinically silent most of the time, undiagnosed PLSVC can lead to catastrophic consequences when the patient undergoes invasive procedures. If PLSVC is suspected, the anatomy of the thoracic venous system must be identified before invasive cardiac procedures.

Application of Dual-Source CT Coronary Angiography in Type 2 Diabetic Patients with Symptomatic Coronary Heart Disease

Objective: To evaluate the epidemiological and morphological characteristics of coronary plaque in diabetic patients with symptomatic coronary heart disease (CHD) by dual-source computed tomography (DSCT).

Materials and Methods: From June 2013 to December 2014, 267 consecutive patients with type 2 diabetes mellitus were examined by DSCT. Plaque type, distribution, as well as extent and obstructive characteristics were determined for each segment.

Results: A total of 225 patients were included in the final study. Among the 225 cases, patients with calcium score >10 accounted for 76.9%. With the increase in calcium score, the number of obstructive stenoses increased from 17 (22.7%) to 150 (66.4%) segments, and non-obstructive stenosis decreased from 58 (77.3%) to 76 (33.6%) segments. A total of 862 (3.8±3.0 per patient) plaques were detected, of which 448 (52%) were calcified plaque, 272 (32%) mixed plaques and 142 (16%) soft plaques. Regarding the stenosis type, there were significantly more mild (54%), followed by moderate (26%) and severe stenosis (20%); 152 (67.6%) patients had 2 vascular lesions, while 73 (32.4%) patients with single diseased vessel. 190 (84.40%) patients with atherosclerotic plaque were located in left anterior descending (LAD) coronary artery, 146 (64.9%) patients in right coronary artery (RCA), 114 (50.7%) patients in left circumflex (LCX) coronary artery. The most common site of all detected plaques was the proximal segment of the LAD (18.7%).

Conclusion: DSCT showed that coronary arteries of diabetic patients with symptomatic CHD were more prone to calcification. There was more non-obstructive than obstructive lumen narrowing; obstructive stenosis and calcification score was positively correlated; coronary plaques were widely distributed, and mainly located in multiple diseased vessels.

Brain-gut Axis and Pentadecapeptide BPC 157: Theoretical and Practical Implications

Background: Brain-gut interaction involves, among others, peptidergic growth factors which are native in GI tract and have strong antiulcer potency and thus could from periphery beneficially affect CNS-disorders. We focused on the stable gastric pentadecapeptide BPC 157, an antiulcer peptidergic agent, safe in inflammatory bowel disease trials and now in multiple sclerosis trial, native and stable in human gastric juice.

Methods: Review of our research on BPC 157 in terms of brain-gut axis.

Results: BPC 157 may serve as a novel mediator of Robert’s cytoprotection, involved in maintaining of GI mucosa integrity, with no toxic effect. BPC 157 was successful in the therapy of GI tract, periodontitis, liver and pancreas lesions, and in the healing of various tissues and wounds. Stimulated Egr-1 gene, NAB2, FAK-paxillin and JAK-2 pathways are hitherto implicated. Initially corresponding beneficial central influence was seen when BPC 157 was given peripherally and a serotonin release in particular brain areas, mostly nigrostriatal, was changed. BPC 157 modulates serotonergic and dopaminergic systems, beneficially affects various behavioral disturbances that otherwise appeared due to specifically (over)stimulated/damaged neurotransmitters systems. Besides, BPC 157 has neuroprotective effects: protects somatosensory neurons; peripheral nerve regeneration appearent after transection; after traumatic brain injury counteracts the otherwise progressing course, in rat spinal cord compression with tail paralysis, axonal and neuronal necrosis, demyelination, cyst formation and rescues tail function in both short-terms and long-terms; after NSAIDs or insulin overdose or cuprizone encephalopathies were attenuated along with GI, liver and vascular injuries.

Conclusion: BPC 157, a gastric peptide, may serve as remedy in various CNS-disorders.

IgG4 Related Syndrome: Another Multiorgan Disease in the Interest Field of Internal Medicine

Background: IgG4-related disease is a rare, clinical and pathologic disease entity of unknown etiology. Its main features are increased serum concentrations of IgG4 > 1,35 g/l, lymphocyte and IgG4+plasma-cell infiltration within tissues, fibrosis or sclerosis. The classical presentation of IgG4-RSD is pancreatitis which is combined with the involvement of biliary ducts in 74 percent of patients. Extrapancreatic manifestations include: abdominal or mediastinal lymphadenopathy; the involvement of salivary glands and lacrimal glands, kidneys, lung, retroperitoneum. Since IgG4-related disease is a multiorgan lymphoproliferative syndrome, it requires a careful differential diagnosis from other distinct disorders (sarcoidosis, immune rheumatic diseases, hematologic diseases, malignancies). Another distinctive feature is a fairly fast response to steroids, that represents the first-choice therapy. Immunosuppressant drugs (azathioprine, mycophenolate mofetil, methotrexate) might be chosen as glucocorticoid-sparing medications or to maintain steroid-induced remission (Fig. 1).

Methods: We report the case of a 70-year-old man and we performed a brief review of loiterature.

Results: Our patient has a clinical history including bronchial asthma, aortic aneurysm, histologically confirmed retroperitoneal fibrosis causing hydroureteronephrosis, prostatitis, interstitial pulmonary fibrosis, sclerosing chronic pancreatitis (histologically documented), previous chronic cholecystitis (histologically confirmed), previous pericarditis, xeroftalmia, polyclonal hypergammaglobulinemia, eosinophilia. His serum IgG4 levels were significantly increased (5560 mg/dl). In regard to the above mentioned elements a systemic disease characterized by elevated serum levels of IgG4 and IgG4-positive lymphoplasmacytic infiltrative lesions in several tissues, was suspected. Immune-rheumatic diseases and infectious diseases were excluded. Steroid treatment was started achieving a significant swift response.

Conclusion: Until now IgG4 related disease has been considered rare in the West and exclusive of Japanese and Korean countries, our case report leads us to reflect on the necessity to take into account this disease in patients with multisystemic involvement.

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.

Pharmacotherapy for Patent Ductus Arteriosus: Current Options and Outstanding Questions

Management of the patent ductus arteriosus (PDA) represents an ongoing challenge in the care of extremely premature neonates. Determining the optimal treatment strategy requires careful consideration of the potential risks and benefits of available therapies. Surgical ligation results in reliable ductal closure, but may result in numerous short-term complications and have a negative impact on long-term outcome. Intravenous indomethacin was the first pharmacologic agent widely utilized for PDA closure. Intravenous indomethacin effectively closes the ductus arteriosus and prevents pulmonary hemorrhage and severe intraventricular hemorrhage, but fails to mitigate short-term morbidities and improve long-term outcomes. Intravenous ibuprofen represents an alternative therapy with fewer renal adverse effects. However, intravenous ibuprofen does not prevent severe intraventricular hemorrhage and also has concerning adverse effects, including bilirubin displacement and the potential to increase the risk of chronic lung disease. Enteral ibuprofen has also been investigated, although gastrointestinal adverse effects limit widespread utilization. Acetaminophen (paracetamol) represents an enticing novel therapy due to wide availability, low cost, and an appealing safety profile. Ongoing investigation is required to determine the role of this agent in PDA treatment algorithms. Pending these results, clinicians must weigh the potential risks and benefits of each therapy for individual neonates considering all available evidence.

