Angiomatosis

Endobronchial Tuberculosis in an HIV-positive Case

Introduction: Tuberculosis is an opportunist infection that is fatal and most frequently seen in HIV-positive patients due to immunosuppression. Endobronchial lesions can portray symptoms in different ways. Endobronchial Tuberculosis is one of these lesions.

Case Report: An HIV-positive, untreated 26-year-old patient with fever, cough, and dyspnea consulted our clinic. In the chest X-ray taken, effusion on the right side and non-homogeneous density increase in the middle and upper lobes, bilaterally more prominent on the right side, were observed. Therefore, the patient underwent bronchoscopy because the CT (computerized tomography) showed mediastinal lymphadenopathy (LAP) and an endobronchial lesion in the left main bronchus. During bronchoscopy, a vegetative endobronchial lesion that causes obstruction in the left main bronchus was monitored. With the help of Pathology and PCR results, endobronchial tuberculosis was diagnosed.

Conclusion: Even if Acid-alcohol-resistant Bacillus (ARB) is detected negative in patients who stop responding to antimicrobial treatment and are being monitored under radiological scanning, a distinctive diagnosis of endobronchial tuberculosis should be kept in mind while performing bronchoscopy.

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

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

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

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

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

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

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

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

Mucocutaneous Manifestations of People Living with HIV in Current Antiretroviral Therapy Era

Objective: It has been reported that approximately 90 % of patients infected with the human immunodeficiency virus (HIV) have various cutaneous symptoms related to the virus. This study aims to describe the cutaneous disorders that have developed in HIV-infected patients and to investigate the factors that may be related, such as relationships to drug use and CD4 counts.

Methods: This cross-sectional study included people living with HIV and being followed by our hospital’s infectious diseases clinic after being referred to the dermatology clinic because of skin lesions. These patients had been diagnosed with HIV by enzyme-linked immunosorbent assay tests and were included in the study if they were older than 18 years and had agreed to participate. Findings from detailed dermatological examinations were recorded, along with the patients’ CD4 counts, the durations of their illnesses, and the treatments they received.

Results: 144 patients were included in the study. The most common mucocutaneous manifestation was seborrheic dermatitis, at 28.5 % (n = 41). The mean CD4 count was 607.1 (min-max = 10.6- 1982). The CD4 counts were divided into three groups in the study as follows: 22 (15.3 %) patients with <200, 35 (24.3 seborrheic dermatitis) patients between 200 and 500, and 87 (60.4 %) patients with >500. There were no statistical differences between these groups in terms of dermatological findings. Nevertheless, the highest rate of patients with three or more dermatological conditions was found among those with CD4 counts <200 (n = 11.50 %).

Conclusion: Skin manifestations are common in patients who are HIV-positive; however, many skin disorders can be seen in HIV/acquired immunodeficiency syndrome (AIDS) patients whatever CD4 cell counts of these patients are.

Primary Tumors of the Sacrum: Imaging Findings

The diagnosis of sacral neoplasms is often delayed because they tend to remain clinically silent for a long time. Imaging is useful at all stages of the management of sacral bone tumors, i.e., from the detection of the neoplasm to the long-term follow-up. Radiographs are recommended as the modality of choice to begin the imaging workup of a patient with known or suspected sacral pathology. More sensitive examinations, such as Computerized Tomography (CT), magnetic resonance (MRI), or scintigraphy, are often necessary. The morphological features of the lesions on CT and MRI help orientate the diagnosis. Although some imaging characteristics are helpful to limit the differential diagnosis, an imaging-guided biopsy is often ultimately required to establish a specific diagnosis. Imaging is of paramount importance even in the long-term follow-up, in order to assess any residual tumor when surgical resection remains incomplete, to assess the efficacy of adjuvant chemotherapy and radiotherapy, and to detect recurrence.

