Cardiomegaly

Advances in the Treatment of Chronic Myeloid Leukemia

Background: The treatment of chronic myeloid leukemia has progressed in recent decades, becoming a model for a disease whose pathogenesis is primarily based on a genetic mutation and has led to survivals comparable to those of the general population.

Objectives: This review aims to present recent therapeutic advances in this area.

Methods: A mini-review was achieved using the articles published in Web of Science and Pub- Med between January 2021 - May 2022, and new patents were made in this field.

Results: The three generations of tyrosine kinase inhibitors have transformed chronic myeloid leukemia into a manageable disorder and greatly improved the treatment results of the chronic phase, the prognosis, survival, and quality of life of patients. The therapeutic goals today include achieving a deep and lasting molecular response as soon as possible, successful treatment-free remission, and discovering and applying new therapeutic strategies to act on impaired immune modulation and dormant leukemic stem cells. The allosteric inhibitor asciminib targets the ABL myristoyl pocket, reduces Abl kinase activity, and is effective against most cells that have mutations in the ABL1 kinase domain. Progress and recommendations for achieving long-term treatment- free remission are set out. Nearly 50% of the patients who received first-line tyrosine kinase inhibitors required a change of treatment by 10 years due to intolerance or resistance to treatment. Their main side effects are presented.

Conclusion: Obtaining a deep and persistent molecular response contributes to achieving longterm treatment-free remission.

Toxicological Advancements in Cocaine Detection: A Review

Cocaine, also known as methyl benzoylecgonine, is one of the most used drugs of abuse and one of the oldest; however, there has been a recent increase in the consumption of this substance. This trend has once again caught the attention of the scientific community. We discuss the current knowledge about this drug, focusing our attention on the forensic approach. Despite the fact that the cut-off of positivity to cocaine in drug tests is quite high, most current tests are able to detect much lower concentrations and could improve forensic sciences in both post-mortem investigations and in people screening. Immunological assays possessing substantial cross-reactivity to cocaine are particularly useful for screening oral fluid, hair, and post-mortem blood, where significant concentrations of the drug can be found. Liquid chromatography has now supplanted the previous techniques because it is very sensitive and specific and allows samples to be analyzed in a shorter time with only minimal sample preparation. Recent studies have focused on increased sensitivity, reduced processing times, and cheaper analysis.

Recurrent Nausea and Vomiting with Weight Loss Associated with Hypothyroidism: Fact or Myth

Background: Hypothyroidism is a commonly encountered endocrine disorder presenting in various clinical settings. It usually presents with classic manifestations, which are readily recognized and, therefore, easy to diagnose. However, occasionally, patients present with unusual symptoms, which becomes a challenge to diagnose. Thyroid dysfunction affects many body organs, including the gut and viscera. Studies show that intestinal motility might be affected by multiple factors, such as neuromuscular dysfunction, myopathy, or alterations in hormone receptors.

Case Presentation: Here, we present the first case of a 21-year-old female student who had complaints of recurrent nausea, vomiting, loose stool, abdominal pain, and weight loss. In the second case, a 25-year-old male student presented with recurrent nausea, vomiting, loose stool, and weight loss. Their unremarkable blood routines and gastrointestinal-specific investigations failed to ascertain the diagnosis. Later, primary hypothyroidism was established by typical biochemical abnormalities.

Conclusion: Thyroxine replacement treatment successfully resolved the presenting symptoms and normalized biochemical reports.

Multisystem Inflammatory Syndrome in a Newborn (MIS-N): Clinical Evidence and Neurodevelopmental Outcome

Background: Although coronavirus disease-2019 (COVID-19) seems to be milder in children than in adults, children may exhibit severe multisystemic involvement, supported by growing evidence of this incidence in neonates. This case report aimed to demonstrate an inflammatory response syndrome in a full-term neonate born from a 35-old-year woman infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).

Case Presentation: A full-term neonate girl with uneventful perinatal history was admitted with mild tachypnea at the first hour of birth and gradually worsened, resulting in subsequent ventilator support on the second day. The nasal SARS-CoV-2 real-time polymerase chain reaction (RT-PCR) test was positive in several cessations from the time of admission until the tenth day. She revealed cardiomegaly, a diffuse opacification of lungs in the chest radiograph, both side ventricular hypertrophy, valvular regurgitation, and severe pulmonary hypertension on echocardiography. She underwent treatment with surfactant, antibiotics, paracetamol, inotropes, and sildenafil, with beneficial effects. In the lack of a positive fluid culture, she developed necrotizing enterocolitis, transaminitis, and a generalized rash on day six. Furthermore, her mild brain edema that occurred on the second day developed into hydrocephaly. The patient was considered MIS-N and successfully treated with methylprednisolone pulse and intravenous immunoglobulin. She was discharged after 29 days and followed for eight months with persistent mild hydrocephalous and possible evidence of cerebral palsy.

Conclusion: We conclude that maternal exposure to COVID-19 may potentially be associated with multisystem inflammation in the early neonatal period. However, this condition is relatively rare. Immunomodulatory agents may be beneficial in this condition.

Automatic Localization and Identification of Thoracic Diseases from Chest X-rays with Deep Learning

Background: There are numerous difficulties in using deep learning to automatically locate and identify diseases in chest X-rays (CXR). The most prevailing two are the lack of labeled data of disease locations and poor model transferability between different datasets. This study aims to tackle these problems.

Methods: We built a new form of bounding box dataset and developed a two-stage model for disease localization and identification of CXRs based on deep learning. The dataset marks anomalous regions in CXRs but not the corresponding diseases, different from all previous datasets. The advantages of this design are reduced labor of annotation and fewer possible errors associated with image labeling. The two-stage model combines the robustness of the region proposal network, feature pyramid network, and multi-instance learning techniques. We trained and validated our model with the new bounding box dataset and the CheXpert dataset. Then, we tested its classification and localization performance on an external dataset, which is the official split test set of ChestX-ray14.

Results: For classification result, the mean area under the receiver operating characteristic curve (AUC) metrics of our model on the CheXpert validation dataset was 0.912, which was 0.021, superior to the baseline model. The mean AUC of our model on an external testing set was 0.784, whereas the state-of-the-art model got 0.773. The localization results showed comparable performance to the stateof- the-art models.

Conclusion: Our model exhibits a good transferability between datasets. The new bounding box dataset is proven to be useful and shows an alternative technique for compiling disease localization datasets.

Protective Effects of Curcumin against Iron-induced Toxicity

Iron is an essential element in cellular metabolism that participates in many biochemical reactions. Nevertheless, iron overload in the body is the cause of damage in some organs including the liver, glands, brain, heart, gastrointestinal tract and lung. Iron chelation therapy could be considered an effective approach for removing excess iron. Deferoxamine, deferiprone and deferasirox are three common iron chelators in clinical practice but cause several side effects. In this context, the use of curcumin, a dietary phytochemical derived from turmeric, as a natural and safe antioxidant with iron-chelating activity may be a useful strategy for the management of iron overload. This review focuses on the deleterious effect of iron accumulation in different organs of the body as well as the therapeutic potential of curcumin against iron-induced toxicity.

Natural Bioactive as a Potential Therapeutic Approach for the Management of Cyclophosphamide-induced Cardiotoxicity

Cyclophosphamide (CP) is an extensively used anticancer drug, but its cardiotoxic manifestation is a major concern for its widespread clinical use. The observed cardiotoxic attributes have been reported at the therapeutic dose and often result into a high mortality rate and poor clinical outcome. Fall in the level of antioxidant enzymes catalase (CAT), reduced glutathione (GSH), superoxide dismutase (SOD) generation of reactive oxygen species (ROS), inflammatory cytokines nuclear factor kappa-light-chain enhancer of activated B cells (NF-kB), tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL- 1β), apoptotic proteins (caspases) and direct damage to myocardial tissue (histological and ultrastructural damage) are some of the reported manifestations of cardiotoxicity. The observed clinical attributes of CP-induced cardiotoxicity are myocarditis, hemorrhage, thrombosis, myocardial infarction (MI), reduced ejection fraction, altered electrocardiogram (ECG) reading and heart failure. However, unlike Daxarazasone (an adjuvant to reduce doxorubicin-induced cardiotoxicity), no approved adjuvant is available to mitigate CPinduced cardiotoxicity. Thus, various natural bioactives have been explored for the possible cardioprotective effect against CP-induced cardiotoxicity. In the current manuscript, we have discussed the clinical and preclinical aspects of CP-induced cardiotoxicity, its clinically used combination with other anticancer drugs, and the available therapeutic regimen to mitigate this cardiotoxicity. Further, we discussed the limitations of available synthetic drugs used as an adjuvant and discussed various natural bioactive and their experimental details. This manuscript's overall goal is to throw light on CP-induced cardiotoxicity and summarize all the experimental data so that researchers working in this field may scientifically get up-to-date information in one place.

Critical Congenital Heart Disease in Neonates: A Review Article

Critical congenital heart defects (CCHDs) are serious malformations that remain to be an important cause of neonatal mortality and morbidity. The clinical presentations of CCHD are shock, cyanosis, or respiratory distress, which may be similar to that of other neonatal conditions. Failure to diagnose these conditions early on after birth may result in acute cardiovascular collapse and death. Screening with routine pulse oximetry is efficient in distinguishing newborns with CCHD and other hypoxemic illnesses, which may otherwise be potentially life-threatening. If the cardiovascular system cannot be observed by echocardiography, then treatment with continuous prostaglandin-E1(PGE1) infusion should be started in any newborn whose condition deteriorates in the first few days of life. This review aims to provide a concise summary of the presentation and management of various CCHDs and to emphasize the role of timely diagnosis in the management.

The Failing Heart in Pediatric Dilated Cardiomyopathy Caused by Excessive Water Drinking: A Case Report and Brief Review

Background: Acute heart failure in Dilated Cardiomyopathy (DCM) is a rare cardiac disease in the pediatric population. A 15-year-old boy was admitted to the emergency department of Kendal Islamic Hospital, Kendal, Indonesia, on June 26th, 2020, with shortness of breath, tachycardia, and oxygen desaturation.

Case Presentation: The chest X-ray showed significant cardiomegaly with a cardiothoracic ratio of 70% and signs of pulmonary congestion. Transthoracic echocardiography revealed dilation of the left atrium and Left Ventricle (LV), decreased global LV systolic function with reduced left ventricular ejection fraction of 22%. Subsequently, he was diagnosed with acute heart failure in dilated cardiomyopathy and discharged on day six of hospitalization.

Conclusion: Focused initial assessment and time-to-therapy in acute heart failure settings need to be understood by all clinicians, especially emergency care physicians.

Atypical Presentation Of Anti-Retroviral Therapy Induced Lactic Acidosis as Acute Right Ventricular Failure And Severe Pulmonary Hypertension

Background: Lactic acidosis of any etiology is associated with poor prognosis and often fatal. The survival in lactic acidosis depends on the ability to identify and remove the cause and managing organ perfusion. Nucleoside Reverse Transcriptase Inhibitors (NRTIs), which are used widely in the treatment of Human Immune Deficiency Virus (HIV) infection, are known to cause life-threatening Type B lactic acidosis.

Case Presentation: Severe lactic acidosis can cause organ failure, especially in respiratory and cardiovascular systems. However, the role of acute lactic acidosis in these organ failures is mostly suggested by experimental studies in animals or in vitro, as few clinical studies in humans are available. Acidosis elevates pulmonary vascular resistance, giving rise to pulmonary hypertension and peripheral vasodilation with an associated fall in blood pressure and systemic hypotension. Although lactic acidosis presenting as abdominal pain, vomiting, and pancreatitis have been reported in persons receiving antiretroviral therapy, the presentation as acute right heart failure has rarely been documented in the literature. We report a case of severe metabolic and lactic acidosis in a patient receiving stavudine and lamivudine, with a rare and atypical presentation as acute right heart failure and severe pulmonary hypertension.

Conclusion: This case emphasizes the need to consider lactic acidosis as a potential cause in patients presenting with acute unexplained right heart failure and severe pulmonary hypertension.

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.

New Approaches for the Treatment of Chagas Disease

Chagas disease, caused by the protozoan Trypanosoma cruzi is a neglected tropical disease with high prevalence (5.7 million in Latin America, WHO 2015), significant burden, and significant morbimortality mostly due to severe heart disorders during the chronic phase of infection. Chagas disease is endemic in Latin America, and medical care for the disease is the major expense for Brazil’s Universal Healthcare System (Sistema Único de Saúde (SUS). The efficacy of the available drugs benznidazole and nifurtimox are low for the chronic phase of Chagas disease, the phase in which most patients are diagnosed, and there are frequent side effects, and drug resistance occurs. The rapid deployment of new drug regimens that are effective for the chronic phase treatment is low-cost and less toxic than the currently available therapy, which is a global priority. Repurposing drugs already in clinical use with other combinations would be the fastest and safest strategy for treating Chagas disease patients. We hypothesize that the combined treatment using repurposing drugs with benznidazole will be more efficacious than benznidazole alone. This needs to be tested further both in vitro and in animal models to understand the efficacy of the treatment before performing human clinical trials. We further hypothesize that producing nanoparticle formulation of the drugs can reduce their toxicity and improve therapeutic use.