Patent Ductus Arteriosus in Extreme Prematurity: Role of Echocar-diography and Other Imaging Techniques

Clinical signs alone are unreliable in the diagnosis of patent ductus arteriosus (PDA) in preterm infants, and therefore echocardiography remains the mainstay of diagnosis of this common condition. Echocardiography also facilitates understanding of the hemodynamic effects of a PDA, and thus aids in management decisions. Several echocardiographic parameters, including duct size, maximum ductal velocity, left atrial: aorta ratio, mitral inflow E:A ratio, and isovolumic relaxation time, have been utilized in the assessment of PDA, but no single measurement can be used in isolation to inform clinical judgement. Therefore, it is important that echocardiographers on the neonatal unit have a comprehensive understanding of available methods and their limitations.

Newer echocardiographic techniques, such as 3 Dimensional echocardiography, tissue Doppler imaging and strain imaging, are now providing insights into myocardial function in the adaptation of preterm infants to extra-uterine life, and into the effects of a PDA causing systemic-to-pulmonary artery shunting.

Magnetic resonance imaging delivers excellent diagnostic information and accurate hemodynamic evaluation; however this modality is not easily accessible for most preterm infants, in comparison to echocardiography, which is readily available at the cotside in most neonatal units.

Further developments in echocardiography may further refine the contribution it makes to individualized clinical decisionmaking in the management of premature infants with PDA.

Novel Oral Anticoagulants for Venous Thromboembolism with Special Emphasis on Risk of Hemorrhagic Complications and Reversal Agents

Warfarin was the only oral anticoagulant available for the treatment of venous thromboembolism for about half a century until the recent approval of novel oral agents dabigatran, rivoraxaban and apixaban. This presents new classes of medications less cumbersome to use. They do not require frequent laboratory monitoring or have nurmerous drug interactions. On the other hand it also poses a challenge to the physicians deciding which agent to use in specific patient populations, how to predict the bleeding risk compared to warfarin and between the different novel agents and how to manage bleeding with relatively recent discovery of few potential antidotes. This review summarizes the major trials that led to the approval of these agents and their exclusion criteria helping physicians understand which patient types might not benefit from these agents. It provides clinical pearls invaluable in everyday practice such as transitioning between traditional and novel anticoagulants, dose adjustments for high risk populations, drug interactions and cost analysis. Futhermore, the review provides direct comparisons with warfarin and indirect comparisons among the novel agents in terms of efficacy and bleeding risk narrating the numbers of patients with intracranial, gastrointestinal and fatal hemorrhages in each of the major trials. We hope that this review will help the physicians inform their patients about the benefits and risks of these agents and enable them to make an informed selection of the most appropriate anticoagulant.

Hemodynamic Monitoring in the Acute Management of Pediatric Heart Failure

One of the basic tenets of cardiac critical care is to ensure adequate tissue oxygenation. As with other critical illness such as trauma and acute myocardial infarction studies have demonstrated that making the right diagnosis at the right time improves outcomes. The same is true for the management of patients at risk for or in a state of shock. In order to optimize outcomes an accurate and timely assessment of cardiac function, cardiac output and tissue oxygenation must be made. This review discusses the limitations of the standard assessment of cardiovascular function, and adjunctive monitoring modalities that may be used to enhance the accuracy and timely implementation of therapeutic strategies to improve tissue oxygenation.

Clinical Characteristics and Treatment of Cardiomyopathies in Children

Cardiomyopathies are diseases of the heart muscle, a term introduced in 1957 to identify a group of myocardial diseases not attributable to coronary artery disease. The definition has since been modified to refer to structural and or functional abnormalities of the myocardium where other known causes of myocardial dysfunction, such as systemic hypertension, valvular disease and ischemic heart disease, have been excluded. In this review, we discuss the pathophysiology, clinical assessment and therapeutic strategies for hypertrophic, dilated and hypertrophic cardiomyopathies, with a particular focus on aspects unique to children.

Modeling Loss of Microvascular Wall Homeostasis during Glycocalyx Deterioration and Hypertension that Impacts Plasma Filtration and Solute Exchange

The fiber matrix of the surface glycocalyx layer internally coating the endothelial cells and plugging the intercellular clefts is crucial for microvascular wall homeostasis. Disruption of the glycocalyx is found in clinical conditions characterized by microvascular and endothelial dysfunction such as atherosclerosis, diabetes mellitus, chronic renal failure and cerebrovascular disease. Shedding of its components may also occur during oxidative stress and systemic inflammatory states including septis. In this work, we investigate the effects of glycocalyx degradation, either due to enzymatic digestion or to agonist recruitment, on plasma filtration and solute extravasation. We also take into account the possibility of a physiological or pathological increase in blood pressure, as in hypertensive zones such as pre- and post-stenotic blood vessels. Our mathematical model shows that a seriously damaged glycocalyx produces an augmentation of flux of both solvent and solute, thus losing its role of transport barrier and macro-molecular sieve, in agreement with experimental evidence. Similarly, hypertension causes an increase in both volume and solute fluxes, also according to physiological findings. The combination of glycocalyx deterioration and hypertension further raises plasma and solute fluxes, potentially leading in most severe cases to edema and hemorrhage, as in the case of diabetes.

The Challenges of Blood Pressure Control in Dialysis Patients

Hypertension is very prevalent among patients with chronic kidney disease (CKD) and end-stage kidney disease (ESRD). However, there are still several unsolved issues pertaining to the definition, variability, diagnosis and management of hypertension in these patients. This manuscript critically reviews the current challenges in clinical practice in defining, diagnosing and treating hypertension in CKD and ESRD patients. Moreover, the manuscript reviews the pharmacokinetics, pharmacodynamics and safety of most anti-hypertensive drugs used in the management of these patients.

Pharmacological Manipulation of Peripheral Vascular Resistance in Single Ventricle Patients (Stages I, II, and III of Palliation)

Pharmacological manipulation of afterload is often used in the management of single ventricle patients, both in the acute post-operative setting and more chronically. After the first stage of palliation the pulmonary and systemic circulations are in parallel and afterload reduction is often used to increase total cardiac output and systemic oxygen delivery. The effectiveness of this approach is likely to be dependent on the intrinsic contractile state of the myocardium as well as the post-operative vascular tone. A variety of clinical studies and theoretical models support this approach. The use of afterload reduction in this context must be balanced with the need to maintain a critical systemic blood pressure for organ perfusion and to promote pulmonary blood flow. After the second and third stages of palliation the use of acute afterload reduction is less complex and primarily directed at promoting cardiac output when it is low and/or controlling high blood pressure. Second stage palliation is particularly unique in that the cerebral and pulmonary circulations are in series and respond differently to many manipulations designed to control vascular resistance. The incidence of long-term circulatory failure in single ventricle patients has led to frequent use of afterload reducing agents in this population but data to suggest that this improves overall outcomes is lacking. Newer studies suggest there may be a role for drugs that reduce pulmonary vascular resistance. This chapter will discuss the principles of manipulation of systemic vascular resistance, or afterload, following each of the three stages of single ventricle reconstruction. This article addresses the seventh of eight topics comprising the special issue entitled “Pharmacologic strategies with afterload reduction in low cardiac output syndrome after pediatric cardiac surgery”.