Medicinal Herbs with Anti-Inflammatory Activities for Natural and Organic Healing

One of the principal causes of different disorders is an uncontrolled inflammatory response. Alkaloids, flavonoids, polyphenolic, proanthocyanidin, terpenoid, and steroid compounds are the main reasons for the anti-inflammatory activities of medicinal herbs and plants. The current manuscript introduces a series of potential anti-inflammatory plants, particularly those which are routines in Iranian and Chinese traditional herbal medicine, and simplifies the function and mechanisms of natural constituents for the prevention and treatment of inflammatory disorders. PubMed, Science Direct, Google Scholar, Wiley Online Library, Springer, Taylor, Francis, etc., have been used to search for collecting of scientific publications for a full evaluation of current documentation in the literature showing the importance of medicinal plants with anti-inflammatory characteristics and natural medicines. The most notable medicinal plants with anti-inflammatory activities are Baccharis dracunculifolia, Aconitum bulleyanum, Crateya adansonii, Alliums spp., Centella asiatica, Flos lonicerae, Corydalis dubia, Syringae folium, Coptis chinensis, Casearia decandra, Nigella sativa, Cannabis sativa, Tamarindus indica L., Glycyrrhiza glabra, Panax ginseng, Panax notoginseng, Pistacia vera, Smilax china, Scutellaria baicalensis, Rosemarinus officinalis, Moringa olifera, Pulsatilla radix, Pistacia atlantica, Rullia tuberose, Canarium album, Dodonaea polyandra, Forsythia suspense, Polygala tenuifolia, Radiz Isatidis, Hypericum sampsonii, Geranium koreanum, Typha capensis, Isatidis folium, Ginkgo biloba, Houttuynia cordata, snow lotus, etc. Herbal medicine mainly uses numerous parts of plants or combinations of them to prevent and remedy diseases and promote health. More investigations and clinical experiments are needed to provide more information on the importance of medicinal plants as well as their roles in the treatment and prevention of inflammatory diseases.

Cutaneomeningospinal Angiomatosis (Cobb Syndrome) in a Young Patient

Cobb Syndrome (Spinal Arteriovenous Metameric Syndrome 1-31 (SAMS 1-31)) is a rare, non-hereditary disorder. Approximately 100 cases of CS have been described to date. The actual incidence may be much higher since only symptomatic patients were documented. In particular, post mortem studies suggest a possibly higher incidence of this syndrome. The main clinical manifestations of this syndrome include skin stains of vascular nature on the torso, in combination with spinal vascular malformations localized in one and the same metameric or spinal segment. A rare diagnosis of this syndrome in patients over 18 is probably related to the fact that the disease may be asymptomatic throughout a long period of time, while patients may tend to disregard the skin lesions. As a result, most publications on this pathology are based on separate case reports.

Significant variability of clinical manifestations as well as prolonged progress of the disease often cause errors in diagnosis. What follows is a case report of a young patient with Cobb Syndrome, who was admitted to a regional vascular centre with a misdiagnosis of stroke.

20 patients of young age (from 20 to 35 years old), with a diagnosis of stroke, who were admitted to a University Clinic (of the Russian National Research Medical University Named After Pirogov N.I., Moscow). Among this group of patients, a patient with Cobb syndrome was identified. Patient P., of 22 years, presented with acute, intensive cervical spinal pain, predominantly on the right, numbness and weakness in the arms and legs. About 3 weeks before admission to the hospital, the patient had ARVI with a fever of up to 37.5°C: two weeks before the onset of symptoms, he had undergone extirpation of 2 teeth, for which reason he spent over 2 hours in a forced position with his head thrown back (prolonged overextension in the cervical spine). Multiple skin angiomas on the chest spreading to the shoulder and scapula region. Tetraparesis up to 4 points: tetraparesis in hands with low muscle tone, low reflexes, tetraparesis in legs with high muscle tone, high reflexes, foot clonus when causing Achilles reflexes, tremor in the extremities and no plantar reflex pathology were detected, sensitivity disorders in the hands “the high gloves” and no pelvic disorders were detected. Given the presence and exacerbation of neurological symptoms and cutaneous angiomas, MRI with a contrast agent of the cervical spine was recommended. MR-image of an advanced arteriovenous malformation (AVM) of the cervical spinal cord with signs of gliosis and spinal cord oedema at the C2-C7 level. Endovascular embolization of the AVM in the cervical spinal cord was performed. The treatment led to the complete reversal of neurological symptoms. In the presence of skin lesions, the diagnosis of CS does not present particular difficulties, so in children and young patients with skin angiomatosis, it is advisable to conduct a comprehensive examination using selective spinal angiography or MR angiography to exclude arteriovenous malformations in the spinal cord.