Fetal Cardiac Cellular Damage Caused by Anemia in Utero in Hb Bart’s Disease

Background: Severe fetal anemias can cause high output cardiac failure. Mitochondria are key regulators of cardiac function. However, the effects of an early phase of fetal anemia on the fetal heart and cardiac mitochondrial function are not known.

Objective: The aim of this study is to compare mitochondrial function and cardiac biochemical alterations in the fetal cardiac tissue between anemic and non-anemic fetuses.

Materials and Methods: A cross-sectional study was conducted in Fetuses affected by Hb Bart’s disease (n=18) and non-anemic fetuses (n=10) at 17-20 weeks. Echocardiograms had been carried out in all cases to assess prenatal cardiac function. Cardiac tissues were collected after pregnancy termination for the determination of cardiac iron accumulation, mitochondrial function, including mitochondrial ROS production, mitochondrial depolarization and mitochondrial swelling, mitochondrial dynamics, inflammation, and apoptosis.

Results: Prenatal cardiac function evaluated by ultrasound was comparable between the Hb Bart’s and non-anemic groups. In Bart’s group, the levels of cardiac mitochondrial depolarization and swelling, and the TNF-α level were significantly higher, compared to the non-anemic group. On the contrary, anti-inflammatory (IL-10) levels were significantly lower in the Hb Bart’s group. Additionally, active caspase-3 and Bcl-2 expression were also significantly higher (P= 0.001, P=0.035) in Bart’s group. The mitochondrial fission protein expression, including p-DRP1/total DRP1, was significantly higher in Bart’s group. However, there was no difference in cardiac iron accumulation levels between these two groups.

Conclusion: Despite equivalent prenatal cardiac function and comparable cardiac iron accumulation in the Bart’s and non-anemic groups, fetal anemia is significantly associated with cardiac mitochondrial dysfunction, increased mitochondrial fission, and increased inflammation and apoptosis. These findings indicate that an early phase of fetal anemia without cardiac iron overload can lead to cardiac mitochondrial dysfunction in fetuses with Hb Bart’s.

Paget’s Disease of Bone and Cardiovascular Risk: A Pilot Study

Background: The association between Paget’s disease of bone (PDB) and increased cardiovascular (CV) risk has been suggested, but the literature is conflicting.

Objective: Our study aimed to evaluate two markers of CV risk, namely, common carotid artery intimamedia thickness (cIMT) and the aortic pulse wave velocity (PWV) in patients with PDB.

Methods: We enrolled 12 patients with PDB and 58 control subjects, matched for age. The diagnosis of PDB was based on clinical, radiological and biochemical parameters.

Results: Patients with PDB showed higher PWV values than the controls, whereas cIMT was slightly but not significantly increased.

Conclusion: These findings, although limited by the small study population, represent an original observation that deserves further study. The higher arterial stiffness in PDB could be related to the increased bone turnover or the high levels of oxidative stress that characterize this population.

A Deep Neural Network to Distinguish COVID-19 from other Chest Diseases Using X-ray Images

Background: Scanning a patient’s lungs to detect Coronavirus 2019 (COVID-19) may lead to similar imaging of other chest diseases. Thus, a multidisciplinary approach is strongly required to confirm the diagnosis. There are only a few works targeted at pathological x-ray images. Most of the works only target single disease detection which is not good enough. Some works have been provided for all classes. However, the results suffer due to lack of data for rare classes and data unbalancing problem.

Methods: Due to the rise in COVID-19 cases, medical facilities in many countries are overwhelmed and there is a need for an intelligent system to detect it. Few works have been done regarding the detection of the coronavirus but there are many cases where it can be misclassified as some techniques are not efficient and can only identify specific diseases. This work is a deep learning- based model to distinguish COVID-19 cases from other chest diseases.

Results: A Deep Neural Network model provides a significant contribution in terms of detecting COVID-19 and provides an effective analysis of chest-related diseases taking into account both age and gender. Our model achieves 87% accuracy in terms of GAN-based synthetic data and presents four different types of deep learning-based models that provide comparable results to other state-of-the-art techniques.

Conclusion: The healthcare industry may face unfavorable consequences if the gap in the identification of all types of pneumonia is not filled with effective automation.

Cardiac Amyloid - A Hidden Contributor to Cardiac Dysfunction Following Cardiac Surgery: Case Report and Literature Review

We present two patients who underwent cardiac surgery followed by post-operative low cardiac output, diastolic dysfunction and resistance to inotropic support. Despite aggressive medical management, both patients died. At autopsy, the hearts were enlarged and showed previously undiagnosed myocardial and vascular amyloidosis. Occult cardiac amyloidosis is an uncommon, often occult, contributor to post-operative complications post cardiac surgery. Pre-operative or intraoperative myocardial biopsy may be useful in patients with unexplained diastolic dysfunction.

Brief Summary: We present two patients who underwent cardiac surgery followed by low cardiac output, diastolic dysfunction and resistance to inotropic support. Cardiac dysfunction was due to occult amyloidosis. Pre-operative or intra-operative myocardial biopsy may be useful in patients with unexplained diastolic dysfunction. With recent therapy advances, classification and possible treatment of amyloid are possible.

Expression of microRNAs (133b and 138) and Correlation with Echocardiographic Parameters in Patients with Alcoholic Cardiomyopathy

Introduction: Alcoholic Cardiomyopathy (ACM) is a disease with a difficult diagnosis. The real mechanisms related to its pathophysiology are not fully understood.

Objective: The aims of this study were to investigate whether miR-133b and miR-138 could be associated with ACM.

Methods: Forty-four patients were included comprising 24 with ACM and 20 with cardiomyopathies of different etiologies (control group). Real-time PCR was performed to verify the relative expression among the studied groups. In the statistical analysis, the quantitative variables t-student Mann- Whitney and correlation of Pearson tests were carried out, while the qualitative variable comprised the chi-square test, with p<0.05 being considered statistically significant.

Results: There was no association between clinical and sociodemographic characteristics of the groups. The patients with ACM presented downregulation of miR-133b in comparison with control patients (p=0.004). On the other hand, for the miR-138, there was no association when the ACM group was compared with the control group. The presence of miR-133b among cases and controls was not correlated with any of the echocardiographic parameters. However, the increase in the expression of miR-138 was correlated with an increase in the ejection fraction (r=0.28, p=0.01) and the diameter of the left atrium (r=0.23, p=0.04) in patients with ACM.

Conclusion: The downregulation of miR-133b might be a marker for ACM and, in addition, miR- 138 could be used to correlate the increase in ejection fraction with and normalization of the diameter of the left atrium diameter in patients with this disease.

Large Unrepaired Aortopulmonary Window Presenting in Adulthood

Background: Aortopulmonary window is an uncommon congenital heart disease, with untreated cases not surviving beyond childhood. However, very rarely it can present in adult patients with features of pulmonary hypertension. Clinically these patients cannot be differentiated from other more common conditions with left to right shunt. Transthoracic echocardiography if performed meticulously, can depict the defect in aortopulmonary septum.

Results: We report a case of large unrepaired aortopulmonary window in a 23 years old patient, diagnosed on transthoracic echocardiography.

Carfilzomib: A Tale of a Heartbreaking Moment: Case Report and Concise Review of the Literature

Background: Carfilzomib, a proteasome inhibitor, known as a therapeutical option for people who have already received one or more previous treatments for multiple myeloma, has well known cardiac and systemic adverse effects.

Objective: There is evidence supporting that adverse effects are dose dependent, yet there is no known patient phenotype characterized by worse associated consequences, nor are there widely accepted monitoring protocols.

Results: In this article we describe two patients with cardiovascular adverse events related to carfilzomib treatment and their clinical course. Our goal was to present two cases of daily practice, which highlighted the complexity of their management and led to underline how baseline evaluation and close follow-up with echocardiography and cardiac biomarkers, including natriuretic peptides, remain an important tool for the cardiotoxicity surveillance.

Conclusion: These reflections should lead to further studies in order to identify high risk patients for cardiovascular adverse event and clarify the real incidence of cardiotoxicity of this drug and adequate follow-up timing. Finally further research is needed to evaluate strategies for prevention and attenuation of cardiovascular complications of cancer therapy.

Reduction of Autophagic Accumulation in Pompe Disease Mouse Model Following Gene Therapy

Background: Pompe disease is a fatal neuromuscular disorder caused by a deficiency in acid α-glucosidase, an enzyme responsible for glycogen degradation in the lysosome. Currently, the only approved treatment for Pompe disease is enzyme replacement therapy (ERT), which increases patient survival, but does not fully correct the skeletal muscle pathology. Skeletal muscle pathology is not corrected with ERT because low cation-independent mannose-6-phosphate receptor abundance and autophagic accumulation inhibits the enzyme from reaching the lysosome. Thus, a therapy that more efficiently targets skeletal muscle pathology, such as adeno-associated virus (AAV), is needed for Pompe disease.

Objective: The goal of this project was to deliver a rAAV9-coGAA vector driven by a tissue restrictive promoter will efficiently transduce skeletal muscle and correct autophagic accumulation.

Methods: Thus, rAAV9-coGAA was intravenously delivered at three doses to 12-week old Gaa-/- mice. 1 month after injection, skeletal muscles were biochemically and histologically analyzed for autophagy-related markers.

Results: At the highest dose, GAA enzyme activity and vacuolization scores achieved therapeutic levels. In addition, resolution of autophagosome (AP) accumulation was seen by immunofluorescence and western blot analysis of autophagy-related proteins. Finally, mice treated at birth demonstrated persistence of GAA expression and resolution of lysosomes and APs compared to those treated at 3 months.

Conclusion: In conclusion, a single systemic injection of rAAV9-coGAA ameliorates vacuolar accumulation and prevents autophagic dysregulation.

Medical Complications in Anorexia and Bulimia Nervosa

Background and Objective: Anorexia Nervosa (AN), Bulimia Nervosa (BN) and their variants are characterized by persistent alteration of eating behaviour, such as restricted intake or bingeing and purging, as well as excessive concerns about body shape and body weight. Purging behaviour may include self induced vomiting and/or abuse of laxatives, diuretics and physical hyperactivity. Unlike other psychiatric disorders, patients suffering from AN and BN have a high prevalence of many different medical complications, through the sequelae of undernutrition and purging, often with a serious impairment of health status and quality of life. This article describes the main diagnostic and clinical aspects of medical complications in AN and BN.

Results: The medical complications of ED are extremely variable and can occur with only modest biological and physical damage up to extremely serious and life-threatening conditions; the mortality rate of young subjects with AN is 4 - 11% with a risk of death about 12 times higher than that of subjects of the same age of the general population. The management of the medical-internship aspects of AN and BN is rightly placed within complex and articulated programs of interdisciplinary treatment with different levels of intensity of care (outpatient, semi-residential/residential, hospital in cases of emergency/medical and/or psychiatric emergency).

Conclusion: the results of the investigations carried out, describe the functions of the various organs and apparatuses and the alterations detected, the possible complications and physiological adaptations to malnutrition.

Halving Your Cake and Eating it, Too: A Case-based Discussion and Review of Metabolic Rehabilitation for Obese Adults with Diabetes

Background: The global epidemic of obesity will see normal weight adults constituting a mere one-third of the global population by 2025. Although appetite and weight are regulated by a complex integration of neurological, endocrine and gastrointestinal feedback mechanisms, there is a constant interaction between psychological state, physical impairment, presence of comorbid chronic disease and medications.

Methods: We discuss two cases and reveal a practical approach to investigating and managing patients with obesity and diabetes in the ‘real world'. Within this scope, the aetiology, associated disease burden, and pharmacological therapies for the treatment of the obese patient with type 2 diabetes are reviewed. An insight into non-surgical metabolic rehabilitation is also provided.

Summary: Lifestyle, including diet, exercise, medications, as well as genetic predisposition, and rarely, endocrinopathies should be considered in the assessment of the obese patient. Investigations are not complex and include cardiometabolic and nutritional screens and an assessment for institution of graded, safe levels of exercise. In more complicated patients, referral to a multidisciplinary outpatient program may be necessary and it is not uncommon for patients to lose between 10-20% of their initial weight. Despite this, metabolic surgery may be necessary as further weight loss with long-term weight maintenance may be medically indicated. The type of surgery is tailored to the patient’s medical risk and co-morbidities as well as likelihood of compliance with the required follow-up.

Conclusion: It is the opinion of the authors that metabolic rehabilitation should be intensive, multidisciplinary, and have a supervised exercise program, as the gold standard of care. These suggestions are based on the clinical pearls gained over two decades of clinical experience working in one of Australia’s most innovative multidisciplinary metabolic rehabilitation programs caring for patients with severe obesity.

Chest X-ray in Sarcoidosis: The Association of Age, Gender, and Ethnicity with Different Radiological Findings

Background: Sarcoidosis is a granulomatous disease that primarily affects the lung and lymphatic systems of the body. The Chest X-ray (Roentgenology) is the most common first imaging modality used in the diagnostic approach and follow-up of sarcoidosis, and is still used to determine the stage of sarcoidois based on the classification system proposed by Scadding (1961).

Objective: We will assess the relation between different chest x-ray findings in sarcoidosis patients and both, demographic variables of sarcoidosis patients (age, gender, and race), along with different Scadding stages.