Essential Roles of Intracellular Calcium Release Channels in Muscle, Brain, Metabolism, and Aging

Calcium (Ca²⁺) release from intracellular stores controls numerous cellular processes, including cardiac and skeletal muscle contraction, synaptic transmission and metabolism. The ryanodine receptors (RyRs: RyR1, RyR2, RyR3) and inositol 1,4,5-trisphosphate receptors (IP3Rs: IP3R1, IP3R2, IP3R3) are the major Ca²⁺ release channels (CRCs) on the endo/sarcoplasmic reticulum (ER/SR). RyRs and IP3Rs comprise macromolecular signaling complexes that include modulatory proteins which regulate channel activity in response to extracellular signals resulting in intracellular Ca²⁺ release. Here we focus on the roles of CRCs in heart, skeletal muscle, brain, metabolism, and aging.

Impact of Jugular Vein Valve Function on Cerebral Venous Haemodynamics

We quantify the effect of internal-jugular vein function on intracranial venous haemodynamics, with particular attention paid to venous reflux and intracranial venous hypertension. Haemodynamics in the head and neck is quantified by computing the velocity, flow and pressure fields, and vessel cross-sectional area in all major arteries and veins. For the computations we use a global, closed-loop multi-scale mathematical model for the entire human circulation, recently developed by the first two authors. Validation of the model against in vitro and in vivo Magnetic Resonance Imaging (MRI) measurements have been reported elsewhere. Here, the circulation model is equipped with a sub-model for venous valves. For the study, in addition to a healthy control, we identify two venous-valve related conditions, namely valve incompetence and valve obstruction. A parametric study for subjects in the supine position is carried out for nine cases. It is found that valve function has a visible effect on intracranial venous haemodynamics, including dural sinuses and deep cerebral veins. In particular, valve obstruction causes venous reflux, redirection of flow and intracranial venous hypertension. The clinical implications of the findings are unknown, though they may relate to recent hypotheses linking some neurological conditions to extra-cranial venous anomalies.

Heart Failure Models: Traditional and Novel Therapy

Cardiovascular disease (CVD) is among the most major causes of morbidity and mortality worldwide. Great progress has been made in the management of CVD which has been influenced by the use of experimental animal models. These models provided information at cellular and molecular levels and allowed the development of treatment strategies. CVD models have been developed in many species, including large animals (e.g. pigs and dogs) and small animals (e.g. rats and mice). Although, no model can solely reproduce clinical HF, simulations of heart failure (HF) are available to experimentally tackle certain queries not easily resolved in humans.

Induced HF may also be produced experimentally through myocardial infarction (MI), pressure loading, or volume loading.

Volume loading is useful to look at hormone and electrolyte disturbances, while pressure loading models is helpful to study ventricular hypertrophy, cellular imbalance and vascular changes in HF. Coronary heart disease is assessed in MI animal models. In this review we describe various experimental models used to study the pathophysiology of HF.

Interventional Radiology in Paediatrics

As in adult practice, there is a growing role for paediatric interventional radiology expertise in the management of paediatric pathologies. This review is targeted for clinicians who may refer their patients to paediatric interventional radiology services, or who are responsible for patients who are undergoing paediatric interventional radiology procedures. The article includes a brief overview of the indications for intervention, techniques involved and the commonest complications. Although some of the procedures described are most commonly performed in a tertiary paediatric centre, many are performed in most Children’s hospitals.

Current Management of Neonatal Neuroblastoma

Neonatal neuroblastoma accounts for less than 5% of all cases of neuroblastoma but carries a favorable prognosis with most patients being stratified into low- or intermediate-risk groups for recurrence of disease. The epidemiology of neonatal (age less than 30 days) neuroblastoma contrasts greatly with patients older than 30 days. Owing to the unique potential for spontaneous regression of this tumor type, several groups have sought to reduce therapy given to neonates with neuroblastoma and use a watch-and-wait approach for many low-risk patients. Ongoing studies also seek to reduce therapy for some intermediate-risk patients in an attempt to lessen exposure to surgical intervention and cytotoxic chemotherapy. In this review, we discuss the epidemiology, clinical presentation, staging, and treatment for neonates with neuroblastoma.

Current Management of Neonatal Liver Tumors

This review is focused on the special issues and challenges confronting physicians and surgeons caring for an unborn child, or a newborn with a liver tumor. Liver tumors at this age are very rare and they make it difficult for pediatric surgeons to gain experience necessary to obtain good results. On the other hand, adult hepatobiliary surgeons faced with a fetus or infant with a liver mass are ill equipped to care for the patient even if they have done a high volume of adult liver surgery and are expert in the field. Often a team approach is the best solution.

Diagnostic Imaging of Fetal and Neonatal Abdominal and Soft Tissue Tumors

Imaging plays a key role in the diagnosis and staging of prenatal and neonatal tumors, and is essential in treatment planning. Though obstetrical ultrasound is the first choice prenatally, fetal MRI continues to play an increasing role as experience with this imaging modality increases. In the neonate, in addition to ultrasound and MRI, CT and nuclear medicine studies can also play an important role. We describe the prenatal and neonatal imaging findings of some of the most common congenital abdominal and soft tissue neoplasms including neuroblastoma, renal, liver and soft tissue tumors.

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.

Currently Used Biologic Agents in the Management of Behcet’s Syndrome

Behcet’s s yndrome (BS) is a multisystem vasculitis with frequent mucocutaneous, joint, eye and visceral organ involvement. From early 2000s, biologic drugs have been increasingly used in the management of BS, enabling rapid and complete remission in most cases with critical organ involvement. Despite the current experience with steroids and traditional immunosuppressives, biologics are exceptionally promising for treatment of resistant cases. Among the biologics used in BS, TNF-alpha antagonists are the oldest and their efficacy has been proven in recalcitrant ocular, vascular, gastrointestinal and neurologic involvements. These drugs have significantly reduced morbidity and mortality in BS and they have an acceptable safety profile. Tocilizumab, an IL6 receptor antibody, has been shown to be effective in BS patients with neurologic involvement and amyloidosis, and IL1β antagonists such as anakinra, canakinumab, gevokizumab were effective in the management of ocular involvement. Studies investigating the efficacy of daclizumab, IL2 receptor antibody, and secukinumab, IL17 monoclonal antibody, in the management of BS with eye involvement failed to demonstrate significant clinical improvement and both studies were halted. A monoclonal vascular endothelial growth factor antagonist, bevacizumab, was shown to be effective in BS-related macular edema. Alemtuzumab and ustekinumab are among other biologics which were effective in controlling disease symptoms. In this review, we discuss the efficacy and safety of various recently developed biologic agents targeting different pathways involved in the pathogenesis of BS.