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

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

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

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

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

Cystic Hygroma with Multiple Benign Bone Lymphangiomas in an Adult Patient: A Rare Entity in the Differential Diagnosis of Multiple Osseous Lesions in Oncology Practice

Cystic lymphangioma presenting with multiple bone lesions in an adult patient is a rare occurrence, with a limited number of reported cases in the literature. In this case report, we describe a 32-year old female patient with chronic neck and pelvic pain, and multiple lytic bone lesions on radiological imaging, which were eventually discovered to originate from cystic hygroma and widespread bone lymphangiomas that were present for more than 10 years. It should be kept in mind that there may be multiple benign causes of differential diagnosis in patients presenting with findings suggestive of diffuse bone metastasis. Misdiagnosis may cause the patient to receive unnecessary treatments, especially radiotherapy. In this case, we reached the diagnosis of benign disease, diffuse bone lymphangiomatosis. For this purpose, we also examine the long and stable medical history of the patient with the findings of BT, ultrasound, and bone scintigraphy.

We think that as long as there are no stable and serious results ofclinical and radiological findings of the patient, the patient should be approached with medical follow-up without treatment.

The Protective of Baicalin on Myocardial Ischemia-Reperfusion Injury

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

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

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

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

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

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

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

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

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

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

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

Connexin43 and Myocardial Ischemia-Reperfusion Injury

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

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

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

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

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

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

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

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

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

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

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

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

Short-Term Transfer of Knowledge Assessment in the Military International HIV Training Program (MIHTP)

Background: The Military International HIV Training Program (MIHTP) was established in 2002 to address the overwhelming needs of international military personnel concerning HIV and AIDS prevention, care, and treatment. The purpose of this study was to determine shortterm knowledge transfer in trainees attending the MIHTP by comparing data collected from pretraining and post-training knowledge assessments.

Methods: We used identical 40-question multiple choice pre-training and post-training assessments to determine the short-term transfer of knowledge of international HIV military physicians attending the MIHTP.

Results: Findings revealed a statistically significant increase in short-term transfer of knowledge of HIV prevention, care, and treatment in a population of international military physicians, nurses, and auxiliary medical personnel from 47 developing countries (n=136). Trainees had significantly higher post-test scores (67.9%) compared with pre-test scores (50.5%, p<0.001). Trainees showed a similar level of HIV knowledge as assessed by pre-training evaluations (F=1.38).

Conclusion: We found significant increases in acquired individual knowledge after a 4-week HIV training program. Results of this study are important as many developing countries rely heavily on international training programs to aid in the development of health care systems in an ever-changing infrastructure.

Prognostic Significance of Asymptomatic Myocardial Ischemia in Women vs. Men

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

Current Advances in the Identification and Characterization of Putative Drug and Vaccine Targets in the Bacterial Genomes

The development in sequencing technologies over the past few decades have increased the pace of decoding genetic and functional information present in the genomes of pathogenic microorganisms. The knowledge obtained through sequencing projects facilitated the identification of genes that codes for virulence factors. A major portion of genomes of pathogenic of bacteria contains genes which are classified as “hypothetical or uncharacterized”. Due to unavailability of precise information about the functionality of these genes, the pathogenic mechanisms utilized by varieties of microorganisms are not fully understood. This respective class of proteins draws a significant interest of pharmaceutical research as they have potential to provide new clues regarding the development of novel therapeutics particularly against the multidrug resistant strains of bacteria. The in silico identification of putative drug and vaccine targets in the set of uncharacterized proteins through comparative and subtractive genome analyses facilitates the increase usability and efficiency of the present drugs. The functional annotation of these characterized target proteins can uncover varieties of biochemical pathways important for the survival and pathogenesis of bacteria. This review focuses on the current protocols available for identification and functional annotations of these uncharacterized potential therapeutic targets.

microRNAs: Promising Biomarkers and Therapeutic Targets of Acute Myocardial Ischemia

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

Interrelated Roles for the Aryl Hydrocarbon Receptor and Hypoxia Inducible Factor-1α in the Immune Response to Infection

Cells of the immune system utilize multiple mechanisms to respond to environmental signals and recent studies have demonstrated roles for two closely related proteins, the aryl hydrocarbon receptor (AHR) and hypoxia inducible factor-1α (HIF1α), in these processes. The AHR is a transcription factor that is activated by diverse ligands found in the diet and environmental pollution as well as by microbial and host-derived products. In contrast, HIF1α is a transcription factor that is active under low oxygen conditions and mediates cellular responses to hypoxia. These evolutionarily conserved proteins have roles in the interrelated processes of metabolism, tumorigenesis, and vascular development. Additionally, the AHR and HIF1α have multiple effects on innate and adaptive immunity. This article provides an overview of the biology of these transcription factors and reviews the effects of AHR and HIF1α signaling on immunity to infection. There are many parallels between these two pathways and their functions highlight the importance of AHR and HIF1α activity particularly at barrier surfaces in coordinating responses to pathogens.