Method: We included data regarding cases in the case-control ACCESS study, including demographic and clinical data, in addition to X-ray findings. From those with a biopsy-confirmed diagnosis of sarcoidosis in the ACCESS trial, we excluded patients with diseases that might contribute to X-ray abnormalities, including cardiac and respiratory non-sarcoidosis diseases (e.g. asthma and chronic bronchitis). We also excluded sarcoidosis patients without lung involvement.

Results: A total of 499 patients were included in this study, of which 195 (39.1%) were men and 304 (60.9%) were women. We found that pleural abnormalities are most commonly associated with Scadding stage 2 (42.9%, p= 0.001), whereas Scadding stage 4 is associated with hilar retraction (52.8%, p< 0.001), bullae and bleps (73.7%, p< 0.001), and pulmonary artery enlargement (66.7%, p< 0.001). Finally, we also observed significant relations between demographic variables (age, gender, and race) and different imaging findings.

Conclusion: Upon interpreting chest X-ray of sarcoidosis patients, patients' age, gender, and race should be kept in mind, as demographic variables are associated with chest X-ray findings in those patients. Moreover, each Scadding stage is associated with several findings on chest X-ray in sarcoidosis patients and should be interpreted accordingly.

Parasite Polyamines as Pharmaceutical Targets

There is an urgent need for the identification and validation of new therapeutic targets in protozoan parasites because currently available drugs are limited in number and usefulness, and no vaccines are available. The discovery that alpha-difluoromethylornithine, an inhibitor of polyamine biosynthesis, is an efficacious treatment for African Sleeping Sickness caused by the protozoan parasite Trypanosoma brucei, has validated the polyamine pathway as a target in protozoan parasites. Polyamines are ubiquitous organic cations that play critical roles in key cellular processes such as growth, differentiation, and macromolecular biosynthesis. In recent years, remarkable progress has been made in the characterization of the polyamine pathway in a variety of protozoan parasites and this review will highlight surprising and unique features that could lead to new therapeutic strategies.

Vitamins B1, B2, B3 and B9 – Occurrence, Biosynthesis Pathways and Functions in Human Nutrition

Background: Vitamins are chemical compounds whose derivatives are involved in vital metabolic pathways of all living organisms. The complete endogenous biosynthesis of vitamins can be performed by many bacteria, yeast and plants, but humans need to acquire most of these essential nutrients with food. In recent years, new types of action of the well-recognized vitamins or their more sophisticated relationships have been reported.

Objectives: In this review we present the current knowledge of factors that can influence the yield and regulation of vitamin B1, B2, B3 and B9 biosynthesis in plants which can be important for human nutrition. A summary of modern methods applied for vitamin analysis in biological materials is also provided. Contributions of selected vitamins to the homeostasis of the human organism, as well as their relations to the progress or prevention of some important diseases such as cancer, cardiovascular diseases, diabetes and Alzheimer’s disease are discussed in the light of recent investigations. Better understanding of the mechanisms of vitamin uptake by human tissues and possible metabolic or genetic backgrounds of vitamin deficiencies can open new perspectives on the medical strategies and biotechnological processes of food fortification.

Protective Effects of Terpenes on the Cardiovascular System: Current Advances and Future Perspectives

Background: Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide that seriously affect patient’s life quality and are responsible for huge economic and social burdens. It is widely accepted that a plant-based diet may reduce the risk of CVDs by attenuating several risk factors and/or modulating disease’s onset and progression. Plants are rich in secondary metabolites, being terpenes the most abundant and structurally diverse group. These compounds have shown broad therapeutic potential as antimicrobial, antiviral, anti-inflammatory and antitumor agents. Despite their popularity, scientific evidence on terpenes cardiovascular effects remains sparse, limiting their potential use as cardioprotective and/or cardiotherapeutic agents.

Objective: Bearing in mind the lack of comprehensive and systematic studies, the present review aims to gather the knowledge and some of the most scientific evidence accumulated over the past years on the effect of terpenes in the cardiovascular field with focus on CVDs namely ischemic heart disease, heart failure, arrhythmias and hypertension.

Method: Several popular search engines including PubMed, Science Direct, Scopus and Google Scholar were consulted. The bibliographic research focused primarily on English written papers published over the last 15 years.

Results: A systematic and comprehensive update on the cardiovascular effects of terpenes is provided. Moreover, whenever known, the possible mechanisms of action underlying the cardiovascular effects are pointed out as well as an attempt to identify the most relevant structure- activity relationships of the different classes of terpenes.

Conclusion: Overall, this review enables a better understanding of the cardiovascular effects of terpenes, thus paving the way towards future research in medicinal chemistry and rational drug design.

The Effects of Vitamin B in Depression

Vitamins are dietary components which are necessary for life. They play a major role in health and their deficiency may be linked to symptoms of psychiatric disorders. B vitamins are required for proper functioning of the methylation cycle, monoamine oxidase production, DNA synthesis and the repair and maintenance of phospholipids. Vitamin B deficiency could influence memory function, cognitive impairment and dementia. In particular, vitamins B1, B3, B6, B9 and B12 are essential for neuronal function and deficiencies have been linked to depression. We discuss the causes of depression and the neurochemical pathways in depression. In particular, we provide evidence that vitamin B contributes to the complexity of depressive symptoms.

Beta-Blockers are Associated with Decreased In-Hospital Mortality and Stroke in Acute Decompensated Heart Failure: Findings from a Retrospective Analysis of a 22-Year Registry in the Middle East (1991-2013)

Background: Beta-blockers reduce mortality in chronic heart failure.

Objectives: To study intra-hospital mortality and adverse cardiovascular (CV) outcomes in relation to beta-blockade therapy in acute decompensated heart failure.

Methods: We retrospectively analyzed a 22-year registry of acute decompensated heart failure (ADHF) in the Middle East.

Results: Out of the total 8066 patients admitted for ADHF, 1242(15.4%) were on beta-blockers on admission. Among those, beta-blockers were discontinued in 26.5%. Despite the existence of less CV comorbidities in patients not treated by beta-blockers, in-hospital mortality and stroke/transient ischemic attacks rates were higher in those patients compared with patients on beta-blockers on admission (14.4 vs. 3.6%, p=0.001, 0.6 vs. 0.1%, p=0.02; respectively). Additionally, continuation of beta-blockers during acute decompensation was associated with less mortality risk (p=0.001). The use of beta-blockers on admission and discharge increased significantly with time whereas in-hospital mortality decreased (p=0.001). Nevertheless, admission year was not a predictor of reduced mortality in patients treated with beta-blockers on admission (OR 0.93, 95% CI [0.56-1.54], p=0.77).

Conclusion: Previous beta-blockade therapy in patients presenting with ADHF decreases intra-hospital mortality and the incidence of CV events and stroke/transient ischemic attacks. Moreover, nonwithdrawal of beta-blockers during hospitalization has a favorable outcome.

Cardiomyopathy of Pregnancy

Heart failure is a leading cause of long-term maternal morbidity and mortality in developed countries. The most common cause of maternal heart failure is cardiomyopathy. Peripartum Cardiomyopathy (PPCM) is a distinct idiopathic disease that is not triggered by the hemodynamic changes and myocardial overload associated with pregnancy. Diagnostic criteria include the development of heart failure in the time frame between the last months of pregnancy and the months following delivery, the absence of prior heart disease or other identifiable causes of heart failure and an echocardiography demonstrating LV ejection fraction<45% and/or fractional shortening. Diagnosis requires a high level of suspicion; signs of heart failure may be masked by the pregnancy itself and/or by associated diseases such as hypertension and preeclampsia. The hallmark of the disease is the typical reduction in LV function. The incidence of PPCM ranges between 1:100 to 1:3000 live births, and is particularly high among women of African descent. It remains unclear whether race is a modifier of the disease or a risk factor unto itself. Plausable causes for the disease include: exacerbation of pregnancyinduced myocardial injury caused by certain virus strains, genetic and/or environmental factors, circulating autoantibodies, and a flaw in the normal cardioprotective mechanisms of pregnancy allowing development of a vasculopathy triggered by abnormal peripartum hormonal changes. Treatment is comprised of standard heart failure therapy (restriction of salt and water intake, diuretics, angiotensinconverting enzyme (ACE) inhibitors, mineralocorticoid receptor antagonists, beta blockers and digoxin) and preventive anticoagulation if the ejection fraction ≤35%. Delivery should be planned and carried out by a multidiscipliniary team. Maternal health should always take precedence over fetal health. Failed therapy should prompt further workup (magnetic resonance imaging (MRI) of the heart and/or cardiac catheterization and endomyocardial biopsy) and consideration of less conventional treatment modalities (e.g. immune modulation, bromocriptine), resynchronization, mechanical support and even heart transplant. The prognosis of PPCM is associated with the severity of heart failure at presentation and the response to therapy and is generally better than that of other cardiomyopathies. Approximate mortality rates are <2% in-hospital, 10-15% at 6 months after diagnosis and 25-30% at 2-4 years. Recovery of LV function occurs in one-third to one-half of the women and may carry on for almost 2 years after diagnosis. Subsequent pregnancies have been associated with a high likelihood of relapse due to residual impairment of the LV contractile reserve. There is insufficient data on neonatal outcome.

Pompe Disease and Autophagy: Partners in Crime, or Cause and Consequence?

Pompe disease or glycogen storage disease type II (OMIM: 232300) is a lysosomal storage disorder resulting from a partial or total lack of acid alphaglucosidase, which may produce muscle weakness, gait abnormalities, or even death by respiratory failure. In the last decade, autophagy has been proposed as a mechanism involved in the severity of symptoms related to this disorder and as a potential therapeutic target to alleviate disease progression. This review summarizes the relationship between autophagy and Pompe disease, including what information has been recently discovered and what remains unclear.

Natural Alpha-Glucosidase Inhibitors: Therapeutic Implication and Structure- Activity Relation Ship

Background: Alpha-glucosidase is the key enzyme involved in catalyzing the carbohydrate alpha-glucosidase through hydrolysis. It is implicated in several metabolic pathways, including carbohydrate digestion in the intestine, and glycoprotein and glycolipid processing. Alpha-glucosidase inhibitors are currently being investigated for their therapeutic effect against some diseases such as diabetes, cancer, hepatitis B and human immunodeficiency virus (HIV).

Objective: The aim of this review is to clarify the effect of alpha-glucosidase inhibitors in the treatment of some diseases, and to evaluate the structure-activity relationship of about 270 inhibitors isolated from about 60 plants.

Methods: We reviewed 121 articles published between 1965 and 2013 (PubMed and Sciencedirect). All the molecules structures were provided in ChemDraw software.

Results and Conclusions: In this work we elucidated the therapeutic effect of alpha-glucosidase inhibitors against some diseases and we concluded that alpha-glucosidase flavonoid inhibitors (representing 22% of the reviewed inhibitors) have common components that are responsible of their inhibitory activity. The general structure of these inhibitors is composed of three rings. It seems that the hydroxyl groups in each ring have an important role in the α-glucosidase inhibitory activity.

Stairway to Heaven or Hell? Perspectives and Limitations of Chagas Disease Chemotherapy

In this review, we intend to provide a general view of the evolution of experimental studies in the area of chemotherapy for Chagas disease. We can follow the process of drug development through three phases. The first phase began almost at the same time as the discovery made by Carlos Chagas and proceeds to 1970, during which time an extensive list of compounds was subjected to preclinical and clinical trials. The second phase began with the introduction of nifurtimox and benznidazole into the clinical setting, followed with the search for alternative drugs. In this phase, a dichotomy existed between rational and empirical approaches in preclinical studies. The third phase began with the unravelling of the T. cruzi genome. The development of transgenic parasites has allowed the development of solid HTS protocols, and the establishment of bioluminescent T. cruzi has allowed in vivo drug evaluations using a reduced number of animals. Among the wide variety of compounds subjected to preclinical studies, we have discovered azolic and non-azolic inhibitors of sterol C14α-demethylase (CYP51) and nitro compounds. Two compounds evaluated during the second phase, namely, MK-436 and allopurinol, could be revisited. Clinical studies of posaconazole and E1224 yielded disappointing results, and it is critical to understand the reason for their failure as a monotherapy. Currently, the combination and repositioning of drugs with different mechanisms of action are complementary approaches. The use of drug combinations, particularly those of nitro compounds with CYP51 inhibitors, is considered a real alternative for the treatment of Chagas disease.

Nursing Assessment, Education, and Care of Extremely Premature Neonates with Patent Ductus Arteriosus

The care of extremely premature neonates with suspected or confirmed diagnosis of patent ductus arteriosus (PDA) is a frequent challenge for pediatric nurses. It is important for nurses to have adequate knowledge of the normal postnatal changes in cardiovascular and pulmonary function to recognize any adverse symptoms. Nurses caring for these vulnerable neonates must have a thorough understanding of the pathophysiology of a PDA in order to assess, plan, and implement patient-centered care. Recognition of characteristic symptoms of PDA in a timely manner is essential for optimal management and outcomes. Understanding the science behind treatment options is also imperative for pediatric nurses to provide the best care and effectively educate parents. Pediatric nurses are a significant resource in managing extremely premature neonates through comprehensive assessment, effective parent education, and high-quality patient-centered care.

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.

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.

Multimodality Imaging in Cardiac Sarcoidosis: Is There a Winner?