Management of Incidental Findings in the Era of Next-generation Sequencing

Next-generation sequencing (NGS) technologies allow for the generation of whole exome or whole genome sequencing data, which can be used to identify novel genetic alterations associated with defined phenotypes or to expedite discovery of functional variants for improved patient care. Because this robust technology has the ability to identify all mutations within a genome, incidental findings (IF)- genetic alterations associated with conditions or diseases unrelated to the patient’s present condition for which current tests are being performed- may have important clinical ramifications. The current debate among genetic scientists and clinicians focuses on the following questions: 1) should any IF be disclosed to patients, and 2) which IF should be disclosed – actionable mutations, variants of unknown significance, or all IF? Policies for disclosure of IF are being developed for when and how to convey these findings and whether adults, minors, or individuals unable to provide consent have the right to refuse receipt of IF. In this review, we detail current NGS technology platforms, discuss pressing issues regarding disclosure of IF, and how IF are currently being handled in prenatal, pediatric, and adult patients.

Serpin Regulation of Fibrinolytic System: Implications for Therapeutic Applications in Cardiovascular Diseases

Fibrinolysis is the ultimate outcome of a cascade of enzymatic reactions in which serine proteases such as plasmin, tissue plasminogen activator (tPA), and urokinase plasminogen activator (uPA) are the key players. Plasmin degrades fibrin into soluble fibrin degradation products. The tPA-mediated plasminogen activation is mainly involved in the dissolution of fibrin in the circulating blood whereas the uPA binds to a specific cellular receptor, resulting in an enhanced activation of cell membrane bound plasminogen. These proteases are regulated by serine protease inhibitors (serpins). Serpin-mediated regulation may occur either at the level of plasmin, mainly by α2-antiplasmin (α2-AP) or at the level of the PAs, mainly by plasminogen activator inhibitor -1 (PAI-1). Other serpins may also be involved including plasminogen activator inhibitor -2 and -3 (PAI-2 and PAI-3), protease nexin-1 (PN-1), C1-inhibitor (C1-INH), placental thrombin inhibitor (PTI), neuroserpin, and yukopin. The serpin-protease reactions serve as potential platforms to develop therapeutics for the treatment and prevention of cardiovascular diseases such as thrombosis and hemorrhage. This review will describe key serpins involved in the regulation of fibrinolytic system, particularly α2-AP and PAI-1, with the focus on their biochemical and biophysical aspects, the pathologies related to their dysfunction or deficiency, their therapeutic roles, and their reported cofactors or modulators.

Atrial Tachycardias Occurring Late After Open Heart Surgery

Atrial tachycardias are common after open heart surgery. Most commonly these are macro-reentrant including cavotricuspid isthmus dependent atrial flutter, incisional right atrial flutter and left atrial flutter. Focal atrial tachycardias occur less frequently. The specific type of atrial tachycardia highly depends on the type of surgical incision. Catheter ablation can be very effective, however requires a thorough understanding of anatomy and surgical technique.

Lone Atrial Fibrillation: Electrophysiology, Risk Factors, Catheter Ablation and Other Non-pharmacologic Treatments

Atrial fibrillation occurring in the absence of cardiovascular disease in individuals younger than 60 years is known as lone atrial fibrillation. Nearly 1-12% of atrial fibrillation is considered to be lone atrial fibrillation. As our understanding of atrial fibrillation grows, we wonder as to whether there is such as thing as “lone” atrial fibrillation? We know that male sex, obesity, obstructive sleep apnea, alcohol consumption and endurance sports increase the risk of developing lone atrial fibrillation. Family history of atrial fibrillation increases the risk strongly and there are several recognized mutations that are causative of lone atrial fibrillation. Common triggers for origin of atrial fibrillation are the pulmonary veins. The atrial substrate provides the reentry circuits for perpetuating the arrhythmia. The autonomic nervous system is a key modulator and allows the continuation of the atrial fibrillation. Catheter ablation has been very effective in the treatment of this condition. The ablation procedure involves isolation of the pulmonary veins, antrum, complex fractionated electrograms and other sites. Alternatively surgical techniques can be used to isolate the pulmonary veins and surgical techniques have evolved to minimally invasive procedures and these are as effective as catheter ablation. Early intervention improves the left atrial remodeling and may lead to fewer recurrences.

Catheter Ablation of Lone Atrial Fibrillation

Atrial fibrillation is the most common sustained arrhythmia in clinical practice, associated with increased mortality, risk of stroke and heart failure, as well as the reduction of the quality of life. Atrial fibrillation may be encountered in young otherwise healthy individuals, due to the isolated electrophysiological disorder limited mostly to the pulmonary veins and posterior left atrial wall, or associated with the presence of advanced underlying heart disease and numerous cardiac and non-cardiac comorbidities with significant structural remodeling of the atrial myocardium. Due to limited efficacy and serious side effects of antiarrhythmic drugs, catheter ablation of atrial fibrillation, based on the pulmonary vein isolation for paroxysmal atrial fibrillation and adjunctive substrate modification for persistent atrial fibrillation, has emerged as an attractive and promissing alternative therapeutic option for selected patients with atrial fibrillation. In this review article, we discuss the electrophysiological left atrial abnormalities underlying lone atrial fibrillation and the role of pulmonary veins in pathophysiology of arrhythmia, and we summarize results of the studies on the long term outcome of catheter ablation of atrial fibrillation, as well as the studies on comparison of antiarrhythmic drugs with catheter ablation for treatment of atrial fibrillation. In addition, we present available data that provide better understanding of mechanisms, diagnosis, prevention and treatment of specific procedure-related complications and discuss current periprocedural anticoagulation strategies and their impact on the thromboembolic risk reduction.

A Brief History of ‘Lone’ Atrial Fibrillation: From ‘A Peculiar Pulse Irregularity’ to a Modern Public Health Concern

Ever since the original description of a ‘peculiar pulse irregularity’, atrial fibrillation (AF) has been studied extensively and has come a long journey from the recognition of its cardiac origins, to the modern concept of AF as a serious public health challenge with profound social and economic implications. This arrhythmia affects around 2% of adult population, and the most common underlying heart diseases accompanying AF in the modern era are hypertension, heart failure and coronary artery disease, as well as valvular heart diseases and numerous other cardiac as well as non-cardiac disorders which have been shown to predispose to AF.

On occasions, AF occurs in young otherwise apparently healthy individuals (so called ‘lone AF’). For a long time, ‘lone’ AF has been believed to bear a favourable prognosis as compared to AF with underlying structural heart disease, but increasing evidence suggests that ‘lone’ AF patients represent a rather heterogeneous cohort, with highly variable individual risk profiles due to the presence of various subclinical cardiovascular risk factors or genetically determined subtle alterations at the cellular or molecular level. For these reasons, the existence of truly ‘lone’ AF has recently been questioned.

In this review article, we present a brief history of the recognition of the public health burden of AF. We discuss some of the misconceptions and breakthroughs on modern knowledge on AF, including the rise (and fall) of the ‘lone’ AF concept.