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

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

Vascular Endothelium and Vector Borne Pathogen Interactions

The endothelium is the thin layer of cells that lines the lumen of blood and lymphatic vessels. Endothelial cells (ECs) from different locations have distinct and characteristic expression patterns that persist during in vitro culture. Although gene expression patterns in cultured cells clearly reveal the molecular heterogeneity of these ECs, their corelation with their in vivo counterparts remains to be defined. Situated at the interface between blood and tissues, the endothelium plays a central role for critical functions and represents a physical barrier for both blood-borne pathogens and immune cells, which must cross this barrier for trafficking between the bloodstream and tissues. Endothelial cells are target cells for several infectious agents, including Anaplasma, Bartonella, Orientia and Rickettsia. The lack of appropriate spontaneous or experimentally-induced animal models is a serious limitation for the study of pathogen-ECs interactions and is the major justification for the use of ECs cultures. Bartonella adherence to ECs is mediated by type-IV like pili and some outer membrane proteins. Some differences exist among Bartonella species adherence mechanisms. ECs are invaded either by an endocytic uptake or by engulfment of Bartonella. The activation of ECs by chronic inflammation and direct or indirect action of some Bartonella species leads to proliferation, angiogenesis and vasoproliferative tumor growth. Interactions between Anaplasma, Orientia, Rickettsia and ECs are less documented than Bartonella but differ significantly from the mechanisms described for Bartonella. At the least, they do not induce vasoproliferation. This review summarizes our understanding of the diversity of ECs, the vector borne bacterium-ECs interactions and the mechanisms of bacterial virulence and persistence.

Vertebral Lesions from AIDS-Related Kaposi's Sarcoma

Background: Kaposi's sarcoma is commonly described in HIV/AIDS patients but usually manifests as overt skin lesions or visceral involvement. Bone involvement, particularly vertebral, is uncommon, especially when there is no adjacent cutaneous lesion but a small number of cases have been reported. Unlike many other diseases associated with HIV, Kaposi's sarcoma can occur despite a normal CD4 count.

Case Presentation: A 44 year-old HIV positive Nigerian man presented with a 20 day history of severe, worsening lumbar back pain, nearly three years after an earlier diagnosis of a single cutaneous lesion consistent with Kaposi's sarcoma, for which he received chemo-radiotherapy. Despite varying previous compliance with his anti-retroviral therapy, he was thought to be taking his medications at time of presentation and his CD4 count was 408 cells/mm3. No other organ involvement was found but a pathological fracture was seen on magnetic resonance imaging affecting L1 vertebra. A CTguided needle aspiration biopsy was performed and a histological diagnosis subsequently confirmed Kaposi's sarcoma. The patient was treated with further courses of radiotherapy but had little clinical improvement. Indeed, a follow-up MRI four months later showed new involvement of a further four vertebrae, fortunately in the absence of progressive focal neurology.

Conclusion: Vertebral Kaposi's sarcoma is a rare diagnosis but can be accurately diagnosed with CT or MRI imaging in conjunction with a histological diagnosis. An immunosuppressed patient presenting with bone pain should be thoroughly investigated for Kaposi's sarcoma as modern chemotherapeutic agents alongside anti-retroviral therapy may delay or prevent further devastating complications such as spinal cord compression.

Critical Questions for Preclinical Trials on Safety and Efficacy of Vascular Endothelial Growth Factor-Based Therapeutic Angiogenesis for Ischemic Stroke