Sarcoidosis is a multisystem granulomatous disease of unknown cause that can affect the heart. Cardiac sarcoidosis may be present in as many as 25% of patients with systemic sarcoidosis, and it is frequently underdiagnosed. The early and accurate diagnosis of myocardial involvement is challenging. Advanced imaging techniques play important roles in the diagnosis and management of patients with cardiac sarcoidosis.

Recent advances in the management of autoimmune myocarditis: insights from animal studies.

A growing body of evidence has been accumulating to demonstrate that human myocarditis and dilated cardiomyopathy involve a complex interaction with autoimmunity triggered by cardiotropic microbial infections. Animal experiments have provided direct evidence that infections with a particular microbe can incite autoimmune myocarditis, and this autoimmune response can be mimicked by immunization with the cardiac autoantigen, - myosin. Animal models greatly advanced our understanding of the molecular mechanisms of myocarditis, and various novel therapeutic strategies have been reported during the last two decades. In this review we present animal models of autoimmune myocarditis and describe the outlook of possible drug targets by showing the latest findings from animal studies.

Pathophysiology of Post-Operative Low Cardiac Output Syndrome

Low cardiac output syndrome frequently complicates the post-operative care of infants and children following cardiac surgery. The onset of low cardiac output follows a predictable course in the hours following cardiopulmonary bypass, as myocardial performance declines in the face of an elevated demand for cardiac output. When demand outstrips supply, shock ensues, and early recognition and intervention can decrease mortality. Multifactorial in etiology, this article will discuss the pathophysiology of low cardiac output syndrome, including myocardial depression following bypass, altered cardiac loading conditions, and inflammation driving a hypermetabolic state. Contributions from altered neurohormonal, thyroid, and adrenal axes will also be discussed. Sources included the clinical experiences of four cardiac intensivists, supported throughout by primary sources and relevant reviews obtained through PubMed searches and from seminal textbooks in the field. This article addresses the second of eight topics comprising the special issue entitled “Pharmacologic strategies with afterload reduction in low cardiac output syndrome after pediatric cardiac surgery”.

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.

New Insights into the Surgical Management of Tetralogy of Fallot: Physiological Fundamentals and Clinical Relevance

The surgical treatment of tetralogy of Fallot can be considered as a success story in the history of congenital heart diseases. Since the early outcome is no longer the main issue, the focus moved to the late sequelae of TOF repair, i.e. the pulmonary insufficiency and the secondary adaptation of the right ventricle. This review provides recent insights into the pathophysiological alterations of the right ventricle in relation to the reconstruction of the right ventricular outflow tract after repair of tetralogy of Fallot. Its clinical relevance is documented by addressing the policy changes regarding the optimal management at the time of surgical repair as well as properly defining criteria and timing for late pulmonary valve implantation.

Anabolic Androgenic Steroid (AAS) Related Deaths: Autoptic, Histopathological and Toxicological Findings

Anabolic androgenic steroids (AASs) represent a large group of synthetic derivatives of testosterone, produced to maximize anabolic effects and minimize the androgenic ones. AAS can be administered orally, parenterally by intramuscular injection and transdermally. Androgens act by binding to the nuclear androgen receptor (AR) in the cytoplasm and then translocate into the nucleus. This binding results in sequential conformational changes of the receptor affecting the interaction between receptor and protein, and receptor and DNA.

Skeletal muscle can be considered as the main target tissue for the anabolic effects of AAS, which are mediated by ARs which after exposure to AASs are up-regulated and their number increases with body building. Therefore, AASs determine an increase in muscle size as a consequence of a dose-dependent hypertrophy resulting in an increase of the cross-sectional areas of both type I and type II muscle fibers and myonuclear domains. Moreover, it has been reported that AASs can increase tolerance to exercise by making the muscles more capable to overload therefore shielding them from muscle fiber damage and improving the level of protein synthesis during recovery.

Despite some therapeutic use of AASs, there is also wide abuse among athletes especially bodybuilders in order to improve their performances and to increase muscle growth and lean body mass, taking into account the significant anabolic effects of these drugs.

The prolonged misuse and abuse of AASs can determine several adverse effects, some of which may be even fatal especially on the cardiovascular system because they may increase the risk of sudden cardiac death (SCD), myocardial infarction, altered serum lipoproteins, and cardiac hypertrophy.

The aim of this review is to focus on deaths related to AAS abuse, trying to evaluate the autoptic, histopathological and toxicological findings in order to investigate the pathophysiological mechanism that underlines this type of death, which is still obscure in several aspects. The review of the literature allowed us to identify 19 fatal cases between 1990 and 2012, in which the autopsy excluded in all cases, extracardiac causes of death.

Neonatal Hypertension: An Underdiagnosed Condition, A Review Article

Advances in neonatology and intensive monitoring has increased our ability to identify and measure blood pressure in sick premature and term infants and this has contributed to an increased awareness of hypertension in the NICU. A few recent studies done by Zubrow and others have offered many new information on blood pressure values over the first month after birth and on other many intrinsic and extrinsic factors that can cause effects on the blood pressure in the neonatal period. There are no definite cut off for labelling hypertension in newborn period and also doubts are there on the pharmacological treatment. This is a field in neonatology which is least studied hence requires further inquiry. This review article will cover several aspects of neonatal hypertension like definition, normotensive data, etiology, clinical characteristics, diagnostic modalities, treatment choices and long term effect of these newborns.

Giant Pulmonary Artery Aneurysm Secondary To Patent Ductus Arteriosus: A Case Report

Aneurysms involving the main pulmonary artery and its branches are rare. Clinical experience is limited, and their management is not well established. We present the case of a 35-year-old male patient with dyspnea and hemoptysis in whom subsequent imaging studies revealed a giant pulmonary artery aneurysm associated with an uncorrected patent ductus arteriosus and Eisenmenger’s syndrome. We chose to treat the patient conservatively with medical management due to the development of Eisenmenger’s physiology while waiting for heart-lung transplantation.

Biomarkers in Lone Atrial Fibrillation-An Additional ‘Fine Tuning’ of Risk?

Lone atrial fibrillation (LAF) is generally regarded as a benign disorder that does not significantly increase the risk of thromboembolism and mortality. However, there is growing evidence that “lone” atrial fibrillation (AF) is a “heterogeneous” disorder with varying risk for thromboembolism based on the patient’s underlying cardiovascular risk factors. Blood biomarkers, including markers of myocardial strain, inflammation, endothelial injury, platelet activation, and hypercoagulability, have potential to improve our risk stratification and management of LAF.

Currently, there is a paucity of data on biomarkers in strictly defined LAF. The majority of studies that aimed to study lone atrial fibrillation excluded patients with structural heart disease, but did not exclude patients with co-existing cardiovascular risk factors such as hypertension or diabetes mellitus. Moreover, many of the studies did not exclude patients based on age, thereby increasing the likelihood of including patients with cardiovascular co-morbidities. There are currently a limited number of studies aimed to investigate the role of biomarkers in true LAF. The results are conflicting as to whether these biomarkers are associated with LAF or stroke risk. Future studies enrolling patients with true LAF using strict definition are needed. Herein, we review our current knowledge of biomarkers in association with atrial fibrillation and LAF and discuss their potential clinical utility.

Contribution of ALDH2 Polymorphism to Alcoholism-Associated Hypertension

Chronic alcohol intake is considered as an independent lifestyle factor that may influence the risk of a number of cardiovascular anomalies including hypertension. In healthy adults, binge drinking and chronic alcohol ingestion lead to the onset and development of hypertension although the precise mechanism(s) remains obscure. Although oxidative stress and endothelial injury have been postulated to play a major contributing role to alcoholism-induced hypertension, recent evidence depicted a rather unique role for the genotype of the acetaldehyde-metabolizing enzyme mitochondrial aldehyde dehydrogenase (ALDH2), which is mainly responsible for detoxifying ethanol consumed, in alcoholism-induced elevation of blood pressure. Genetic polymorphism of ALDH2 in human results in altered ethanol pharmacokinetic properties and ethanol metabolism, leading to accumulation of the ethanol metabolite acetaldehyde following alcohol intake. The unfavorable consequence of the ALDH2 variants is believed to be governed by the accumulation of the ethanol metabolite acetaldehyde. Presence of the mutant or inactive ALDH2*2 gene often results in an increased risk of hypertension in human. Such association between blood pressure and ALDH2 enzymatic activity may be affected by the interplay between gene and environment, such as life style and ethnicity. The aim of this mini-review is to summarize the possible contribution of ALDH2 genetic polymorphism in the onset and development of alcoholism-related development of hypertension. Furthermore, the double-edged sword of ALDH2 gene and genetic polymorphism in alcoholism and alcoholic tissue damage and relevant patents will be discussed.

Perinatal Heart Programming: Long-term Consequences

Objective: evaluate the relationship between impaired growth during intrauterine life and adult risk of cardiovascular disease and death. Materials: review of the most important contributions to the relationship between intrauterine fetal life and heart disease insurgence in childhood and adulthood, starting with a schematic representation of the principal steps in human heart development, discussion of the new theory on the relevance of the number of cardiomyocytes that every heart shows at birth. Results: intrauterine environment defines the epigenetic profile of newborns, with implications for the risk of developing diseases later in adult life. This means that the programming of cardiovascular risk and other pathologies, such as obesity, in adulthood takes place starting from intrauterine life. Conclusions: it can be hypothesized that by preventing and eventually treating cardiovascular diseases in the pediatric age, if these are already present in their early and/or in light forms, the long-term management of complications could be approached differently and more effectively than by postponing the treatment to adulthood. The future challenge in this fascinating field of clinical research is the discovery of the molecular mechanisms underlying the association between intrauterine growth restriction and fetal onset of adult cardiac disease, so as to make a dream come true by applying primary prevention of adult heart disease in the womb.

Peripartum Cardiomyopathy: Current State of Knowledge, New Developments and Future Directions

Peripartum cardiomyopathy (PPCM) is a form of idiopathic dilated cardiomyopathy affecting women in late pregnancy or early puerperium. Although initially described in the late 1800s, it has only recently been recognized as a distinct cardiac condition. The reported incidence and prognosis varies according to geography. The clinical course varies between complete recovery to rapid progression to chronic heart failure, heart transplantation or death. In spite of significant improvements in understanding the pathophysiology and management of the PPCM many features of this unique disease are poorly understood, including incidence, etiology, epidemiology, pathophysiology, predictors of prognosis and optimal therapy. The present article revisits these concepts and recent advances in PPCM.

Perinatal and Neonatal Outcomes of Lithium-Treated and Untreated Bipolar Women During Pregnancy: A Review of Present Literature

Many women with a bipolar disorder are in their reproductive age and will need to continue their psychopharmacological treatment during pregnancy, being abrupt discontinuation of these medications associated with an increase of the probability of relapse, high-risk behaviours, significant family dysfunction, and suicide. Lithium is a first line drug for acute and maintenance treatment of bipolar disorder. Its teratogenic and perinatal effects are controversial, so as its longterm effects on neurodevelopment of the children. Our purpose is to review the most up-to-date literature dealing with growth, neurological, cognitive and behavioural development of children exposed to Lithium in utero. A PubMed search was performed with the following keywords: bipolar disorder, Lithium, pregnancy, lactation, perinatal disease, child development. Studies were included in the review if they investigated one or more of the adverse events of interest. Of the 26 studies included in our review, some show an association between Lithium treatment and several grades of malformations (most commonly minor), both cardiac and involving other organs, and dysfunctions which are often reversible. Some studies reported no collateral effects due to in utero exposure to Lithium. Even though literature points out a slightly increased risk of major malformations due to Lithium therapy during pregnancy, the drug should not be discontinued, yet monitoring of serum Lithium levels and foetal echocardiography are recommended.

Heart Failure in South America

Continued assessment of temporal trends in mortality and epidemiology of specific heart failure in South America is needed to provide a scientific basis for rational allocation of the limited health care resources, and strategies to reduce risk and predict the future burden of heart failure. The epidemiology of heart failure in South America was reviewed. Heart failure is the main cause of hospitalization based on available data from approximately 50% of the South American population. The main etiologies of heart failure are ischemic, idiopathic dilated cardiomyopathy, valvular, hypertensive and chagasic etiologies. In endemic areas, Chagas heart disease may be responsible by 41% of the HF cases. Also, heart failure presents high mortality especially in patients with Chagas etiology. Heart failure and etiologies associated with heart failure may be responsible for 6.3% of causes of deaths. Rheumatic fever is the leading cause of valvular heart disease. However, a tendency to reduction of HF mortality due to Chagas heart disease from 1985 to 2006, and reduction in mortality due to HF from 1999 to 2005 were observed in selected states in Brazil. The findings have important public health implications because the allocation of health care resources, and strategies to reduce risk of heart failure should also consider the control of neglected Chagas disease and rheumatic fever in South American countries.

The GH/IGF-1 Axis in Chronic Heart Failure

The classic model of Chronic Heart Failure (CHF) is rooted in the overexpression of neurohormonal molecules. To complement this paradigm, increasing evidence indicates that a variety of hormones may be down-regulated in CHF patients. The list includes growth hormone (GH) and its tissue effector insulin-like growth factor-1 (IGF-1).

The GH/IGF-1 axis regulates cardiac growth, stimulates myocardial contractility, and influences the vascular system. The relationship between the GH/IGF-1 axis and the cardiovascular system has been extensively demonstrated in numerous studies in animals models and confirmed by the cardiac derangements secondary to both GH excess and deficiency in humans.