Prognostic Markers in Small Cell Lung Cancer

Small cell lung cancer (SCLC) is a rapidly progressive malignancy with no improvement in survival outcome or change in the standard of care over the past thirty years. In this review, we examine molecular tissue markers, serum/ plasma markers, laboratory data and clinical markers that have been reported to have prognostic influence in SCLC. We discovered that the following held a poor prognosis in limited (LD) and extensive-stage (ED) SCLC: Autocrine growth loop activity via C-kit, gastrin-releasing peptide, or pro-gastrin releasing peptide, high pre-treatment beta fibroblast growth factor, increased cathepsin B or D expression, reduced intracellular fragile histidine triad protein expression, her-2/neu over-expression, high matrix metalloproteinase-11 or -14 activity, loss of function of Rb, elevated serum levels of ALT, CEA, CRP, LDH, or VEGF, hyponatremia, elevated lymphatic/vascular endothelial progenitor, disease extent, male gender, weight loss, anemia, neutrophilia, thrombocytopenia, prolonged PT or aPTT, and superior vena cava syndrome as part of an initial presentation of disease. Hypourecemia, elevated neuron-specific enolase, and age over 70 years conveyed a poorer prognosis in LD and elevated creatinine, higher performance status (>2), and liver, bone, or brain metastases conveyed a poorer prognosis in ED SCLC. The following conveyed a favorable prognosis in LD and ED SCLC: E-cadherin expression, increased cytoplasmic levels of inhibitor of DNA binding/differentiation-2, increased numbers of tumor-infiltrating lymphocytes, high MAPK activity, normal to elevated albumin levels, female gender, performance status <2, and smoking cessation at time of diagnosis. Age <70 and the absence of a pleural effusion were associated with a better prognosis in LD only. The data supporting many of these prognostic factors are somewhat weak and reflect that lack of translational research in this disease.

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.

Thrombotic Complications of Neonates and Children with Congenital Nephrotic Syndrome

Congenital nephrotic syndrome (CNS) refers to a disease presenting with massive proteinuria in association with hypoalbuminemia, hyperlipidemia, and edema at birth or within the first three months of life. In the past, most children with CNS had extremely poor prognosis and succumbed to various complications, usually within the first 6 months. Recent advancements in protein supplementation and nutritional support, renal replacement therapy and renal transplantation in infancy, render these patients to have much better outcomes [1-5]. However, there are still many hurdles in the management of this disease. Thromboembolism is an uncommon, yet important complication which the healthcare givers must be aware of. This article reviews the challenges in the management of the thrombotic complications with special emphasis on the unique characteristics of the newborn hemostasis system and anti-thrombin (AT) depletion in nephrotic syndrome. Due to the relatively low incidence of CNS in children and scarce information in the literature on the optimal management of the thromboembolic complications, most of the recommendations are based on the authors’ experience.

Variations and Abnormalities of Major Thoracic Vascular Structures

Purpose: To determine the variations and abnormalities of major thoracic vascular structures in patients exposed to thoracic examination via computerized tomography with 64 detectors.

Materials and Methods: In this retrospective study, 2,479 patients who underwent thoracic computed tomography between May 2006 and October 2007 in the Radiation Department at Dicle University’s School of Medicine were examined. Of these patients, 1,389 were male and 1,090 were female. No variations or abnormalities were detected in 1,588 of the patients.

Results: In 1,588 out of 2,479 patients (64.1%), no abnormalities or variations were detected. The most frequently detected variations occurred in the brachiocephalic trunk and the sole root point of the carotid artery from the aorta; these variations were detected in 838 (33.8%) patients.

In 74 of the 2,479 patients (3.0%) examined, it was found that the left vertebral artery directly initiated from the arch of the aorta. In addition, in 33 patients, the right brachiocephalic trunk and left major carotid artery initiated from the aorta as a single root.

Conclusion: Via multi-slice CT, it is possible to detect variations and abnormalities of major thoracic vascular structures; therefore, there is no need for extra diagnostic invasive digital subtraction angiography.

Interatrial Block in the Modern Era

Interatrial block (IAB; P-wave duration ≥ 110 ms), which represents a delay in the conduction between the atria, is a pandemic conduction abnormality that is frequently underappreciated in clinical practice. Despite its comprehensive documentation in the medical literature, it has still not received adequate attention and also not adequately described and discussed in most cardiology textbooks. IAB can be of varying degrees and classified based on the degree of P-duration and its morphology. It can transform into a higher degree block and can also manifest transiently. IAB may be a preceding or causative risk factor for various atrial arrhythmias (esp. atrial fibrillation) and also be associated with various other clinical abnormalities ranging from left atrial dilation and thromboembolism including embolic stroke and mesenteric ischemia. IAB certainly deserves more attention and prospective studies are needed to formulate a standard consensus regarding appropriate management strategies.

Need for Ongoing Anti Arrhythmic Drugs After Ablation of Atrial Fibrillation. Review

Ablation of atrial fibrillation (AF) is increasingly common. Newer techniques have been developed and indications broadened to a greater number of patients with drug-resistant AF. The first end point of ablation is to cure AF without further need for Anti Arrhythmic Drugs (AADs), but the success rate at 1 year and over, after a single procedure, though higher than the success rate of AADs alone, is not 100% yet. The aim of the present work is to understand the added value of a persistent administration of previously ineffective AADs on the long-term success rate and to evaluate the timing of AADs suspension after ablation in different types of FA, when patients are in constant sinus rhythm after several months. The reduction of symptoms and the fear of asymptomatic recurrences of AF make physicians reluctant to discontinue AADs at the end of the blanking period, though the efficacy of AADs as a permanent solution late after procedure, to increase the sinus rhythm maintenance rate, is still a matter of ongoing debate. At the time, every patient undergoing ablation of AF should be assessed individually about the need to suspend AADs or not. To do this, good knowledge of AF recurrence predictors and long term success rates of AF ablation in specific clinical settings is essential. Loop Recorder as well is very useful in guiding the administration of AADs in a patient-tailored manner. Larger registries and controlled clinical trials in well-defined clinical settings are required to further elucidate the effects of a prolonged action of AADs after AF ablation. The article presented a short discussion of recent patents related to Anti Arrhythmic Drugs.

Patent Selections :

Potential Replication of Induced Pluripotent Stem Cells for Craniofacial Reconstruction

The craniofacial region contains many specified tissues, including bone, cartilage, muscle, blood vessels, fat, skin and neurons. A defect or dysfunction of the craniofacial tissue after post-cancer ablative surgery, trauma, congenital malformations and progressive deforming skeletal diseases has a huge influence on the patient’s life. Therefore, functional reconstruction of damaged tissues is highly sought. The use of cell-based therapies represents one of the most advanced methods for enhancing the regenerative response for craniofacial wound-healing. The recently acquired ability to reprogram human adult somatic cells to induced pluripotent stem cells (iPSCs) in culture may provide a powerful tool for in vitro disease modeling and an unlimited source for cell replacement therapy. This review focuses on the generation, biological characterization and discussion of the potential application of iPSCs for craniofacial tissue-engineering applications.