Therapeutic angiogenesis is a novel treatment for ischemic stroke, and vascular endothelial growth factor (VEGF) is a key angiogenic and neuroprotective pharmacological candidate for therapy. However, the greatest challenge of preclinical studies is demonstrating that VEGF-based therapeutic angiogenesis is safe and effective for ischemic stroke patients. This review presents the following crucial questions which must first be answered by preclinical studies before VEGF-based therapeutic angiogenesis advances to human stroke trials, (1) Does angiogenesis induced by VEGF monotherapy promote neuroprotection or further damage the nervous tissue? (2) Does angiogenesis by VEGF in combination with other agents (combination therapy) promote greater neuroprotection than monotherapy, and without additional side effects? (3) Which exogenous VEGF isoform best promotes angiogenesis and neuroprotection, with least adverse effects on other organs? (4) Does angiogenesis induced by exogenous VEGF produce similar results in different animal models of ischemic stroke, including variations in age, gender and coexisting chronic diseases? (5) Can angiogenesis be induced by exogenous VEGF without clinically-significant alterations of systemic hemodynamics? (6) Are gene therapy and stem cells more beneficial than recombinant protein for VEGF-based therapeutic angiogenesis? (7) What are the best routes, timing and duration for administering VEGF, and how do these parameters influence inflammation? (8) Does exogenous VEGF exacerbate inflammation when traumatic or other injuries are present with ischemia? (9) Are VEGF doses not causing tissue alterations at the light microscopy level associated with clinically-significant ultrastructural damages of the neurovascular unit? Both published and unpublished preclinical data from the authors laboratory are presented.

Anti-Angiogenic Therapies for Children with Cancer

Tumor angiogenesis, i.e. the development of neovascularisation in and around solid tumors, plays a key role in the local and distant growth of cancer and anti-angiogenic treatments are now established strategies to treat cancer patients. Specific inhibitors of angiogenesis such as bevacizumab or receptor tyrosine kinase inhibitors targeting VEGFR or PDGFR are now in clinical trials and are being increasingly validated for the treatment of poor prognostic cancers. Other anti-angiogenic strategies such as cilengitide or metronomic chemotherapy (low-dose anti-angiogenic chemotherapy) have been developed to treat certain types of adult cancer. In children, the clinical potential of anti-angiogenic approach is still in an early stage of investigation. This review will focus on the role of angiogenesis in pediatric solid tumors and will describe the pre-clinical and clinical experience with several anti-angiogenic compounds as a potential treatment for children with cancer.

CXCR4-CXCL12-Dependent Inflammatory Network and Endothelial Progenitors

The endothelial progenitor cells (EPCs) are angiogenic cells having properties similar to those of embryonal angioblasts. The number and function of EPCs are affected by a variety of conditions, including cytokines and chemokines, which are pivotal inflammatory signaling molecules. The purpose of this paper is to review current knowledge about the role of these progenitor in different vascular diseases, emphasizing the important biological role played from the CXCR4-CXCL12 axis in the cellular trafficking. Indeed, as described in detail in this review, the CXCR4/CXCL12 interaction produces pleiotropic effects in stem cells and plays a pivotal role in several processes related to development, tissue regeneration and development/progression of malignancies.

The Role of a Human Hematopoietic Mesenchymal Progenitor in Wound Healing and Fibrotic Diseases and Implications for Therapy

The human peripheral blood contains a multipotent precursor that shows hematopoietic stem cell features and transiently expresses markers of the myeloid lineage. Under permissive conditions, this precursor gives rise to committed progenitors of various lineages, including a mesenchymal progenitor cell known by the name of fibrocyte. The fibrocytes still express some hematopoietic and myeloid antigens together with fibroblast markers. They constitutively release profibrotic and angiogenic factors and can modulate ongoing inflammatory reactions through the release of a number of chemokines. Under appropriate stimulation, fibrocytes produce increased amounts of extracellular matrix components and acquire a contractile phenotype similar to that of activated fibroblasts (myofibroblasts). Fibrocytes synthesizing new collagen or acquiring myofibroblast markers have been detected in pulmonary diseases characterized by an extensive remodeling of the bronchial wall or progressive fibrosis, in the skin of patients affected by nephrogenic systemic fibrosis, in human hypertrophic scars, in proliferative vitreoretinopathies and atherosclerotic lesions. Similar cells also participate in the stromal reaction to tumor development. Prevention of detrimental tissue remodeling in fibrotic diseases may be achieved by inhibiting the accumulation of fibrocytes. In-vitro expanded fibrocytes may be used to improve ineffective tissue repair or may be engineered for the delivery of gene constructs in anti-cancer therapy.