Impaired activity of the GH/IGF-1 axis in CHF has been described by several independent groups and includes a wide array of abnormalities, including low IGF-1 levels, GH deficiency (GHD), and GH resistance that may be related to the severity of heart disease. According to several observations, these derangements are associated with poor clinical status and outcome.

Since the first study of GH therapy in CHF in 1996, several placebo-controlled trials have been conducted with conflicting results. These discordant findings are likely explained by the degree of CHF-associated GH/IGF-1 impairment that may impact on individual responsiveness to GH administration.

Biological actions of GH and IGF-1, cardiovascular implication of GH deficiency and GH excess, relation between somatotrophic axis and CHF are discussed. Results from trials of GH therapy, emerging therapeutic strategies, safety issues, and lack in evidence are also reported.

Antimicrobial Drug Interactions in the Critically Ill Patients

Critically ill patients are typically polymedicated and therefore at a high risk for potential drug interactions. Clinical consequences of drugs interactions vary in severity from mild to lethal events. Since infection is an important issue in the Intensive Care Unit (ICU), a significant number of patients will receive an antimicrobial at some stage during their ICU admission. Therefore an adequate knowledge about possible interactions between antimicrobials and other drugs is necessary, since it may not only impact on the effectiveness of the antimicrobial but also in the incidence of drug adverse events.

This review describes important drug interactions involving antimicrobials in the critically ill patient.

Cellular Mechanisms for Diastolic Dysfunction in the Human Heart

Left ventricular (LV) diastolic dysfunction is an important contributor to many different cardiovascular diseases. LV diastolic dysfunction can manifest itself as slow LV relaxation, slow LV filling or high diastolic LV stiffness. Diastolic abnormalities have been described in the senescent heart, in heart failure with preserved ejection fraction (HFPEF), in diabetic cardiomyopathy, in aortic valve stenosis (AVS), in hypertrophic cardiomyopathy (HCM), as well as in Fabry disease (FD), however, exact cellular and molecular alterations behind the diastolic deterioration in these diseases are not yet completely characterized. Several studies thoroughly investigated altered cardiomyocyte function, changes of contractile myofilaments, extracellular collagen deposition and advanced glycation end products (AGEs) cross-linking in the background of diastolic dysfunction. These clinical and experimental data suggest that underlying mechanisms of LV diastolic dysfunction are divergent in different cardiac pathologies, therefore the present review aims to summarize mechanisms at the cellular level of diastolic abnormalities in various cardiovascular diseases.

Gene Therapy in Liver Diseases: State-of-the-Art and Future Perspectives

Gene therapy is a fundamentally novel therapeutic approach that involves introducing genetic material into target cells in order to fight or prevent disease. A number of different strategies of gene therapy are tested at experimental and clinical levels, including: a) replacing a mutated gene that causes disease with a healthy copy of the gene, b) inactivating a mutated gene that its improper function causes pathogenesis, c) introducing a new gene coding a therapeutic compound to fight a disease, d) introducing to the target organ an enzyme converting an inactive pro-drug to its cytotoxic metabolite. In gene therapy, the transcriptional machinery of the patient is used to produce the active factor that exerts the intended therapeutic effect, ideally in a permanent, tissue-specific and manageable way. The liver is a major target for gene therapy, presenting inherited metabolic defects of single-gene etiology, but also severe multifactorial pathologies with limited therapeutic options such as hepatocellular carcinoma. The initial promising results from gene therapy strategies in liver diseases were followed by skepticism on the actual clinical value due to specificity, efficacy, toxicity and immune limitations, but are recently re-evaluated due to progress in vector technology and monitoring techniques. The significant amount of experimental data along with the available information from clinical trials are systematically reviewed here and presented per pathological entity. Finally, future perspectives of gene therapy protocols in hepatology are summarized.

Neuroprotection and Sex Steroid Hormones: Evidence of Estradiol- Mediated Protection in Hypertensive Encephalopathy

Besides their effects on reproduction, estrogens exert neuroprotective effects for brain diseases. Thus, estrogens ameliorate the negative aspects of aging and age-associated diseases in the nervous system, including hypertension. Within the brain, the hippocampus is sensitive to the effects of hypertension, as exemplified in a genetic model, the spontaneously hypertensive rat (SHR). In the dentate gyrus of the hippocampus, SHR present decreased neurogenesis, astrogliosis, low expression of brain derived neurotrophic factor (BDNF), decreased number of neurons in the hilus and increased basal levels of the estrogen-synthesizing enzyme aromatase, with respect to the Wistar Kyoto (WKY) normotensive strain. In the hypothalamus, SHR show increased expression of the hypertensinogenic peptide arginine vasopressin (AVP) and its V1b receptor. From the therapeutic point of view, it was highly rewarding that estradiol treatment decreased blood pressure and attenuated brain abnormalities of SHR, rendering hypertension a suitable model to test estrogen neuroprotection. When estradiol treatment was given for 2 weeks, SHR normalized their faulty brain parameters. This was shown by the enhancement of neurogenesis in the dentate gyrus, according to increased bromodeoxyuridine incorporation and doublecortin labeling, decreased reactive astrogliosis, increased BDNF mRNA and protein expression in the dentate gyrus, increased neuronal number in the hilus of the dentate gyrus and a further hyperexpression of aromatase. The presence of estradiol receptors in hippocampus and hypothalamus suggests the possibility of direct effects of estradiol on brain cells. Successful neuroprotection produced by estradiol in hypertensive rats should encourage the treatment with non-feminizing estrogens and estrogen receptor modulators for age-associated diseases.

Moxifloxacin-induced Hypoglycemia in a Non-diabetic Patient

Hypoglycemia is a rare life threatening adverse drug reaction associated with various fluoroquinolones like ciprofloxacin, gatifloxacin and levofloxacin. Moxifloxacin was considered safe in this regard. Only one case has been reported for moxifloxacin-induced hypoglycemia in a renal failure patient. Here, we are reporting the second case of hypoglycemia due to moxifloxacin without any major co-morbid condition.

Lung Ultrasound in the Management of Acute Decompensated Heart Failure

Once thought impracticable, lung ultrasound is now used in patients with a variety of pulmonary processes. This review seeks to describe the utility of lung ultrasound in the management of patients with acute decompensated heart failure (ADHF). A literature search was carried out on PubMed/Medline using search terms related to the topic. Over three thousand results were narrowed down via title and/or abstract review. Related articles were downloaded for full review. Case reports, letters, reviews and editorials were excluded. Lung ultrasonographic multiple B-lines are a good indicator of alveolar interstitial syndrome but are not specific for ADHF. The absence of multiple B-lines can be used to rule out ADHF as a causative etiology. In clinical scenarios where the assessment of acute dyspnea boils down to single or dichotomous pathologies, lung ultrasound can help rule in ADHF. For patients being treated for ADHF, lung ultrasound can also be used to monitor response to therapy. Lung ultrasound is an important adjunct in the management of patients with acute dyspnea or ADHF.

Ibubrofen in the Treatment of Patent Ductus Arteriosus in Preterm Infants: What We Know, What We Still Do Not Know

The patency of the ductus arteriosus has ever been considered as a pathological situation in preterm infants and one likely cause of mortality and morbidity, including broncho-pulmonary dysplasia, necrotizing enterocolitis, intraventricular haemorrhage, retinopathy of prematurity. The incidence of patent ductus arteriosus is inversely proportional to gestational age and infants with the lowest gestational ages are the most exposed to the complications of prematurity. So, associations between patent ductus arteriosus and the other morbidities may not be causative and patent ductus arteriosus could be more a sign of immaturity and severity of disease than the cause of these problems. Non-steroidal anti-inflammatory agents, such as indomethacin or ibuprofen, have been shown to be effective in closing or preventing patent ductus arteriosus, with differences in side effects. However nearly all randomized controlled trials have been designed with the closure of the ductus arteriosus, not mortality or morbidity, as the main endpoint. Thus, evidence is still lacking on the eventual benefits for the patient of pharmacological or surgical intervention on PDA. Moreover, both ibuprofen and indomethacin efficacy seems markedly reduced in extremely low gestational age infants, who are the most likely to benefit from such intervention. The explanation of the reduced pharmacodymanic effect in such population is unclear; so far, studies using increased dosing of ibuprofen have failed to show a clear benefit. Prophylaxis with indomethacin or ibuprofen has failed to show sustained benefits on neurodevelopment at 2 years of age in low gestational age infants. New curative trials may aim at investigating the effects of early curative administration of ibuprofen, which has reduced side effects compared to indomethacin, on immature kidney function, on mortality and morbidity in very low gestational age infants, ideally with a combined endpoint such as survival in the absence of severe neurodevelopmental alteration at 2 years age. Despite an understandable reluctance given the historical background of systematic, therapeutic closure of ductus arteriosus in preterm infants, there are no definite ethical obstacles to a placebo-controlled design.

Characterization of Single Nucleotide Polymorphisms of Cytochrome P450 in an Australian Deceased Sample

The genetically variable CYP450 isozymes are responsible for the metabolism of up to 80% of commonly used drugs, many of which are detected in cases of unexpected or suspicious death in Australia. The aim of this study was to examine the genetic profiles of individuals in a cohort of Australian deceased individuals dying of drug toxicity (219), natural disease (150), external injury (109) or unascertained (8) causes, to determine if there was an over-representation of individuals with a genetic predisposition to altered drug metabolism in cases attributed to drug toxicity compared with other causes. Single nucleotide polymorphisms (SNP) of CYP1A2, 2C9, 2C19, 2D6, 3A4 and 3A5 were analyzed. There were 27 cases (6.1%) that were CYP2D6 poor metabolizers (PM) and an additional 8 cases (1.7 %) that were CYP2C19 PMs. Around 31% of the cases were CYP2D6 intermediate-poor metabolizers, with a number of cases exhibiting drug combinations that were likely to have caused pharmacokinetic or pharmacodynamic interactions. There was no correlation between cause of death type and CYP2D6 metabolizer status. Increased enzyme activity was also indicated by the presence of hyperinducible variants such as CYP1A2*1F, which was observed at a frequency of 48%.

Update on the Adverse Effects of Clozapine: Focus on Myocarditis

Clozapine, an atypical antipsychotic, is a dibenzodiazepine derivative and its therapeutic effects are probably mediated by dopaminergic and serotonergic activity. In accordance to several studies, it appears to be the most effective antipsychotic drug for treatment-resistant schizophrenia. Moreover, clozapine appears to be particularly beneficial in patients with schizophrenia who are suicidal and in those with comorbid substance use disorder. However, despite its efficacy, the general use of clozapine in clinical practice is somewhat limited because of the risk of several serious adverse effects such as agranulocytosis and thromboembolism. Clozapine may be associated with fatal myocarditis and cardiomyopathy in physically healthy young adults. Consequently, the FDA and the drug's manufacturer have strengthened warnings to include that a potentially fatal myocarditis may occur when taking clozapine. In the present paper the literature on clozapine-related myocardis will be reviewed and practical advice will be given concerning the diagnosis and management of such potentially fatal adverse effect.

The Two Faces of Iminoalditols: Powerful Inhibitors Trigger Glycosidase Activation

Understanding and controlling carbohydrate processing enzymes (CPE) have been major issues and challenges for chemists, biochemists and clinical practitioners alike. One of the most powerful families of substances for probing active sites as well as allosteric interactions with CPEs are basic sugar analogues, in particular iminoalditols. This compound class presents a basic trivalent nitrogen instead of oxygen in the sugar ring as the common feature. Depending on the task, such molecules may show two faces, acting as powerful competitive inhibitors or as folding templates for the same CPE protein. When applied at sub-inhibitory concentration iminoalditols and derivatives thereof have become attractive as pharmacological chaperones for the treatment of lysosomal storage diseases. As such these structures can restore protein activity by assisting correct folding of mutant enzymes thus facilitating transportation to the lysosome and consequently substrate hydrolysis. This review surveys iminoalditol structures which have recently been investigated as potential pharmacological chaperones for the treatment of lysosomal storage diseases.

Carbon Monoxide - Toxicity of Low-Dose Application

Carbon monoxide (CO) has long been considered a purely toxic by-product of incomplete combustion processes. Acute exposure to high concentrations of CO is one of the leading causes of fatal poisoning in industrial countries. However, after two decades of intensive research, there is ample evidence that CO endogenously produced by heme oxygenase enzymes has essential physiological functions and is of vital importance for cellular hemostasis. Furthermore, exogenously applied CO in low concentrations mediates potent cytoprotective effects. An overwhelming number of different in vitro and in vivo models demonstrated the protective action of CO application, e.g., in ischemia/reperfusion, transplantation, oxidative stress, inflammation, and others. Protection by this gaseous molecule could be illustrated for most organs, most species, and for different routes of administration. Now being on the verge of entering clinical trials, the question emerges whether the administration of low-dose CO would be safe for patients when used as a potential therapeutic. Therefore, this review summarizes in particular toxicological data obtained from low-dose CO exposure and discusses its impact on a possible clinical application.

