Acoustic Neuroma

Treating Sensorineural Hearing Loss: Recent Advances in Inner Ear Drug Delivery

This review aims to provide historical, present, and future drug deliveries for treating inner ear disorders. Systemic delivery, such as antibiotics and steroids for the inner ear, was the basis on which current drug delivery systems and devices have been researched and developed. Researchers and clinicians had to develop and deliver drugs locally due to adverse effects caused by drugs systemically. Intratympanic method of antibiotics and steroid delivery has been common; however, newer techniques such as microcatheter implantation, hydrogels, nanoparticles, and intracochlear implants are being investigated successfully. Recently advances in microfluidic and microsystems technology have applied medications directly into the inner ear. This technology will also be adopted to deliver gene therapy, RNA interference technology, and stem cell therapy by clinicians in the future.

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.

An Overview of Radiolabeled RGD Peptides for Theranostic Applications

Angiogenesis phenomenon, as a highly affecting factor on the growth and spread of cancer cells, depends on specific molecular interactions between components of the extracellular matrix and vascular cells. αv integrin acts as a cell adhesive molecule involved in tumor invasion and angiogenesis. Among the various combinations of integrin subunits expressed on the surface of cells, α_vβ₃ integrin has a particularly interesting expression pattern during angiogenesis. The α_vβ₃ integrin is a vital receptor affecting tumor growth, tumor invasiveness, metastasis, and angiogenesis overexpressed on various human tumors, leading to the development of different theranostics probes and radiopharmaceuticals. The α_vβ₃ integrin can recognize several extracellular matrix molecules in the base of the RGD adhesive sequence. This review provides an overview of the status, trends and future of the most studied α_vβ₃ integrin-binding ligand, RGD tripeptides, labeled with various radioisotopes. An overview of the pre-clinical models for radiolabeled RGD peptides and clinical aspects of the RGD- based radiopharmaceuticals is provided with some new considerations and ways forward.

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.

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.

Poly (Lactic-co-Glycolic Acid) & Tocopheryl Polyethylene Glycol Succinate Nanoparticles for the Treatment of Different Brain Cancers

Nanotechnology and material science developments emerge in the manufacturing of various novel modes of drug delivery, which have proven scientifically promising. Polymer nanoparticles have high stability, high specificity, high drug-carrying power, control release, and potential to be used in various pathways. They usually supply hydrophilic and hydrophobic molecules with medicines. In this review, we have discussed the different types of brain tumour, different PLGA (Poly Lactic-co-Glycolic Acid) nanostructures, PLGA in brain tumour targeting, and the recent advancement of PLGA based nanoparticles. This review focused on the method of preparation of polymeric nanoparticles, the significance of EPR (Enhanced Permeability and Retention) effect with PLGA, the significance of TPGS in cancer, and discussed the pharmaceutical application of PLGA nanoparticles. We expect these polymeric nanoparticles will be very successful and efficient for disease targeting in the future and new techniques will emerge.

Brain Tumor Causes, Symptoms, Diagnosis and Radiotherapy Treatment

The strategy used for the treatment of given brain cancer is critical in determining the post effects and survival. An oncological diagnosis of tumor evaluates a range of parameters such as shape, size, volume, location and neurological complexity that define the symptomatic severity. The evaluation determines a suitable treatment approach chosen from a range of options such as surgery, chemotherapy, hormone therapy, radiation therapy and other targeted therapies. Often, a combination of such therapies is applied to achieve superior results. Radiotherapy serves as a better treatment strategy because of a higher survival rate. It offers the flexibility of synergy with other treatment strategies and fewer side effects on organs at risk. This review presents a radiobiological perspective in the treatment of brain tumor. The cause, symptoms, diagnosis, treatment, post-treatment effects and the framework involved in its elimination are summarized.

Therapeutic Potential of Ultrasound Neuromodulation in Decreasing Neuropathic Pain: Clinical and Experimental Evidence

Background: For more than seven decades, ultrasound has been used as an imaging and diagnostic tool. Today, new technologies, such as focused ultrasound (FUS) neuromodulation, have revealed some innovative, potential applications. However, those applications have been barely studied to deal with neuropathic pain (NP), a cluster of chronic pain syndromes with a restricted response to conventional pharmaceuticals.

Objective: To analyze the therapeutic potential of low-intensity (LIFUS) and high-intensity (HIFUS) FUS for managing NP.