Pathophysiology and Pharmacologic Treatment of Venous Thromboembolism

Venous thrombosis is a common medical disorder affecting nearly one million Americans each year. This review will focus primarily on the formation of venous thrombosis as well as current and future treatment options. While the full pathophysiology of venous thrombosis is not known, recent evidence points to a role for von Willebrand Factor, platelets, and neutrophils in thrombus formation. Many laboratory and imaging tests may be used for the diagnosis of venous thrombosis (VTE), but risk factor identification and clinical examination should not be overlooked as they are vital in assuring accurate treatment and patient identification. Historically heparin followed by a vitamin K antagonist has been the standard of care for treatment of VTE, but increasing data involving factor Xa inhibitors and direct thrombin inhibitors may mean a shift in first-line therapy in the very near future. Invasive therapies such as catheter-directed thrombolysis have also shown promise in the treatment of venous thrombosis and will likely see increased use in the future.

Prophylaxis of Venous Thromboembolism in Major Orthopedic Surgery: A Practical Approach

Deep venous thrombosis (DVT) is a common cause of morbidity after orthopedic surgery, both in the early post operative period when pulmonary embolism may complicate in hospital clinical course or occur after discharge and later due to development of post thrombotic syndrome.

At present, clear evidence has been provided that pharmacological primary prophylaxis of venous thromboembolism (VTE) is associated with an impressive decrease in the incidence of DVT and related complications. The main limitation of VTE prophylaxis with anticoagulant drug is the risk of bleeding. Both pharmacological and non pharmacological measures are available and indication, clinical results and limitations will be discussed for each. For drug prophylaxis at present mainly are used as parenteral agents, low dose un fractionated heparin, low molecular weight heparin and fondaparinux; however, limited compliance may be a concern. Newer oral anticoagulants, dabigatran, rivaroxaban and apixiban, may be indicated in elective surgery in particular in patients with expected poor adherence to parenteral route. Non pharmacological treatment includes measures directed to decrease the effects of blood stasis, intermittent pneumatic compression device (IPCD) and graduated compression stockings, mechanical devices, inferior caval vein filters. Aim of the present review was to suggest practical approach to DVT prophylaxis in patients undergoing major orthopedic surgery.

Advanced Echocardiographic Imaging of the Congenitally Malformed Heart

There have been significant advancements in the ability of echocardiography to provide both morphological and functional information in children with congenitally malformed hearts. This progress has come through the development of improved technology such as matrix array probes and software which allows for the off line analysis of images to a high standard. This article focuses on these developments and discusses some newer concepts in advanced echocardiography such is multi-planar reformatting [MPR] and tissue motion annular displacement [TMAD].

Our aim is to discuss important aspects related to the quality and reproducibility of data, to review the most recent published data regarding advanced echocardiography in the malformed heart and to guide the reader to appropriate text for overcoming the technical challenges of using these methods. Many of the technical aspects of image acquisition and post processing have been discussed in recent reviews by the authors and we would urge readers to study these texts to gain a greater understanding [1]. The quality of the two dimensional image is paramount in both strain analysis and three dimensional echocardiography. An awareness of how to improve image quality is vital to acquiring accurate and usable data.

Three dimensional echocardiography (3DE) is an attempt to visualise the dynamic morphology of the heart. Although published media is the basis for theoretical knowledge of how to practically acquire images, electronic media [eg.www.3dechocardiography.com] is the only way of visualising the advantages of this technology in real time.

It is important to be aware of the limitations of this technology and that much of the data gleaned from using these methods is at a research stage and not yet in regular clinical practice.

The LIM Protein fhlA is Essential for Heart Chamber Development in Zebrafish Embryos

Four-and-a-half LIM proteins FHL1-3 play important roles in cardiovascular pathophysiology. However, their roles in heart development remain unclear. Here, we report that fhlA, the zebrafish homolog of human FHL1, was found to be expressed around the 22-somite stage. After 24 hpf, expression was restricted to the heart. fhlA knockdown caused an enlarged cardiac chamber phenotype with up-regulated expression of the cardiac markers, but fhlA overexpression reduced the sizes of the cardiac chambers and down-regulated expression of the markers. The morphology associated with the cmlc2, amhc, and vmhc expression patterns at the 22 somite and 24 hpf stages included a broadened domain in embryos lacking fhlA and a smaller domain in embryos overexpressing fhlA. The changes in the sizes of the chambers were attributed to the changes in the number of ventricular and atrial cells. Loss of fhlA caused a longer heart period and pause between heartbeats in M-modes than in controls, but fhlA overexpression caused shorter systolic and diastolic intervals. Abnormal cardiac chambers and physiological function were found to be largely rescued. We also showed the expression of fhlA in the heart to be increased by retinoic acid (RA) and decreased by the RA synthase inhibitor DEAB. Both fhlA and RA signaling caused a phenotype characterized by the morphological alterations in the chamber sizes, suggesting that the role of fhlA in heart development is probably regulated by RA signaling. Taken together, these results showed that fhlA regulates the size of the heart chamber by reducing the number of cardiac cells.

Protective Effects of Intermedin On Cardiovascular, Pulmonary and Renal Diseases: Comparison with Adrenomedullin and CGRP

Intermedin/adrenomedullin-2 (IMD/AM2) belongs to the calcitonin gene-related peptide (CGRP) / adrenomedullin (AM) family. The biological actions of this family are attributed to their actions at three receptor subtypes comprising the calcitonin receptor-like receptor (CLR) complexed with one of three receptor activity modifying proteins. In contrast to AM and CGRP, IMD binds non-selectively to all three receptor subtypes: CGRP, AM1, AM2. The peptide displays an overlapping but differential and more restricted distribution across the healthy systemic and pulmonary vasculature, heart and kidney relative to CGRP and AM. This, combined with tissue, regional and cell-type specific receptor expression, underpins differences in regard to magnitude, potency and duration of haemodynamic, cardiac and renal effects of IMD relative to those of AM and CGRP, and receptor-subtype involvement. In common with other family members, IMD protects the mammalian vasculature, myocardium and kidney from acute ischaemia-reperfusion injury, chronic oxidative stress and pressure-loading; IMD inhibits apoptosis, attenuates maladaptive tissue remodelling and preserves cardiac and renal function. Robust upregulation of IMD expression in rodent models of cardiovascular and renal disease argues strongly for the pathophysiological relevance of this particular counter-regulatory peptide. Such findings are likely to translate well to the clinic: early reports indicate that IMD is expressed in and protects cultured human vascular and cardiac non-vascular cells from simulated ischaemia-reperfusion injury, primarily via the AM1 receptor, and may have utility as a plasma biomarker in cardiovascular disease. These observations should provide the rationale for short-term administration of the peptide in acute disease, including myocardial infarction, cerebrovascular insult, cardiac and renal failure.

Diagnosis and Treatment of Unilateral Forms of Primary Aldosteronism

Primary aldosteronism (PA) is now recognized as the most frequent form of secondary arterial hypertension. The importance of a correct and prompt diagnosis of PA is determined by its relevant prevalence, its increased cardiovascular risk compared to essential hypertension and by the possibility of reversing this increased risk with a targeted therapy. Surgical treatment of unilateral forms of PA (mainly aldosterone-producing adenomas) is at present recommended in well-selected patients because of its cost-effectiveness. Therefore, subtype differentiation of PA forms is of fundamental importance, and available guidelines recommend contrast-enhanced CT-scanning and adrenal venous sampling (AVS) as the main diagnostic tests for this purpose. In this review, we discuss the value of adrenal non-invasive imaging and AVS, the recent advances in complementary tests and, finally, the available data on the outcome of surgical treatment for PA.