Health Benefits of Honey: Implications for Treating Cardiovascular Diseases

Honey offers many medicinal uses described in traditional medicine, in addition to just commonly being used as a sweetener. The composition of honey varies depending on the floral source, seasonal and environmental factors, as well as processing techniques used. Honey is rich in phenolic acids and flavonoids, and exhibits a broad spectrum of biological activities. It has been hypothesized that honey contributes to the reduction in cardiovascular diseases mainly due to flavonoid-mediated antioxidant, anti-inflammatory, immunomodulatory, and antimicrobial activities. The consumption of natural honey has been shown to inhibit oxidation of low density protein, vasodialate blood vessels due to nitric oxide production, decrease platelet aggregation, and exert analgesic and anti-atherogenic effects; each of which may decrease cardiovascular risk. This overview explores the potential therapeutic role of honey in treating cardiovascular diseases, mainly focusing on its potential molecular mechanism(s) underlying flavonoid-mediated actions that may be cardioprotective. However, well designed, double blind, clinical trials on a large scale are needed to confirm therapeutic efficacy of honey in humans.

Selective Peroxisome Proliferator-Activated Receptor-γ Modulation to Reduce Cardiovascular Risk in Patients with Insulin Resistance

The thiazolidinediones (TZDs) rosiglitazone and pioglitazone improve glucose homeostasis through activation of peroxisome proliferator-activated receptor (PPAR)-γ. Their use, however, has been limited due to adverse effects that include body weight gain and edema leading to congestive heart failure. Selective PPAR-γ modulators (SPPARMs) are second generation PPAR-γ ligands designed to improve insulin sensitivity with minimal undesirable effects associated with first generation PPAR-γ agonists. INT131 is one of the first SPPARMs to reach human trials. Early phase human studies with INT131 look promising with changes in plasma lipids and glucose being equal or better than what is seen with rosiglitazone and pioglitazone treatment but without evidence of edema. This profile of improved glucose homeostasis, improved plasma lipids, and reduced inflammation in the absence of edema would be expected to reduce cardiovascular risk in patients with Type 2 diabetes mellitus. Recent patents of novel approaches for the use of PPAR-γ related compounds with the potential for this improved risk-benefit ratio are discussed.

Cardiotoxicity of Molecularly Targeted Agents

Cardiac toxicity of molecularly targeted cancer agents is increasingly recognized as a significant side effect of chemotherapy. These new potent therapies may not only affect the survival of cancer cells, but have the potential to adversely impact normal cardiac and vascular function. Unraveling the mechanisms by which these therapies affect the heart and vasculature is crucial for improving drug design and finding alternative therapies to protect patients predisposed to cardiovascular disease. In this review, we summarize the classification and side effects of currently approved molecularly targeted chemotherapeutics.

Value of Carnitine Therapy in Kidney Dialysis Patients and Effects on Cardiac Function from Human and Animal Studies

Cardiovascular complications are the leading cause of mortality, accounting for 50% of all deaths among patients with end-stage renal disease (ESRD). The majority of these deaths are from cardiac causes. The mechanisms underlying the enhanced susceptibility to myocardial ischaemia and subsequent morbidity in ESRD remain ill-defined. Numerous metabolic derangements accompany myocardial ischaemia and reperfusion and play a pivotal role in the development of concurrent myocardial dysfunction. Carnitine plays a critical role in myocardial energy metabolism, as the transporter of long chain fatty acyl intermediates across the inner mitochondrial membrane for β oxidation and as a central regulator of carbohydrate metabolism. Myocardial carnitine is significantly depleted during ischaemia and more particularly in uraemic patients and those on dialysis therapy. Carnitine treatment has cardiovascular benefits including modulation of myocardial metabolism, reduction in necrotic cell death and infarct size, decrease in the incidence of arrhythmias and preservation of mechanical function. This review details the profile of substrate metabolism in the uraemic heart and the impact of carnitine supplementation on metabolism and function of the reperfused heart and finally the experimental and clinical evidence for carnitine replacement therapy, in particular its impact on the uraemic heart via modulation of function and energetics.

Current Pharmacologic Management of Pediatric Heart Failure in Congenital Heart Disease

Pharmacologic therapy represents the mainstay of treatment for heart failure in children. However, medical therapy for this population is not widely standardized. This is mainly due to the heterogeneity of potential etiologies, the specific challenge of patients with univentricular physiology and the lack of evidence-based prospective randomized clinical trials in pediatric patients. In fact, most current strategies are based largely on extrapolated data from adult studies. Although the classic drugs for heart failure i.e. diuretics, angiotensin-converting enzyme inhibitors, β-blockers and cardiac glycosides, still play a major role in the treatment of pediatric heart failure, newer alternative therapies such as levosimendan and nesiritide are increasingly utilized with promising early results. A systematic literature search of PubMed and MEDLINE databases using relevant terms was performed. All clinical trials and relevant manuscripts about the current pharmacologic treatment of heart failure in the pediatric population were reviewed. New drugs such as levosimendan and nesiritide and the treatment of single-ventricle patients were also included.

Pompe Disease: From New Views on Pathophysiology to Innovative Therapeutic Strategies

Pompe disease (PD) is a metabolic myopathy caused by the deficiency of the lysosomal hydrolase acid α- glucosidase (GAA) and characterized by generalized glycogen storage. Heterogeneous GAA gene mutations result in wide phenotypic variability, ranging from the severe classic infantile presentation to the attenuated intermediate and late-onset forms. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) is at present the only approved treatment for PD, in addition to supportive and physical therapies. However, ERT shows limited efficacy in some patients and does not completely correct the disease phenotype. Recently, an improved knowledge of PD pathophysiology has provided clues to explain the limitations of ERT. A mechanical effect of lysosomal inclusions on muscle contractility has been proposed as a key factor of disease resulting in a severe loss of contractility. In addition, it has been shown that secondary abnormalities of housekeeping cellular functions, such as autophagy, have an important role in the pathogenesis of cell damage in PD. Abnormalities of intra-cellular trafficking of vesicles and membrane-bound proteins, such as the cation-independent mannose-6-phosphate receptor, may be deleterious for the efficacy of ERT. At present, new therapeutic strategies, in addition to ERT, are under investigation. An emerging strategy for the treatment of PD is pharmacological chaperone therapy, based on the use of chaperone molecules that assist the folding of mutated enzymes and improve their stability and lysosomal trafficking. Pre-clinical studies demonstrated a synergistic effect of pharmacological chaperones and ERT. Other approaches, also in a pre-clinical stage, include substrate reduction and gene therapy.

Peripartum Cardiomyopathy: An Intensivist's Perspective

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

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

Heart Disease Induced by AAS Abuse, Using Experimental Mice/Rats Models and the Role of Exercise-Induced Cardiotoxicity

The anabolic-androgenic steroids (AAS) are all synthetic derivates of testosterone and are commonly used as sport performance enhancers in athletes. The heart is one of the organs most frequently affected by administration of anabolic steroids. A direct myocardial injury caused by AAS is supposed to determine marked hypertrophy in myocardial cells, extensive regional fibrosis and necrosis. A number of excellent studies, using animal models, were performed to evaluate the cardiac effects of AAS. It is known that exogenous administration induced cardiac hypertrophy in vitro and in vivo, and when combined with exercise, anabolic steroid use has been shown to change exercise-induced physiological cardiac hypertrophy to pathophysiological cardiac hypertrophy. However the molecular mechanisms are still poorly understood. Its described that sudden cardiac death, myocardial infarct; ventricular remodelling and cardiomyopathy do to AAS is related to apoptosis and oxidative stress when associated with exercise. Mechanical stimuli and circulating humoral factors (TNF-α, HSP-70, IL-1β) released by the heart and peripheral organs are responsible.

Testosterone and derivates can work through genomic (activation of specific androgen receptor, interaction with coactivators and co-repressors transcription factors, gene regulation) and non-genomic mechanism (membrane-receptorsecond messenger cascades).

Chronic AAS abuse results in different patterns of pathologic alterations, which depend on type, dose, frequency, and mode of use. The difficulty in interpreting experimental data on animals (mice and rats) lies in the diversity of experiments (the diversity of substances, which show different properties, different mice / rats by sex and age, duration of treatment with AAS, dosages used, type, scope and exercise duration).

NK-1 Receptor Antagonists: A New Paradigm in Pharmacological Therapy

The neuropeptide substance P (SP) shows a widespread distribution in both the central and peripheral nervous systems and it is known that after binding to the neurokinin-1 (NK-1) receptors, SP regulates many biological functions in the central nervous system such as emotional behaviour, stress, depression, anxiety, emesis, migraine, alcohol addiction and neurodegeneration. SP has been also implicated in pain, inflammation, hepatotoxicity and in virus proliferation, and it plays an important role in cancer (e.g., tumour cell proliferation, angiogenesis, and the migration of tumour cells for invasion and metastasis). By contrast, it is known that after binding to NK-1 receptors, NK-1 receptor antagonists specifically inhibit the above-mentioned biological functions mediated by SP. Thus, these antagonists exert an anxyolitic, antidepressant, antiemetic, antimigraine, antialcohol addiction or neuroprotector effect in the central nervous system, and they play a role in analgesic, antiinflammatory, hepatoprotector processes and in antivirus proliferation. Regarding cancer, NK-1 receptor antagonists exert an antitumour action (inducing tumour cell death by apoptosis), and induce antiangiogenesis and inhibit the migration of tumour cells. It is also known that NK-1 receptors have a widespread distribution and that they are overexpressed in tumour cells. Thus, NK-1 receptor antagonists are molecularly targeted agents. In general, current drugs have a single therapeutic effect, although less commonly they may exert several. However, the data reported above indicate that NK-1 receptor antagonists are promising drugs, exerting many therapeutic effects (the action of such antagonists is dose-dependent and, depending on the concentration, has more positive effects). In this review, we update the multiple therapeutic effects exerted by NK-1 receptor antagonists.

Pulmonary Complications After Congenital Heart Surgery

Pulmonary complications are the most common causes of morbidity and mortality in the postoperative period after congenital heart surgery. In this review we discuss the diverse pathological mechanisms that contribute to these pulmonary complications. Both mechanical and gas exchange abnormalities result in increased ventilatory requirements, ICU stay and mortality. Parenchymal lung disease can be caused by a variety of conditions including nosocomial pneumonia, atelectasis and use of cardiopulmonary bypass. Direct surgical trauma to the respiratory system can result in diaphragmatic paralysis, chylothorax, subglottic stenosis or vocal cord paralysis. Disturbances in the pulmonary vasculature can also trigger complications including pulmonary embolism, plastic bronchitis and even pulmonary hypertensive crises in certain at risk populations. Close monitoring with early detection and treatment of complications often prevents prolonged ventilation and hospitalization, e.g., cases of chylothorax where early intervention is beneficial. However, the therapies used to manage some of these complications in the pediatric population are nonspecific and varied e.g., therapies for postoperative atelectasis or treatment of plastic bronchitis. There is a paucity of studies that directly address therapy for many of these complications and more randomized controlled trials in the pediatric population are needed.

Complications of the Chest Wall and the Respiratory System After Surgery and Functional Performance

In a population of patients after successful heart surgery for congenital heart defects (CHD) might emerge noncardiac morbidities. Malfunction of the respiratory system (RS) including chest wall deformities (CWD) may represent risk for a long-term functional performance and QoL of these subjects. This review aims for the long-term (abnormal pulmonary hemodynamics prior to surgery) or short-term (e.g. thoracotomy) harmful impacts on the developing RS. CHD with redundant lung recoil may induce dramatic worsening of the mechanical properties of the RS. Despite successful repair of CHD harmful and successive adaptive processes may affect future development of the RS. Surgical treatment of CHD requires thoracic wall incision (median sternotomy or lateral thoracotomy), which currently with other perioperative impacts may represent unfavourable formation of CWD. Surprisingly, heart surgery itself does not lead either to an improvement or marked change in the severity or frequency of preoperative lung abnormalities (mostly lung volume restriction, hyperinflation, stiff lung or airway obstruction). Causes of RS dysfunction and CWD in patients after surgical repair of CHD are multifactorial. Therefore, a management of these abnormalities especially in adult and aged CHD is difficult. The early primary repair of CHD and recent interventional approaches (e.g., superior ministernotomy or usage of Amplatz occluder) may provide advantages regarding developing organ systems and prevent secondary changes of the heart and the RS. Further research should focus on individual factors in the development of CWD and postoperative respiratory changes. Long-term and/or probably permanent follow up of subjects after CHD repair is a must.

Calcium Related Genes in Dogs as Potential Cardiac Biomarkers for the Detection of Chronic Mitral Valve Disease

Chronic mitral valvular insufficiency (CMVI) is probably the most common cause of congestive heart failure (CHF) in dogs. Although, recent advances in veterinary diagnostic imaging technology have enabled us to detect CHF earlier and more accurately, the accuracy and reliability of this technology heavily hinders on the experience and skill of the operator. Assays for cardiac biomarkers are a reliable method for the detection and evaluation of cardiac diseases in humans and dogs. Although, several cardiac biomarkers have been used and being widely used in small animal practice, several problems are encountered and hinders the clinical application of cardiac biomarker assays in small animal practice. Therefore, recent studies focus on developing new type of cardiac biomarkers, which can overcome limitations of pre-existing markers such as NT-pro BNP, cardiac troponins. This review focused on new cardiac biomarkers and patents about calcium related genes involving in myocardial contraction in dogs.