Methods: We performed a narrative review, including clinical and experimental ultrasound neuromodulation studies published in three main database repositories.

Discussion: Evidence shows that FUS may influence several mechanisms relevant for neuropathic pain management such as modulation of ion channels, glutamatergic neurotransmission, cerebral blood flow, inflammation and neurotoxicity, neuronal morphology and survival, nerve regeneration, and remyelination. Some experimental models have shown that LIFUS may reduce allodynia after peripheral nerve damage. At the same time, a few clinical studies support its beneficial effect on reducing pain in nerve compression syndromes. In turn, Thalamic HIFUS ablation can reduce NP from several etiologies with minor side-effects, but some neurological sequelae might be permanent. HIFUS is also useful in lowering non-neuropathic pain in several disorders.

Conclusion: Although an emerging set of studies brings new evidence on the therapeutic potential of both LIFUS and HIFUS for managing NP with minor side-effects, we need more controlled clinical trials to conclude about its safety and efficacy.

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.

Benign Intracranial Lesions - Radiotherapy: An Overview of Treatment Options, Indications and Therapeutic Results

Background: Radiation Therapy (RT) is an established treatment option for benign intracranial lesions. The aim of this study is to display an update on the role of RT concerning the most frequent benign brain lesions and tumors.

Methods: Published articles about RT and meningiomas, Vestibular Schwannomas (VSs), Pituitary Adenomas (PAs), Arteriovenous Malformations (AVMs) and craniopharyngiomas were reviewed and extracted data were used.

Results: In meningiomas RT is applied as an adjuvant therapy, in case of patientrefusing surgery or in unresectable tumors. The available techniques are External Beam RT (EBRT) and stereotactic ones such as Stereotactic Radiosurgery (SRS), Fractionated Stereotactic RT (FSRT), Intensity Modulated RT (IMRT) and proton-beam therapy. The same indications are considered in PAs, in which SRS and FSRT achieve excellent tumor control rate (92-100%), acceptable hormone remission rates (>50%) and decreased Adverse Radiation Effects (AREs). Upon tumor growth or neurological deterioration, RT emerges as alone or adjuvant treatment against VSs, with SRS, FSRT, EBRT or protonbeam therapy presenting excellent tumor control growth (>90%), facial nerve (84-100%), trigeminal nerve (74-99%) and hearing (>50%) preservation. SRS poses an effective treatment modality of certain AVMs, demonstrating a 3-year obliteration rate of 80%. Lastly, a combination of microsurgery and RT presents equal local control and 5-year survival rate (>90%) but improved toxicity profile compared to total resection in case of craniopharyngiomas.

Conclusion: RT comprises an effective treatment modality of benign brain and intracranial lesions. By minimizing its AREs with optimal use, RT projects as a potent tool against such diseases.

Nimodipine Reappraised: An Old Drug With a Future

Nimodipine is a dihydropyridine calcium channel antagonist that blocks the flux of extracellular calcium through L-type, voltage-gated calcium channels. While nimodipine is FDAapproved for the prevention and treatment of neurological deficits in patients with aneurysmal subarachnoid hemorrhage (aSAH), it affects myriad cell types throughout the body, and thus, likely has more complex mechanisms of action than simple inhibition of cerebral vasoconstriction. Newer understanding of the pathophysiology of delayed ischemic injury after a variety of acute neurologic injuries including aSAH, traumatic brain injury (TBI) and ischemic stroke, coupled with advances in the drug delivery method for nimodipine, have reignited interest in refining its potential therapeutic use. In this context, this review seeks to establish a firm understanding of current data on nimodipine’s role in the mechanisms of delayed injury in aSAH, TBI, and ischemic stroke, and assess the extensive clinical data evaluating its use in these conditions. In addition, we will review pivotal trials using locally administered, sustained release nimodipine and discuss why such an approach has evaded demonstration of efficacy, while seemingly having the potential to significantly improve clinical care.

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.

Beam Commissioning Data Acquisition for the Iris Variable Aperture Collimator of CyberKnife VSI

Objective: To minimize the risk inherent to the use of medical radiation and robotic radiosurgery, this research introduced the basis and method of beam commissioning data acquisition for the Iris variable aperture collimator of CyberKnife VSI.