Post-cardiac Arrest Syndrome in Children

Although sustained return of spontaneous circulation (ROSC) can be initially established after resuscitation in children, many of the children do not survive to discharge because they developped a post cardiac arrest syndrome.

The post-cardiac arrest syndrome includes systemic ischaemia/reperfusion response, post-cardiac arrest brain injury, postcardiac arrest myocardial dysfunction, and persistent precipitating pathology. The main cause of death after ROSC in children is brain injury.

Physiopathology and management are reviewed in regards of pediatric specificities. Management according to ABCDE includes airway and ventilation management, oxygen therapy, hemodynamic management with early goal directed therapy and protection of the brain against secondary injury by therapeutic hypothermia, management of seizures and control of glycemia.

Resuscitation of the Patient with the Functionally Univentricular Heart

Neonates and infants with functional single ventricle anatomy face nearly certain early mortality without cardiac transplantation or successive palliation through a pathway of staged interventions. Patients with single ventricle variants typically have multiple hospitalizations and high incidence of cardiac arrest. Few studies have directly addressed the physiology, pharmacology, techniques or outcomes of resuscitation of this high-risk group. The unique challenge posed by resuscitation of this patient group was recently recognized within the 2010 International Liaison Committee on Resuscitation consensus statement, where, for the first time, two worksheets were devoted exclusively to the resuscitation of the single ventricle patient before and after S1P and those patients with bidirectional Glenn/hemi-Fontan and Fontan physiology. This article will review the consensus on science, treatment recommendations, and areas of uncertainty in the resuscitation of the infants and children with single ventricle physiology during each stage of surgical repair.

Thrombosis and Nephrotic Syndrome in Children

Nephrotic syndrome is comprised of massive proteinuria in association with hypoalbuminemia, hyperlipidemia, and edema. Thromboembolism is an important source of morbidity and mortality in nephrotic syndrome and virtually any location may be affected. This review focuses on the epidemiology, pathophysiology, clinical features, and diagnosis of thromboembolism in pediatric nephrotic syndrome.

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.

Current Guidelines and Strategies in Management of Renal Vein Thrombosis

Renal vein thrombosis (RVT) is a common type of venous thrombosis in neonates. The reported incidence in literature is 2.2 per 100,000 live births in Germany [1]. In Canada, the number of live births is an estimated 350,000 per year [2]; a 10-year review reports an annual incidence of 2.3 cases of RVT [3]. RVT in children and adults is so rare that the exact incidence is unknown. However, physicians managing such patients need to be aware that both the risk factors and their clinical courses may be different among patients of different age groups. For a comprehensive review of the epidemiology, pathophysiology, etiology, presentation, and diagnosis of RVT, readers are referred to other chapters in this special issue. The present chapter focuses on the management of this disease.

The Diagnosis of Large Airway Pathology and the Role of Rigid Bronchoscopy

With improving awareness, diagnostic techniques and evolving therapeutic strategies, large airway pathology is becoming an increasing, complex and challenging problem for physicians involved in the management of patients with diverse benign and malignant disease. Endobronchial intervention using rigid bronchoscopy has an established role in managing many large airway pathologies e.g. malignant conditions and for other benign diseases it is being developed. Successful outcome depends not only on familiarity with the techniques available but also on a cohesive multidisciplinary team working together with input from doctors skilled in the art of rigid and flexible bronchoscopy, anaesthetists, nurses, theatre recovery staff, operating department assistants and practitioners.

Generating a Biological Pacemaker - Tackling Arrhythmias the Stem Cell Way

Electronic pacemakers have succeeded in saving the lives of millions by providing medical palliation for cardiac conduction abnormalities. However, the caveats associated with usage of the same have prompted research in the development of a biological alternative which could replace or supplement its electronic counterpart. Biopacemaking could be done either by genetic engineering, cellular therapy or a combination of both. Ion channels and calcium handling proteins which form the key molecular players of the cardiac pacemaker action potential were the primary candidates for gene therapy based biopacemaking. Modulation of ion channels and other pacemaking associated proteins, either by gene delivery/ cell therapy or a combination of both have been researched in great detail. Pluripotent/ multipotent stem cells serve as excellent vehicles for carrying such genes which have been tailored to ensure that the implanted cell transforms into a pacemaker-like cell. Implantation of hybrid/ tandem pacemakers could overcome the risk associated with the malfunction of either the biological or electronic pacemaker in the patient. This review article highlights the recent developments in this area of biopacemaking, classifies it based on the principle of possible execution and discusses to fair length patents that could project the biological pacemaker into the clinical scenario very soon.

Clinical Management of the Cardiovascular Failure in Sepsis

Cardiovascular failure in sepsis involves a combination of hypovolemia, decreased vascular tone, myocardial depression and microcirculatory alterations. Fluids represent the first line therapeutic intervention, with controversy regarding the type of fluid. Recent data indicate that albumin is safe and might even be beneficial in specific subgroups. Starches may be an alternative, although concerns exist on potential detrimental effects on renal function of old generation starches. Trials testing new generation starches are ongoing. When fluids fail to correct hypotension, vasopressor agents are used. Various adrenergic agents increase blood pressure, especially dopamine, noradrenaline and adrenaline, by stimulating alpha-adrenergic receptors. They also variably stimulate beta-adrenergic receptors, increasing cardiac contractility, heart rate, and splanchnic perfusion, but with increased risk of arrhythmias, immunomodulation and increased metabolism. Furthermore, dopamine stimulates dopaminergic receptors, resulting in doubtful effects on splanchnic and renal perfusion, but also in endocrine alterations. Do these pharmacologic differences among the various alpha-adrenergic agents translate into clinical differences? Several randomized trials tested the effects of these agents on outcome. Epinephrine produces more undesired effects than norepinephrine, but no clear cut differences on outcome were observed in underpowered trials. Norepinephrine should be preferred over dopamine, as suggested in one large trial and confirmed in a meta-analysis. Vasopressin may be considered as an alternative or in addition to adrenergic agents. In one large trial, no significant difference in outcome was observed, and the exact role of vasopressin still needs clarification. Finally, various inotropic agents can counteract septic myocardial depression. So far, no study supports their routine use, but these may be justified on an individual basis.

Strategies to Tackle Early Low Flow States in the Extremely Preterm Infant

The first 24 hours of a preterm infant’s life is often a period of cardiovascular instability. A complex relationship exists between the heart, brain and systemic and cerebral vasculature and in the immediate neonatal period in which low blood pressure, low systemic blood flow and low cerebral blood flow are common. The preterm infant is at risk of low systemic blood flow (and low blood pressure) due to a combination of intrinsic factors (immaturity of the preterm myocardium and vasculature) as well as extrinsic factors (including mechanical ventilation and vasoactive medications). Low systemic blood flow is common in preterm infants and contributes significantly to the perinatal brain injury, which manifests as peri/intraventricular haemorrhage (P/IVH) and white matter injury. These in turn contribute to the significant neurological and/or developmental disabilities in survivors that impact long term on their quality of life. This paper will look at the evidence currently available for the management of low systemic blood flow in preterm infants.