Hemangiomas, Angiosarcomas, and Vascular Malformations Represent the Signaling Abnormalities of Pathogenic Angiogenesis

Angiogenesis is a major factor in the development of benign, inflammatory, and malignant processes of the skin. Endothelial cells are the effector cells of angiogenesis, and understanding their response to growth factors and inhibitors is critical to understanding the pathogenesis and treatment of skin disease. Hemangiomas, benign tumors of endothelial cells, represent the most common tumor of childhood. In our previous studies, we have found that tumor vasculature in human solid tumors expresses similarities in signaling to that of hemangiomas, making the knowledge of signaling in hemangiomas widely applicable. These similarities include expression of reactive oxygen, NFkB and akt in tumor vasculature. Furthermore, we have studied malignant vascular tumors, including hemangioendothelioma and angiosarcoma and have shown distinct signaling abnormalities in these tumors. The incidence of these tumors is expected to rise due to environmental insults, such as radiation and lumpectomy for breast cancer, dietary and industrial carcinogens (hepatic angiosarcoma), and chronic ultraviolet exposure and potential Agent Orange exposure. I hypothesize that hemangiomas, angiosarcomas, and vascular malformations represent the extremes of signaling abnormalities seen in pathogenic angiogenesis.

AIDS-Related Kaposis Sarcoma: State of the Art and Therapeutic Strategies

In the HAART era Kaposis sarcoma (KS) remains the second most frequent tumor in HIV-infected patients worldwide, and it has become the most common cancer in Sub-Saharan Africa. In western countries the risk for KS in men having sex with men (MSM) is 5 to 10 times higher compared to other groups of individuals practicing other HIVrisk behaviors. Patients with KS in Sub-Saharan Africa have very high tumor burdens and rapid disease progression with a diminished life expectancy of less than 6 months. KS lesions are comprised of both distinctive spindle cells of endothelial origin and a variable inflammatory infiltrate, which suggests that KS may result from reactive hyperproliferation induced by chronic inflammation, and therefore it is not a true neoplasm. KS has a variable clinical course ranging from very indolent forms, requiring no or minimal therapy, to a rapidly progressive disease. Treatment decisions must take into consideration the extent and the rate of tumor growth, patients symptoms, immune system conditions and concurrent HIV-related complications. Several different therapeutic options are available but the optimal therapy is still unclear. Highly Active Antiretroviral Therapy (HAART) including protease inhibitors (PI) may represent the first treatment step for slowly progressive disease; chemotherapy (CT) plus HAART is indicated for visceral and/or rapidly progressive disease, whereas maintenance (M)-HAART after systemic chemotherapy may be an effective anti-KS measure after debulking CT. The angiogenic nature of KS makes it particularly suitable for therapies based on targeted agents such as metalloproteinase inhibitors, angiogenesis inhibitors and tyrosine kinase inhibitors. The aim of this article is to provide an up-to-date review of the current status and perspectives of AIDS-related KS in the HAART era.

The Seattle Structural Genomics Center for Infectious Disease (SSGCID)

The NIAID-funded Seattle Structural Genomics Center for Infectious Disease (SSGCID) is a consortium established to apply structural genomics approaches to potential drug targets from NIAID priority organisms for biodefense and emerging and re-emerging diseases. The mission of the SSGCID is to determine ~400 protein structures over five years ending in 2012. In order to maximize biomedical impact, ligand-based drug-lead discovery campaigns will be pursued for a small number of high-impact targets. Here we review the centers target selection processes, which include pro-active engagement of the infectious disease research and drug therapy communities to identify drug targets, essential enzymes, virulence factors and vaccine candidates of biomedical relevance to combat infectious diseases. This is followed by a brief overview of the SSGCID structure determination pipeline and ligand screening methodology. Finally, specifics of our resources available to the scientific community are presented. Physical materials and data produced by SSGCID will be made available to the scientific community, with the aim that they will provide essential groundwork benefiting future research and drug discovery.

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

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

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

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

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

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

Modulation of Cardiac Metabolism During Myocardial Ischemia

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

Cardiac Metabolism in Myocardial Ischemia

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

HIV-1 Infection: Recent Developments in Treatment and Current Management Strategies