Methods: In this study, clinical dosimetry measurements of the Iris collimator such as tissue-phantom ratios (TPRs), off-center ratios (OCRs), and secondary collimator output factors (OFs) were conducted, and the data was contrasted with that of the Fixed collimator.

Results: The Iris data and the Fixed data were not quite different in TPRs in the same radiation field size. Since the difference of the hardware structure,the OCRs and OFs were quite different, especially in small aperture (5, 7.5 and 10 mm) under the same condition of SAD. For example, the maximum discrepancy of the OFs was 26.67% (5mm aperture, 650mm SAD).

Conclusion: When Iris aperture makes some change, tungsten segments move fast and form an aperture smaller than that we need, and then recover to the right size, which may affect the results of the measurement, and also the dodecagonal design of Iris results in a problem of leakage radiation on the edge.

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.

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.

Application of VEGF Gene Therapy in Two Basic Fields of Plastic- Reparative Surgery: Tissue Reconstruction with Flaps and Peripheral Nerve Surgery

Experimental works in the field of reconstructive plastic surgery have been especially focused in restorative procedures based on flaps and peripheral nerve regeneration. Those involving the use of VEGF gene therapy showed generated particular interest but also many significant conclusions in both fields of reconstructive surgery which are currently introducing in the operating room. Interestingly, composite tissue allotransplantation methods joined the possibility to perform anatomical and functional reconstructions, since skin, muscle or bones can be transferred together, but also the concomitant nerves, which will be responsible to produce the movements of these transplanted tissues like in facial transplantation or limb transplantation. During reconstructive surgeries involving flaps, partial or complete ischemia of tissues can be a common complication, especially after free tissue transfer. For this reason, there is always a reasonable risk of flap necrosis that can lead to the loss of the reconstructive procedure due to venous or/and arterial insufficiency. On the other hand, after nerve damage, axons distal to the nerve crush begin to degenerate. As a consequence, the functional connections between motor axons and muscles are finally damaged leading to progressive muscle atrophy. When nerve continuity is repaired, the proximal stumps of injured axons are in condition to sprout within the distal nerve stumps. Experimental studies demonstrated the utility and efficiency of growth factors in stimulating neoangiogenesis in order to improve flap survival as well as in the promotion of axonal sprouting which is an important point for nerve regeneration. Among the ones, the Vascular Endothelial Growth Factor (VEGF) has shown to be an efficient therapeutic agent in both fields. Gene therapy based on adeno-associated viruses, liposomes or nanoparticles is the accepted method to develop the new angiogenesis and nerve promotion as these carriers are able to efficiently deliver therapeutic genes to flaps and nerves. Nevertheless, there are still many obstacles to be solved like the therapeutic maintenance of VEGF production along the period of time necessary to perform the desired effects, but also the use of VEGF as a preventive factor to avoid flap failure in reconstructive procedures. This reviews describes the advances in regenerative medicine in flap and nerve surgery using VEGF gene therapy and related patents.

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.

Evaluation of the Effect of Nimodipine o.d. (Extended Release) vs Nimodipine t.i.d. in the Treatment of Peripheral Vertigo

Summary: Vertigo has a negative impact on quality of life; therefore, it is important to find an effective and convenient therapy that allows patients to continue their everyday tasks as soon as possible and to have a better quality of life. Methods: There were two formulations used to assess the effectiveness in vertigo treatment from peripheral origin: nimodipine administrated three times daily (Nimotop®) 30 mg versus nimodipine AP administrated once daily (Tropocer ®) 90 mg; both of them in a administrated in a prospective, randomized, double-blind, double dummy, multicenter and parallel-group study, where patients with peripheral vertigo defined as a score ≥7 on the Vertigo-Dizziness Differential Diagnosis Score were included. The patients were evaluated by vertigo severity index and vestibular disability index. Results: In the AP nimodipine group (NAP), vertigo severity index was decreased by 50%: 24% of patients in 14 days, 41% in 4 weeks and 89% in 8 weeks. The vestibular disability index was decreased by 50%: 24% of patients in 15 days, 83% in 4 weeks and 92% of patients in 8 weeks. In the conventional nimodipine group (NC), rate of vertigo severity was decreased by 50%: 17% of patients in 14 days, 41% of patients in 4 weeks and 90% of patients in 8 weeks. The vestibular disability index was decreased by 50%: 15 days in 17% of patients, 53% in 4 weeks and 64% in 8 weeks, without difference between groups. Conclusions: both products were effective and well tolerated in the treatment of peripheral vertigo.