Matrix Metalloproteinases as Potential Targets in the Venous Dilation Associated with Varicose Veins

Varicose veins (VVs) are a common venous disease of the lower extremity characterized by incompetent valves, venous reflux, and dilated and tortuous veins. If untreated, VVs could lead to venous thrombosis, thrombophlebitis and chronic venous leg ulcers. Various genetic, hormonal and environmental factors may lead to structural changes in the vein valves and make them incompetent, leading to venous reflux, increased venous pressure and vein wall dilation. Prolonged increases in venous pressure and vein wall tension are thought to increase the expression/activity of matrix metalloproteinases (MMPs). Members of the MMPs family include collagenases, gelatinases, stromelysins, matrilysins, membrane- type MMPs and others. MMPs are known to degrade various components of the extracellular matrix (ECM). MMPs may also affect the endothelium and vascular smooth muscle, causing changes in the vein relaxation and contraction mechanisms. Endothelial cell injury also triggers leukocyte infiltration, activation and inflammation, which lead to further vein wall damage. The vein wall dilation and valve dysfunction, and the MMP activation and superimposed inflammation and fibrosis would lead to progressive venous dilation and VVs formation. Surgical ablation is an effective treatment for VVs, but may be associated with high recurrence rate, and other less invasive approaches that target the cause of the disease are needed. MMP inhibitors including endogenous tissue inhibitors (TIMPs) and pharmacological inhibitors such as zinc chelators, doxycycline, batimastat and marimastat, have been used as diagnostic and therapeutic tools in cancer, autoimmune and cardiovascular disease. However, MMP inhibitors may have side effects especially on the musculoskeletal system. With the advent of new genetic and pharmacological tools, specific MMP inhibitors with fewer undesirable effects could be useful to retard the progression and prevent the recurrence of VVs.

Therapeutic Hypothermia as a Neuroprotective Strategy in Neonatal Hypoxic-Ischemic Brain Injury and Traumatic Brain Injury

Evidence shows that artificially lowering body and brain temperature can significantly reduce the deleterious effects of brain injury in both newborns and adults. Although the benefits of therapeutic hypothermia have long been known and applied clinically, the underlying molecular mechanisms have yet to be elucidated. Hypoxic-ischemic brain injury and traumatic brain injury both trigger a series of biochemical and molecular events that cause additional brain insult. Induction of therapeutic hypothermia seems to ameliorate the molecular cascade that culminates in neuronal damage. Hypothermia attenuates the toxicity produced by the initial injury that would normally produce reactive oxygen species, neurotransmitters, inflammatory mediators, and apoptosis. Experiments have been performed on various depths and levels of hypothermia to explore neuroprotection. This review summarizes what is currently known about the beneficial effects of therapeutic hypothermia in experimental models of neonatal hypoxic-ischemic brain injury and traumatic brain injury, and explores the molecular mechanisms that could become the targets of novel therapies. In addition, this review summarizes the clinical implications of therapeutic hypothermia in newborn hypoxic-ischemic encephalopathy and adult traumatic brain injury.

Goal Directed Fluid Therapy

The cornerstone of treating patients with shock remains as it has for decades, intravenous fluids. Surprisingly, dosing intravenous fluid during resuscitation of shock remains largely empirical. Recent data suggests that early aggressive resuscitation of critically ill patients may limit and/or reverse tissue hypoxia, progression to organ failure and improve outcome. However, overzealous fluid resuscitation has been associated with increased complications, increased length of intensive care unit (ICU) and hospital stay and increased mortality. This review focuses on methods to assess fluid responsiveness and the application of these methods for goal directed fluid therapy in critically ill and peri-operative patients.

Obesity, Diabetes and Atrial Fibrillation; Epidemiology, Mechanisms and Interventions

The last few decades have witnessed a global rise in adult obesity of epidemic proportions. The potential impact of this is emphasized when one considers that body mass index (BMI) is a powerful predictor of death, type 2 diabetes (T2DM) and cardiovascular (CV) morbidity and mortality [1, 2]. Similarly we have witnessed a parallel rise in the incidence of atrial fibrillation (AF), the commonest sustained cardiac arrhythmia, which is also a significant cause of cardiovascular morbidity and mortality. Part of this increase is attributable to advances in the treatment of coronary heart disease (CHD) and heart failure (HF) improving life expectancy and consequently the prevalence of AF. However, epidemiological studies have demonstrated an independent association between obesity and AF, possibly reflecting common pathophysiology and risk factors for both conditions. Indeed, weight gain and obesity are associated with structural and functional changes of the cardiovascular system including left atrial and ventricular remodeling, haemodynamic alterations, autonomic dysfunction, and diastolic dysfunction. Moreover, diabetic cardiomyopathy is characterized by an adverse structural and functional cardiac phenotype which may predispose to the development of AF [3]. In this review, we discuss the pathophysiological and mechanistic relationships between obesity, diabetes and AF, and the challenges posed in the management of this high-risk group of individuals.

Vasoactive Compounds in the Neonatal Period

Sufficient organ blood flow of healthy newborn babies is maintained by relatively low systemic blood pressure. Premature infants are at an increased risk of systemic hypotension, often but not obviously, resulting in hypoperfusion of the cerebral, renal and intestinal vascular beds. Maintaining a stable blood pressure in preterm babies is of high importance in order to prevent complications such as intraventricular hemorrhage, periventricular leucomalatia, necrotizing enterocolitis or renal failure. The regulation of systemic and local hemodynamics in newborns differs substantially from that of the adults. Developmental changes in catecholamine sensitivity, higher local vasodilator factor activity and structural differences of the immature myocardium should be taken into account when applying vasoactive agents in neonates. The effects of widely used catecholamines such as dopamine, epinephrine or dobutamine can not be directly adapted from adult therapeutics to neonatal care. Their administration should be supported by data on their effects on systemic and cerebral blood flow in addition to blood pressure changes. At the bedside, neonatologists should use new diagnostic tools to differentiate between neonatal hypotension and hypoperfusion, vasoconstriction and myocardial dysfunction in order to choose the appropriate medication. Newer vasoactive agents already used in adult or pediatric cardiovascular therapy such as milrinone, levosimendan or terlipressin need to be carefully evaluated before introducing them to the treatment of neonatal hypotensive states. Welldesigned preclinical and human newborn studies also evaluating their local effects are warranted.

Therapeutic Strategies in Pulmonary Hypertension of the Newborn: Where Are We Now?

Despite recent advances, Persistent Pulmonary Hypertension of the Newborn (PPHN) still represents an important challenge for neonatologists. The care of newborns with PPHN requires meticulous therapeutic and ventilation strategies including, besides the stabilization of the newborn, the use of selective pulmonary vasodilators as inhaled Nitric Oxide (iNO). However, not all the neonates with PPHN are responsive to this clinical approach. Recent studies have proposed the use of alternative therapies to iNO, when it is not available, or there is no or only a transitory response. Sildenafil, a phosphodiesterase 5 inhibitor, appears as a frequent used therapy in refractory forms of PPHN. The aim of this review is to analyze the current therapeutic strategies in PPHN with special emphasis on iNO.