Twenty-four years after the identification of HIV-1 as causative agent of the acquired immunodeficiency syndrome (AIDS) the pandemic continues to call for novel drugs and for new management strategies. Several steps in the HIV-1 replication cycle are potential targets for treatment interventions. Twenty-five compounds are approved by the FDA but there is still urgent need for new classes of antiretroviral drugs. Major concerns are long-term toxicity and development of resistant HIV-1 strains. Currently treatment regimens are combinations of inhibitors of two viral enzymes – the reverse transcriptase and the protease. According to their mechanism of action antiretroviral substances can be divided into the following groups: 1.) Nucleoside reverse transcriptase inhibitors. 2.) Non-nucleoside reverse transcriptase inhibitors. 3.) Nucleotide reverse transcriptase inhibitors. 4.) HIV-1 protease inhibitors. 5.) Entry inhibitors. 6.) Integrase inhibitors, and 7.) Maturation inhibitors. Further subjects of investigation are the development of an AIDS vaccine and the evaluation of preventive strategies like pre-exposure prophylaxis and male circumcision. In contrast to the favourable results of the male circumcision studies the recent suspension of two vaccine trials, the STEP and the Phambili trial, and of the first placebo-controlled study of a vaginal microbicide for prevention of HIV-1 acquisition represents a serious draw back in the fields of vaccine development and prophylaxis. This review summarizes the following topics: 1.) Natural history and immune pathogenesis of HIV-1 infection. 2.) Development of antiretroviral therapy and its viral targets. 3.) Mechanisms of action of antiretroviral drugs. 4.) Approved and novel compounds of existing and new classes. 5.) AIDS vaccine development. 6.) Management strategies with respect to antiretroviral therapy and HIV-1 transmission.

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

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

Testosterone and Cardioprotection Against Myocardial Ischemia

Male gender is a risk factor for cardiovascular diseases. Testosterone being the main male sex hormone is therefore believed to be responsible for the deleterious effect of the male. However, there are recent studies showing that testosterone level is lower in patients with ischemic heart diseases, and testosterone treatment alleviates the symptoms. Earlier studies showed that functional androgen receptors are present in the heart and that testosterone acts directly at the myocardium. There is increasing evidence to suggest testosterone confers cardioprotection by direct action on the myocardium. Here, we review the recent literature on association between testosterone and myocardial ischemia in males, and the signal transduction mechanisms that mediate the action of testosterone in the heart. The studies reviewed in this article provide evidence that testosterone may confer protection via a varieties of mechanisms, which may be both genomic and non-genomic. Further studies are warranted to further delineate the integration of signaling mechanisms and to explore the possibility of using testosterone in the aging male population with ischemic heart diseases.

BXT-51072 and the Prevention of Myocardial Ischemia-Reperfusion Injury

Oxidative stress is responsible for myocardial injury occurring after ischemia and reperfusion (IR) and has been shown to be modulated by the Haptoglobin (Hp) genotype. In this manuscript we demonstrate that the antioxidant BXT -51072, a glutathione peroxidase synthetic mimic, provides protection against IR injury in a Hp genotype dependent fashion.

DNA Microarrays - An Armory for Combating Infectious Diseases in the New Century

DNA microarrays are high-throughput platforms that take advantage of the vast amount of sequence information and allow scientists to perform gene expression profiling or genotyping studies on a “global” or “genomewide” scale. The global monitoring of gene expression in hosts and pathogens, either separately or interactively, has given us systemic views of the disease mechanisms. Ongoing improvements in DNA sequencing and microarray technologies continue to open up new opportunities for better understanding and developing more effective approaches in diagnosis, treatments, and preventions of infectious diseases. This review focuses on the latest developments and applications of the DNA microarray technologies designed for studying pathogens in the areas of pathogenesis, host-pathogen interaction, drug response, vaccine development, and disease agent identification. Issues and challenges in the analysis, management and interpretation of microarray data are also addressed.

Myocardial Ischemia and Reperfusion Injury: Studies Using Transgenic and Knockout Mice

Transgenic and knockout mice are created and used for a large variety of research objectives. This overview describes the (genetically modified) mouse models that have been used to study the development of myocardial ischemia and reperfusion injury. The role of cytokines, chemokines, leukocytes, reactive oxygen species, anti-oxidants, NO, complement system, coagulation system, heat shock proteins, apoptosis and necrosis, and acute phase reactants are presented.