The Prevalence of the Classical and Non-Classical Cardiovascular Risk Factors in Multiple Sclerosis Patients

Background: Inflammation is known to play a role in cererovascular risk. Multiple sclerosis (MS) is a neurodegenerative disease that is initially characterized by inflammatory changes in the brain. We hypothesized that due to chronic inflammation, MS patients would present with a higher levels of cardiovascular (CV) risk factors than non-MS patients.

Methods: We performed a retrospective chart review on 206 MS patients and 142 control patients suffering from meningiomas and acoustic neuromas, non inflammatory, non autoimmune diseases of the brain. The obtained data included fasting lipid profiles, plasma glucose, systolic and diastolic blood pressure (BP), serum levels of homocysteine and uric acid, data on iron status, smoking habit, and list of medications. In addition, data on indicators of MS disease severity was obtained for MS patients.

Results: MS patients had significantly higher total plasma cholesterol, p = 0.01, and plasma high density lipoprotein, P <0.001, but lower plasma glucose, P <0.001, and systolic BP, P = 0.001, than non-MS patients. In addition, MS patients had lower erythrocyte sedimentation rate and serum vitamin B12, but higher serum folic acid and vitamin D3 than non-MS patients. A positive correlation was observed between plasma glucose and the extended disability status scale (EDSS), P = 0.008, and between plasma glucose and the rate of clinical relapse, P = 0.001.

Conclusion: The MS pathophysiology may be among factors for the lower CV risk factors in MS patients. Future studies should examine whether the chronic use of many pharmacological agents influence CV risk factors in MS patients.

Fluorescein Fluorescence Use in the Management of Intracranial Neoplastic and Vascular Lesions: A Review and Report of a New Technique

The use of fluorescent technologies in neurosurgery has a substantial history with applications to vascular and tumor surgery dating back to the 1940s. This review focuses on the applications of fluorescence imaging to intracranial vascular and neoplastic lesions using sodium fluorescein. The authors performed a literature search for articles about the use of sodium fluorescein in neurosurgery. Fifty-five articles were initially retrieved, and 37 of these were appropriate for this review. The subcategorization of these articles revealed 2 describing the properties of fluorescein, 19 articles relating to applications of fluorescein to tumor, 11 relating to vascular applications, and 5 reporting side effects associated with fluorescein use. Articles related to use of this agent in evaluation of CSF leak were excluded. Sodium fluorescein has been reported to be a useful surgical adjunct in resection of neoplastic lesions based on differential fluorescence between normal and neoplastic tissue. There are many reports on the utility of fluorescein in vascular imaging relating to arteriovenous malformations, aneurysms, and vessel anastomosis; however, these reports do not examine primary outcomes. Sodium fluorescein has been judged as generally safe with few reports of severe complications. Sodium fluorescein has demonstrated promise as a useful surgical adjunct in neurosurgery for vascular and neoplastic lesions. It is well tolerated, but further study is required to determine its full utility. Finally, we will introduce a new practical technology that could potentially improve intraoperative application of sodium fluorescein by improving its fluorescence visualization while using substantially lower doses of this dye.

Longitudinal Melatonin Production in Female Laboratory Rats During 1997-2006: Possible Modulatory Effects of Changing Solar Activity

Earlier we reported that the urinary excretion of 6-sulfatoxymelatonin (aMT6s) displayed seasonal rhythms in laboratory rats and hypothesized that the horizontal intensity H of the geomagnetic field may act as seasonal zeitgeber. To test this, long-term experiments were performed with female Sprague-Dawley rats. In experiment I (n=12: 1997-1999) nocturnal aMT6s displayed a winter-summer increase by 30% and a rhythm with a phase-length of 24 months peaking in July 1998. In experiment II (n=12; 1999-2000) the winter-summer increase amounted to 40%. The estimated rhythm had a phase-length of 18 months with a peak in September 2000. Compared to experiment I both the rhythm-adjusted mean (MESOR, + 28%) and amplitude (+68%) were elevated. In experiment III (n=30; 2003-2004) the winter-summer increment was just 20%. A circannual rhythm with a peak in April/May was found. The MESOR was 13% higher than in experiment I but the amplitude was depleted (– 14%). In experiment IV (n=15; 2005-2006) a slight winter-summer increase (+15%) was found and a low-amplitude rhythm of 24 months phase-length peaking in June 2006. The MESOR was similar to experiment I but the amplitude was depressed (– 36%).