The Adult Patient with Eisenmenger Syndrome: A Medical Update After Dana Point Part I: Epidemiology, Clinical Aspects and Diagnostic Options

Eisenmenger syndrome is the most severe form of pulmonary arterial hypertension and arises on the basis of congenital heart disease with a systemic-to-pulmonary shunt. Due to the chronic slow progressive hypoxemia with central cyanosis, adult patients with the Eisenmenger syndrome suffer from a complex and multisystemic disorder including coagulation disorders (bleeding complications and paradoxical embolisms), renal dysfunction, hypertrophic osteoarthropathy, heart failure, reduced quality of life and premature death. For a long time, therapy has been limited to symptomatic options or lung or combined heart-lung transplantation. As new selective pulmonary vasodilators have become available and proven to be beneficial in various forms of pulmonary arterial hypertension, this targeted medical treatment has been expected to show promising effects with a delay of deterioration also in Eisenmenger patients. Unfortunately, data in Eisenmenger patients suffer from small patient numbers and a lack of randomized controlled studies. To optimize the quality of life and the outcome, referral of Eisenmenger patients to spezialized centers is required. In such centers, specific interdisciplinary management strategies of physicians specialized on congenital heart diseases and PAH should be warranted. This medical update emphasizes the current diagnostic and therapeutic options for Eisenmenger patients with particularly focussing on epidemiology, clinical aspects and specific diagnostic options.

Malignant Hypertension: A Rare Problem or is it Underdiagnosed?

Malignant hypertension (MHT) is the most severe form of hypertension which is clinically defined as the presence of high blood pressure in association with bilateral retinal haemorrhages and/or exudates, with or without papilloedema. The aim of this review article is to discuss whether MHT is a problem which is truly becoming a rarity, or is it simply a problem with underdiagnosis. Despite the improvements in the general management of hypertension, we have no strong evidence of a declining incidence of MHT. In contrast, this disorder may appear to become even more common worldwide taking into account the growing hypertensive population in the developing countries. Although the diagnostic criteria of MHT appear to be simple and straightforward, the prompt diagnose of MHT may be difficult in substantial proportion of patients who often present with clinical symptoms only at a late stage of irreversible target organ changes. Furthermore, MHT and the accompanying ocular changes may gradually resolve making retrospective diagnosis problematic, whilst persistent target organ damage can drive the development of complications and have a negative prognosis in these patients. Clearly, MHT should not yet be forgotten nor ignored by clinicians.

Recent Advances and Patents on Coronary Sinus Perfusion Devices for Treatment of Heart Disease

The concepts of arterialization of the coronary venous system and retrograde coronary sinus (CS) perfusion in clinical and experimental studies have inspired novel devices aiming for myocardial preservation and function improvement, especially in ischemic hearts. Based on these concepts, several patented devices using the CS have been developed to improve cardiac function in patients with heart disease. There are three main types of CS perfusion devices: the arterial- CS (A-CS) shunt, left ventricle-CS (LV-CS) shunt, and pressure-controlled CS occlusion device. In addition, catheters are used for drug delivery into the CS. Most of these devices are implanted percutaneously or by means of minimally invasive surgery. By avoiding the need for cardiopulmonary bypass, these devices offer a competitive treatment option for heart disease. This article reviews some CS devices in terms of methods of use and therapeutic concepts.

MDMA Toxicity and Pathological Consequences: A Review About Experimental Data and Autopsy Findings

Studies conducted in humans or in animals explored the presence, nature and potential causes of 3,4- methylenedioxymethamphetamine (MDMA) toxicity. According to literature, there are four principal types of such serious toxicity: hepatic, cardiovascular, cerebral and hyperpyrexic. The molecular mechanisms involved in the genesis of these toxic effects are not yet fully clarified, but the oxidative stress, excitotoxicity, and mitochondrial dysfunction appear to be causal events that converge to mediate MDMA-induced toxicity. Studies conducted on animals demonstrated that the acute administration of MDMA elicits cardiovascular responses that are similar to those elicited by d-amphetamine, and that these responses appear to involve catecholaminergic and non-catecholaminergic-dependent mechanisms. Although there is undeniable evidence of MDMA-induced cardiac toxicity, the mechanism responsible remains to be clarified. While many reports both in humans and in animals have demonstrated MDMA-induced liver damage, the underlying mechanism accounting for hepatic toxicity is poorly understood. Various mechanisms may contribute to MDMA-induced liver toxicity, including the metabolism of MDMA, the increased efflux of neurotransmitters, the oxidation of biogenic amines, and hyperthermia. The molecular mechanisms involved in the genesis of these toxic effects are not yet fully clarified, but the oxidative stress, excitotoxicity, and mitochondrial dysfunction appear to be causal events that converge to mediate MDMA-induced neurotoxicity, as measured by loss of various markers of dopaminergic and serotonergic terminals. The evidence is overwhelming that MDMA produces acute and long-lasting toxic anatomic effects in animals and humans. Anatomical and functional MDMA consequences must be better understood.

Systemic Lupus Erythematosus-Related Interstitial Lung Disease

Systemic lupus erythematosus (SLE) is a systemic, inflammatory disorder with a predilection for young women. A wide array of pulmonary manifestations can occur in patients with SLE, including interstitial lung disease. In this review, we will discuss the scope, pathogenesis, management, and prognosis, along with the clinical and pathologic features of SLE-associated ILD (SLE-ILD).

A Review of Maternal and Fetal Growth Factors in Diabetic Pregnancy

Diabetes mellitus complicates 1-2% of all pregnancies but is associated with high a perinatal morbidity and mortality. Gestational diabetes affects up to 4% of pregnancies and is associated with foetal macrosomia (large for dates). Foetal growth is a complex process influenced by genetics, maternal factors, uterine environment and maternal and foetal hormonal status. Infants of pre-gestational diabetic mothers have an additional influence of maternal fluctuations in glycaemia. The purpose of this paper is to review maternal and foetal growth factors, including insulin, in the aetiology of macrosomia in diabetic pregnancy. Placental Growth Hormone is the major growth hormone secreted during human pregnancy. Leptin may have a role in satiety. Resistin was originally proposed as the link between obesity and diabetes but is now thought to have a more complex role. These hormones and their actions on human foetal growth are reviewed in depth with particular reference to both pre-gestational (type 1 and type 2 diabetes) and gestational diabetes. Previously, increased foetal weight in infants of diabetic mothers was thought to be as a result of maternal hyperglycaemia. It is now evident that the control of foetal growth, in normal as well as diabetic pregnancies, is far more complex than previously understood.

Myocardial Inflammation in Autoimmune Diseases: Investigation by Cardiovascular Magnetic Resonance and Endomyocardial Biopsy

Introduction: Myocardial inflammation often coexists with different types of autoimmune diseases. Our aim was to investigate the presence of myocarditis in these patients by Cardiovascular Magnetic Resonance (CMR) and endomyocardial biopsy. Patients-Methods: Twenty patients, aged 20-55 yrs with autoimmune diseases and cardiac symptoms (3 with Takayasus arteritis, 3 with systemic lupus erythematosus, 5 with rheumatoid arthritis, 7 with autoimmune thyroid disease and 2 with systemic sclerosis) and 20 patients with the same autoimmune diseases but without cardiac symptoms (controls) were studied. The presence of myocarditis and LV function were evaluated by CMR. Myocarditis was documented using T2- weighted (T2-W), T1-weighted (T1-W) before and after contrast media injection and late enhanced images. In 10 patients (positive for myocarditis by CMR with either low LVEF or recent increase in troponin), endomyocardial biopsy was also performed. Myocardial specimens were evaluated by histology and polymerase chain reaction techniques (PCR). Results: Myocarditis was identified in 18/20 patients by CMR. In the T2-W images the signal ratio of myocardium to skeletal muscle was 1.89±0.25 (control values 1.57±0.13, p < 0.05). From the T1-W images the relative myocardial enhancement was 11.31±11.18 (control values 3.09±0.05, p < 0.05). Epicardial late gadolinium enhanced areas were identified in 18/20. In myocardial specimens, histology revealed inflammation in 5/10 (50%) and PCR documented viral or microbial genomes in 8/10 (80%). Positive histology and PCR were in agreement with 50% and 80% of positive CMR examinations, respectively. Herpes virus was identified in 3/10, Adeno in 1/10, Coxsackie B6 in 1/10, echo in 1/10, Parvo-B19 in 3/10, CMV in 1/10 and Chlamydia trachomatis in 8/10. Conclusions: Myocardial inflammation is a common finding in patients with autoimmune diseases and cardiac symptoms. The diagnosis can be confirmed by CMR, which is a noninvasive and reliable tool for the investigation of these patients.

The GH/IGF-1 Axis and Heart Failure

The growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis regulates cardiac growth, stimulates myocardial contractility and influences the vascular system. The GH/IGF-1 axis controls intrinsic cardiac contractility by enhancing the intracellular calcium availability and regulating expression of contractile proteins; stimulates cardiac growth, by increasing protein synthesis; modifies systemic vascular resistance, by activating the nitric oxide system and regulating non-endothelial-dependent actions. The relationship between the GH/IGF-1 axis and the cardiovascular system has been extensively demonstrated in numerous experimental studies and confirmed by the cardiac derangements secondary to both GH excess and deficiency. Several years ago, a clinical non-blinded study showed, in seven patients with idiopathic dilated cardiomyopathy and chronic heart failure (CHF), a significant improvement in cardiac function and structure after three months of treatment with recombinant GH plus standard therapy for heart failure. More recent studies, including a small double-blind placebo-controlled study on GH effects on exercise tolerance and cardiopulmonary performance, have shown that GH benefits patients with CHF secondary to both ischemic and idiopathic dilated cardiomyopathy. However, conflicting results emerge from other placebo-controlled trials. These discordant findings may be explained by the degree of CHF-associated GH resistance. In conclusion, we believe that more clinical and experimental studies are necessary to exactly understand the mechanisms that determine the variable sensitivity to GH and its positive effects in the failing heart.

Cardiac Amyloidosis Responding to Bortezomib: Case Report and Review of Literature

We report a case of a 53-year old patient with symptoms of congestive heart failure in whom a restrictive cardiomyopathy and a kappa-chain monoclonal gammopahty were diagnosed. Treatment with eight cycles of Bortezomib, a proteasome inhibitor, resulted in a significant regression of myocardial amyloid deposition and a notable clinical and hemodynamic improvement. Over the last few years, the management of cardiac amyloidosis has taken advantage of many of the advances of the chemotherapeutic regimens, as well as the wider availability of stem cell transplantation. The management of cardiac amyloidosis is also expected to evolve and improve with the better understanding of the specific mechanisms of amyloidogenesis and myocardial deposition. This will probably make certain molecules targeting specific sites in this process, as potentially effective and minimally toxic compared therapy with the currently used ones. In this article, we describe one of the first reported cases of cardiac amyloidosis, successfully treated with Bortezomib. We describe and discuss the mechanisms of action of Bortezomib and provide a detailed review of cardiac amyloidosis, from pathophysiology to diagnosis and treatment.

Respiratory Tract Manifestations of Rheumatic Diseases in Children

Frequency and type of respiratory manifestations differ among individual rheumatic diseases in childhood as well as among children and adults. It is important to recognise respiratory complications of established diseases like juvenile systemic lupus erythematosus or dermatomyositis early enough to prevent serious disease outcomes. Nevertheless, it is of the same importance to reveal unusual characteristics of respiratory symptoms which rheumatic disease may present with, like in Wegeners granulomatosis. Therefore high degree of suspicion and good access to specialised paediatric care including paediatric rheumatology and intensive care units are often of vital importance. In this review respiratory symptoms are summarised firstly by anatomical location of affected area and secondly by individual rheumatic diseases. Where applicable, differences between paediatric and adult disease are shown and main diagnostic and therapeutic principles overviewed. Disease spectrum covers juvenile idiopathic arthritis, juvenile systemic lupus erythematosus and dermatomyositis, systemic scleroderma and primary systemic vasculitides.

New Perspectives of Infections in Cardiovascular Disease

Infections have been recognized as significant causes of cardiac diseases for many decades. Various microorganisms have been implicated in the etiology of these diseases involving all classes of microbial agents. All components of the heart structure can be affected by infectious agents, i.e. pericardium, myocardium, endocardium, valves, autonomic nervous system, and some evidence of coronary arteries. A new breed of infections have evolved over the past three decades involving cardiac implants and this group of cardiac infectious complications will likely continue to increase in the future, as more mechanical devices are implanted in the growing ageing population. This article will review the progress made in the past decade on understanding the pathobiology of these infectious complications of the heart, through advances in genomics and proteomics, as well as potential novel approach for therapy. An up-to-date, state-of-the-art review and controversies will be outlined for the following conditions: (i) perimyocarditis; (ii) infective endocarditis; (iii) cardiac device infections; (iv) coronary artery disease and potential role of infections.

Novel Strategies for the Detection of Systolic and Diastolic Heart Failure

The incidence and prevalence of dyspnea increases with age. Frequently, for the general practitioner with his limited diagnostic facilities, it is impossible to separate dyspnea from cardiac causes and non-cardiac causes. Without cardiac imaging it is also impossible to separate systolic dysfunction from diastolic dysfunction. After a thorough physical examination, initial screening of systolic and diastolic heart failure can be done by measurement of plasma NT-pro BNP or plasma BNP. Additionally a Chest X-Ray or ECG can be performed. To improve diagnostic performance an open access echocardiographic service can be initiated. Recent studies showed, that open access echocardiography can easily detect systolic and diastolic dysfunction in the community and can separate cardiac from non-cardiac dyspnea.