Anti-Angiogenic Therapy as a Cancer Treatment Paradigm

The inhibition of angiogenesis is an emerging therapeutic strategy for cancer treatment. In contrast to conventional therapies, anti-angiogenic therapies primarily target tumor-associated endothelial cells which serve as a lifeline for tumor growth, progression and metastasis. By blocking the supply of essential nutrients and the removal of metabolites, anti-angiogenic therapies aim to delay both primary and metastastic tumor growth while overcoming the inherent cytotoxicities of classical chemotherapies. Indeed, tumor-related angiogenesis is a multi-step process initiated by a cascade of proangiogenic factors secreted from both the tumor and host tissues. These intricate processes involve a close interaction of tumor and associated endothelial cells as well as an intimate communication between proliferating endothelial cells, stromal cells and extracellular matrix components. Inhibition of these proangiogenic mechanisms has become a major challenge for the development of anti-cancer treatment modalities. In this regard, anti-angiogenic therapies embody a potentially powerful adjunct to traditional cancer therapies. In this review, we provide an overview of traditional anti-cancer drugs and discuss the fundamentals of anti-angiogenic therapies. While presenting the salient features of the anti-angiogenic agents targeting the individual phases of angiogenesis, we highlight the potential for specific agent development as novel anti-angiogenic therapeutics. Finally, we present and summarize emerging angiogenesis inhibitors.

Von Hippel-Lindau Disease

Germline mutations in the VHL tumour suppressor gene may cause a variety of phenotypes including von Hippel-Lindau (VHL) disease, familial phaeochromocytoma and inherited polycythaemia. VHL disease is a multisystem familial cancer syndrome and is the commonest cause of familial renal cell carcinoma (RCC). VHL disease provides a paradigm for illustrating how studies of a rare familial cancer syndrome can produce advances in clinical medicin and important insights into basic biological processes. Thus the identification of the VHL gene has improved the diagnosis and clinical management of VHL disease and provided insights into the pathogenesis of sporadic clear cell RCC. Functional investigations of the VHL gene product have provided novel information on how cells sense oxygen and the role of hypoxia-response pathways in human tumourigenesis. Such information offers prospects of novel therapeutic interventions for VHL disease and common cancers including RCC.

The Role of the Chemokines in Myocardial Ischemia and Reperfusion

Chemokines critically regulate basal and inflammatory leukocyte trafficking and may play a role in angiogenesis. This review summarizes our current understanding of the regulation and potential role of the chemokines in myocardial ischemia and reperfusion. Reperfused myocardial infarction is associated with an inflammatory response leading to leukocyte recruitment, healing and scar formation. Neutrophil chemoattractants, such as the CXC chemokine CXCL8 / Interleukin (IL)-8, are upregulated in the infarcted area inducing polymorphonuclear leukocyte infiltration. In addition, mononuclear cell chemoattractants, such as the CC chemokine CCL2 / Monocyte Chemoattractant Protein (MCP)-1, are expressed, leading to monocyte and lymphocyte recruitment in the ischemic area. However, chemokines may have additional effects in healing infarcts beyond their leukotactic properties. We have recently described a marked transient induction of the angiostatic CXC chemokine CXCL10 / Interferon-γ inducible Protein (IP)- 10 in the infarct. Upregulation of angiostatic factors, such as IP- 10, in the first few hours following injury may inhibit premature angiogenesis, until the infarct is debrided and appropriate supportive matrix is formed. Suppression of IP-10 synthesis during the healing phase may allow formation of the wound neovessels, a critical process for infarct healing. Chemokine expression is also noted after a single brief ischemic insult in the absence of myocardial infarction, suggesting a potential role for a chemokine-induced inflammatory response in noninfarctive ischemic cardiomyopathy. Unlike cytokines, which have pleiotropic effects, chemokines have more specific cellular targets. Understanding of their role in myocardial infarction may allow us to design specific therapeutic strategies aiming at optimizing cardiac repair and preventing ventricular remodeling.

Therapeutic Angiogenesis by Gene Transfer in Critical Limb and Myocardial Ischemia

Cardiovascular atherosclerotic diseases remain leading causes of morbidity and mortality in the world. Despite the significant progress that has been made in the management of these diseases using medical, surgical and percutaneous therapies over the last three decades, there remains a significant population of patients who are not optimal candidates for surgical or percutaneous revascularization. Substantial research has focused on the administration of angiogenic growth factors, either as recombinant protein or by gene transfer, to promote the development of supplemental collateral blood vessels that will constitute endogenous bypass conduits around occluded native arteries, a strategy termed “therapeutic angiogenesis”. While many cytokines have angiogenic activity, the best studied both in animal models and clinical trials are vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). This review will discuss gene transfer strategies for therapeutic angiogenesis in critical limb and myocardial ischemia.