These results demonstrate that female rats within two years of age show elevated aMT6s during summer/spring which supports our initial hypothesis. The apparent inter-experimental amplitude variation indicates the involvement of additional variables. Based on our initial hypothesis, we postulate an involvement of the solar cycle affecting H leading to year to year variations and present supportive analyses.

Drug Delivery to the Inner Ear: Strategies and Their Therapeutic Implications for Sensorineural Hearing Loss

Hearing aids or cochlear implants constitute almost exclusively the treatment options currently available to patients suffering from sensorineural hearing loss and related conditions, such as noise-induced hearing loss, ototoxicity or autoimmune inner ear disease. While some systemic treatments exist, they generally exert adverse secondary effects and their efficacy is hampered by the blood-cochlear barrier that limits drug access to the inner ear. Hence, the new therapies that are being developed for hearing loss focus on strategies for direct drug delivery to the inner ear. The passive and active methods for local delivery can be categorized into two general groups: intratympanic or intracochlear. The intratympanic approach is a non-invasive method that preserves hearing and takes advantage of the permeability of the round window to gain access to the cochlea. However, this technique is limited by not knowing the dose of the drug that reaches the cochlea, (a handicap whichmight be overcome by the use of tagged drugs). While direct access to the inner ear by intracochlear administration avoids this problem, this method requires surgery. Currently, laboratory animals are being used to explore which therapeutic approaches are best suited to address this problem. These include cochleostomy and the insertion of devices that pump drugs into the inner ear without inducing cochlear damage. In this article, we review the different techniques under evaluation in animal models of deafness, and their potential use for drug delivery and treatment of human inner ear diseases.

The Traces of Sound: Taking the Road to Skin

In the latest years there has been an explosive growth in the use of ultrasound for exploring the soft tissues. Thus, the utility of sonography in the musculoskeletal field is now very well supported in literature. Moreover, this sonographic expansion has continued through the dermatologic field. The aim of this article is to review the recent advances in dermatologic ultrasound considering last-generation equipment, and assess the potential of ultrasound on rheumatic disorders that may present concomitant and challenging skin or nail lesions at some point during their clinical course.

Ligaments of the Wrist, Ankle and Foot: Sonoanatomy and Sonopathology

The ligaments of the wrist, ankle and foot play a critical role in the static and dynamic stabilization of the joints of these regions. The advent of high resolution ultrasound has markedly improved the evaluation of pathologic alterations of the structure by enabling direct visualization. In the wrist region, the focus is on the extrinsic ligaments, those ligaments that have their origin in the bones of the forearm and insert on the carpal bones, that include the radio-scaphoid, radioscaphocapitate, long radio-lunate (LRL), the short radio-lunate and radiotriquetral. The anatomy, sonoanatomy and sonopathology of the ankle ligaments (deltoid, anterior and posterior talofibular and calcaneofibular), anterior aspect of the ankle syndesmosis and the spring ligament complex are reviewed. Finally, the ligamentous anatomy of the forefoot is detailed as an understanding of this region is key to evaluation of its important sonopathologies.

Can Dietary Antioxidants Reduce the Incidence of Brain Tumors?

The incidence of brain tumor and other types of cancer are markedly increased during the last few decades. There are many etiological and environmental factors involved in the initiation of different types of cancers including brain tumors. Mutations in tumor suppressor gene p53 and its expression are associated with shorter survival and higher mortality rate of patients with brain tumors. Another factor, N-nitrosamines have received much attention as a potential risk factor for brain tumor. These compounds are potent carcinogens and occur widely in the environment, and also can be formed endogenously in the stomach from the interaction of ingested nitrate or nitrite with secondary amines. Free radicals are another etiological factor of brain tumor and are removed by cellular antioxidants in the human body. Brain tissue is vulnerable to the damaging effects of free radicals as a result of low antioxidant levels. Interestingly, there is an inverse correlation between the total antioxidant levels and oxidative DNA damage in transitional meningioma compared with normal brain tissues. Also, an inverse relationship between antioxidant levels and grades of malignancy has been found after histopathological examination of brain tumors. Moreover, high intake of vitamin E is correlated with greater survival for all patients diagnosed as Grade III malignant glioma. Dietary supplementation with antioxidants [e.g. vitamins C & E] was found to reduce the incidence of brain tumors in children whose mothers took these vitamins throughout pregnancy. On the other hand, decreases in antioxidant levels were correlated with the severity of malignancy of brain tumors, and also with accumulation of considerable amounts of oxidative stress products including free radicals which damage this tissue. The mechanisms of protection of these antioxidants against brain tumors might be due to inhibition of the nitrosation process, decreasing of tumor necrotic factor, scavenging of free radicals, inhibition of telomerase activity which facilitates telomere attrition. It is concluded that administration of antioxidants could reduce the incidence of brain tumors and probably other types of cancer.