Irreversible Inhibition of Serine Proteases – Design and In Vivo Activity of Diaryl α-Aminophosphonate Derivatives

Diaryl esters of α-aminophosphonates are a group of low molecular weight inhibitors of serine proteases. For over 30 years these molecules have captured the attention of biochemists and medicinal chemists due to their similarity to the transition state of peptide bond cleavage observed in enzymatic reactions (transition state analogs) as well as their high potency of action. High reactivity toward serine proteases and complete lack of activity against cysteine or threonine proteases give α-aminophosphonates great advantage over other classes of inhibitors such as chloromethyl ketones or peptidyl derivatives of ketoesters and ketoamides, which are known to react with serine and cysteine proteases. Moreover, the selectivity of α-aminophosphonates action can be easily adjusted – even for serine proteases with similar specificity a small modification in the inhibitor structure could lead to absolute selectivity towards a particular enzyme. Furthermore α- aminophosphonate derivatives are successfully used as the activity based probes (ABP) for serine protease-like activity screening and as covalently reactive antigens for the development of catalytic antibodies (CAbs). The design of α-aminophosphonate diaryl ester inhibitors focuses on enzymes involved in the development and progression of pathophysiological states in living organisms. Examples include cancer growth and metastasis (urokinase-type plasminogen activator, uPA), diabetes or transplant rejection (dipeptidyl peptidase IV, DPPIV), osteoarthritis and lung injury (elastase) or heart failure (mast cell chymase). This review article focuses on the design of new α-aminophosphonic inhibitors as well as on in vivo studies performed previously using this class of inhibitors and includes recently published research data.

Kawasakis Disease, Acrodynia, and Mercury

A superantigen or autoimmunity has been hypothesized to be the main cause of the Kawasakis Disease but the etiology is unknown. Medical literature, epidemiological findings, and some case reports have suggested that mercury may play a pathogenic role. Several patients with Kawasakis Disease have presented with elevated urine mercury levels compared to matched controls. Most symptoms and diagnostic criteria which are seen in children with acrodynia, known to be caused by mercury, are similar to those seen in Kawasakis Disease. Genetic depletion of glutathione S-transferase , a susceptibility marker for Kawasakis Disease, is known to be also a risk factor for acrodynia and may also increase susceptibility to mercury . Coinciding with the largest increase (1985-1990) of thimerosal (49.6% ethyl mercury) in vaccines, routinely given to infants in the U.S. by 6 months of age (from 75μg to 187.5μg), the rates of Kawasakis Disease increased ten times, and, later (1985-1997), by 20 times. Since 1990 88 cases of patients developing Kawasakis Disease some days after vaccination have been reported to the Centers of Disease Control (CDC) including 19% manifesting symptoms the same day. The presented pathogenetic model may lead to new preventive- and therapeutic strategies for Kawasakis disease.

Peroxisome Proliferator-Activated Receptor γ Agonists as Insulin Sensitizers: From the Discovery to Recent Progress

An epidemic of metabolic diseases including type 2 diabetes and obesity is undermining the health of people living in industrialized societies. There is an urgent need to develop innovative therapeutics. The peroxisome proliferatoractivated receptor γ (PPARγ) is one of the ligand-activated transcription factors in the nuclear hormone receptor superfamily and a pivotal regulator of glucose and lipid homeostasis. The discovery of PPARγ as a target of multimodal insulin sensitizers, represented by thiazolidinediones (TZDs), has attracted remarkable scientific interest and had a great impact on the pharmaceutical industry. With the clinical success of the PPARγ agonists, pioglitazone (Actos) and rosiglitazone (Avandia), development of novel and potent insulin-sensitizing agents with diverse clinical profiles has been accelerated. Currently, a number of PPARγ agonists from different chemical classes and with varying pharmacological profiles are being developed. Despite quite a few obstacles to the development of PPAR-related drugs, PPARγ-targeted agents still hold promise. There are new concepts and encouraging evidence emerging that suggest this class can yield improved anti-diabetic agents. This review covers the discovery of TZDs, provides an overview of PPARγ including the significance of PPARγ as a drug target, describes the current status of a wide variety of novel PPARγ ligands including PPAR dual and pan agonists and selective PPARγ modulators (SPPARγMs), and highlights new approaches for identifying agents targeting PPARγ in the treatment of type 2 diabetes.

The Cardiac Microvasculature in Hypertension, Cardiac Hypertrophy and Diastolic Heart Failure

Recent studies revealed an exceedingly high mortality with diastolic heart failure that was previously regarded as relatively benign compared to systolic heart failure. Prominent risk factors for diastolic heart failure are increasing age, hypertension and diabetes. These risk factors are associated with coronary microvascular rarefaction and resultant decreased coronary flow reserve, thereby rendering the myocardium vulnerable to ischemia. We discuss the importance of angiogenic gene programming in preserving the coronary microvasculature, preserving cardiac function and altering disease course. Further, we discuss the possible utility of therapies that activate hypoxia inducible factor-1 in preventing rarefaction of the coronary microvasculature and maintaining cardiac diastolic function.

Cardiac Metabolism in Diabetes Mellitus

Diabetes mellitus is one of the most common chronic illnesses throughout the world. Diabetic cardiomyopathy is a specific syndrome, consisting of cardiomegaly, left ventricular dysfunction, electrical remodeling of the ventricle, and symptoms of congestive heart failure, that is seen in diabetic patients in the absence of other predisposing factors. Many researchers have suggested that inhibition of the renin-angiotensin-aldosterone system and the sympathetic nervous system may exert a therapeutic effect in individuals with diabetic cardiomyopathy. Indeed, angiotensin II and aldosterone blockade may be effective, partly because aldosterone blockade down-regulates Na+/H+ exchanger 1 activity. Further study of the alterations in ion channel physiology in the context of diabetic cardiomyocytes may be of benefit.

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

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

A Murine Model of Vasculitis Induced by Fungal Polysaccharide

CAWS is a mannoprotein-beta-glucan complex obtained from the culture supernatant of the fungal pathogen Candida albicans. CAWS exhibits various biological activities, and induces prominent vasculitis of the aortic valve and the coronary arteries in mouse. A significant difference was noted in the susceptibility to and the degree of vasculitis induction among mouse lines. The difference in cytokine production among mouse lines may be strongly related to that difference, namely, IL-6, IFN-γ and TNF-α presumably act as positive factors, and IL-10, as a negative regulator. On the other hand, as a structural component of the inducing substance, the presence or absence of β-1,2-mannose residues was suggested to be closely related to the activity. An understanding of the molecular mechanisms underlying this model could lead to the conquest of many modern diseases. This model is also expected to be useful for the development of new therapeutic drugs for vasculitis and cardiovascular diseases.

From Dual Peroxisome Proliferator Activated Receptor Agonists to Selective Peroxisome Proliferator Activated Receptor Modulators

Worldwide epidemic of type 2 diabetes mellitus, obesity, dyslipidemia, hypertension and atherosclerosis (i.e. metabolic syndrome) still requires further treatment strategies. Life style change can be regarded as single evidenced option to manage these co-morbid conditions, at the same time. Peroxisome proliferator activated receptors (PPARs) are claimed to play critical roles in metabolic adaptation to changing environmental factors. PPAR alpha and gamma agonists are approved as hypolipidemic and antidiabetic agents, respectively. Combination of PPAR alpha and gamma agonistic effects in a single molecule (i.e. dual PPAR agonists) has been tried to achieve a better multiple cardiovascular risk management. Despite their efficacy, dual PPAR agonists has been discontinued due to safety concerns. New generation of PPAR ligands with a higher safety profile is being actively investigated. Here, we review pursuits for a new PPAR class, and discuss the potential role for selective peroxisome proliferator activated receptor modulators (SPPARMs) as new patented molecules. This article also includes recent patents on this topic.

Perioperative Considerations in Patients with Obstructive Sleep Apnea

Patients with obstructive sleep apnea (OSA) are at increased risk to sustain adverse events during the perioperative period including difficulty with airway control, hypoxemia, airway obstruction requiring reintubation, arrhythmias, myocardial ischemia, and death. Numerous factors appear to be responsible for these consequences, including the effects of anesthetic agents, narcotics, postoperative supine positioning and, in some cases, the surgical intervention itself. The situation is complicated by the fact that most patients with OSA are undiagnosed and there is often insufficient time for adequate evaluation prior to surgery. Perioperative care providers need to maintain a high index of suspicion for OSA and should consider guidelines to help with the recognition and management of these patients. This review will discuss the available literature regarding the preoperative, intraoperative and postoperative evaluation and management of patients with known or suspected OSA undergoing surgery.

Management of Hypertension in Relation to Acute Coronary Syndromes and Revascularisation

In patients with acute coronary syndromes (ACS), hypertension is common. The type of ACS and severity of hypertension would determine the treatment algorithm. In ST elevation myocardial infarction (MI), time to reperfusion is essential whereas in malignant hypertension the reduction of blood pressure to prevent end organ damage is the priority. Many therapeutic drugs available for ACS and hypertension are commonly used to treat both these conditions simultaneously. Once the ACS is treated medically, revascularization therapy is likely to be considered. Importantly, optimization of hypertension management may prevent subsequent complications. In this review, we discuss the frequency of hypertension and ACS as single clinical conditions, as well as combined presentations. The pathophysiology of myocardial perfusion in hypertensive patients and the effect of blood pressure (BP) normalization is discussed. This review focuses on treatment strategies from a non-interventional and interventional perspective. Finally, current medications used in treating hypertension in ACS will be compared with regards to their mode of action and prognostic value.

Long-Term Effects of Perinatal Glucocorticoid Treatment on the Heart

Chronic lung disease in the extremely preterm baby is still a major complication in neonatal intensive care. Perinatal (ante- and neonatal) glucocorticoids are widely used to prevent severe infant respiratory distress syndrome and/or to reduce chronic lung disease respectively. A review of the literature regarding the cardiovascular side effects of antenatal and neonatal glucocorticoids is presented here.

Juvenile Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is an uncommon chronic autoimmune disease in children. In view of its insidious onset and protean manifestations which may involve any body organ system, the diagnosis may become difficult and challenging. We review this condition, and begin by reporting three affected children to highlight its very different modes of presentation. An up-to-date review of the disease is then presented, including diagnosis, complications and recommended therapy including new therapeutic modalities

Pharmacologic Therapy in Growth Hormone Disorders and the Heart

Growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis is not only involved in the regulation of somatic growth but also has important physiological functions in adults. Several studies have shown that GH deficiency in adults is associated with abnormalities in body composition, metabolic derangements, and suboptimal physical performance. Furthermore, GH/IGF-I axis plays an important role in the maintenance of heart structure and function. Until recently, GH therapy was only used to treat short stature children, with or without established GH deficiency, and it remains common practice to discontinue GH replacement therapy when final height is achieved. Acromegaly, entity characterized by GH hypersecretion, is associated with an increased risk of premature death. Cardiac complications are known to be major determinants of the shortened life expectancy. Treatment of acromegaly accounts for a substantial decrease in morbidity and mortality. Surgery, radiation therapy and bromocriptine have only been able to reduce GH levels to normal levels in 10-30% of patients. The synthesis of somatostatin analogs has provided a new approach to acromegaly treatment. These drugs reduce GH and IGF-I levels in 80% of cases and normalize them in 40-60% of cases. Finally, GH/IGF-I system improves left ventricular systolic function and has also indirect effects on the cardiovascular system, mainly as a consequence of the peripheral vasodilatation. These effects are important in the understanding of the potential role of GH on improving ventricular systolic dysfunction and point to the use of GH as a potential therapy for chronic heart failure. The aim of the present review is to provide an update overview describing the role of GH on acromegaly, adult GH deficiency and heart failure, as well as the influence of GH-based therapy on heart structure and function.

Molecular Pathologies of and Enzyme Replacement Therapies for Lysosomal Diseases

Lysosomal diseases comprise a group of inherited disorders resulting from defects of lysosomal enzymes and their cofactors, and in many of them the nervous system is affected. Recently, enzyme replacement therapy with recombinant lysosomal enzymes has been clinically available for several lysosomal diseases. Such enzyme replacement therapies can improve non-neurological disorders but is not effective for neurological ones. In this review, we discuss the molecular pathologies of lysosomal diseases from the protein structural aspect, current enzyme replacement therapies, and attempts to develop enzyme replacement therapies effective for lysosomal diseases associated with neurological disorders, i.e., production of enzymes, brain-specific delivery and incorporation of lysosomal enzymes into cells.

The Fetal Cardiac Function

Despite significant progress in the prenatal diagnosis of congenital heart disease and the postnatal management, the prenatal evaluation of fetal heart function remains difficult. The unique characteristics of the fetal circulation have a significant impact on its cardiac function. Commonly used physiological concepts about the function of the heart can be misleading when applied to the intrauterine situation. Most noninvasive parameters of cardiac function are not validated in the fetus. In addition, unlike structural defects that can be easily confirmed after delivery, functional hemodynamic abnormalities diagnosed in utero cannot be verified postnatally with certainty as the neonatal circulation defers considerably from the fetal circulation. This review attempts to describe commonly used methods of assessment of fetal cardiac function, their physiological basis and, their utility in clinical practice.