Uncovering New Pharmacological Targets to Treat Neuropathic Pain by Understanding How the Organism Reacts to Nerve Injury

The neuropathic pain syndrome is complex. Current drugs to treat neuropathic pain, including anticonvulsivants and antidepressants, fail in up to 40-50% of the patients, while in the rest of them total alleviation is not normally achieved. Increased research advances in the neurobiology of neuropathic pain have not translated in more successful pharmacological treatments by the moment, but recent progress in the experimental methods available for this purpose could result in significant advances in the short term. One rational possibility for the pharmaceutical development of new drugs, including target identification, drug design and evaluation studies, could be to focus on mimicking what organism does to limit nerve damage or to enhance the regeneration of injured axons. Following this strategy, neurotrophic factors such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) have been postulated as potential pharmacological targets to treat neuropathic pain. In addition, during the last few years, strong scientific evidences point to novel neurotrophic factors, such as pleiotrophin (PTN), as important factors to limit neuropathic pain development because of their remodeling and angiogenic actions in the injured area. This review focuses on recent research advances identifying new pharmacological targets in the treatment of the cause, not only the symptoms, of neuropathic pain.

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.

Spatiotemporal Modulation of Central Neural Pathway Underlying Acupuncture Action: A Systematic Review

Acupuncture, an ancient therapeutic technique, is currently gaining popularity as an important modality of alternative and complementary medicine in the West world. Concurrently, scientific interests in exploring whether acupuncture is therapeutically effective are raised alongside those about the means by which it may operate. Modern neuroimaging techniques such as functional magnetic resonance imaging, positron emission tomography, electroencephalography, and magnetoencephalography provide a means to safely monitor brain activity in humans. In this review, we have summarized evidence derived from the neuroimaging studies and tried to elucidate the neurophysiological correlates of acupuncture. Previous investigations on the neural responses to acupuncture mainly focus on its acute effects and explore the correlation between the specific acupoints and cortical activations only in the spatial domain. However, abundant clinical reports and psychophysical analysis suggest the kinetics of acupuncture is longer acting as a function of time. Consequentially, an accurate interpretation of acupuncture actions depends on how effectively we can characterize the nature of temporal variations underlying neural activities, rather than simply detect the occurrence of such changes. This emerging picture indicates that both designing paradigms and statistical models involved in acupuncture studies should be applied with great care.

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.

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.

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.

Role of Progastrins and Gastrins and Their Receptors in GI and Pancreatic Cancers: Targets for Treatment

Accumulating evidence in literature suggests that amidated and non-amidated gastrins (gastrin precursors) may play an important role in the proliferation and carcinogenesis of gastrointestinal and pancreatic cancers, especially in the presence of DNA damaging agents and / or infectious agents. Amidated gastrins appear to have a protective role, while progastrins exert growth promoting effects in cancers. Several receptor subtypes and signal transduction pathways mediate the biological effects of the gastrin peptides. Progastrin and gastrins also exert anti-apoptotic effects, which may additionally contribute to the growth and co-carcinogenic effects of these peptides on GI mucosal cells in vivo. Amidated gastrins additionally play an important role in the migration of GI epithelial cells, and in glandular morphogenesis, while progastrins may play an important role in invasion and metastasis. Therefore, targeting progastrins, gastrins, and their cognate receptors may provide a therapeutic tool for treating GI and pancreatic cancers. Targeting CCK2-receptors has, so far, not provided optimal beneficial effects. However, targeting gastrins via a vaccine approach has provided some encouraging results for treating GI and pancreatic cancers. It is expected that targeting precursor gastrins (progastrins and gly-gastrins), exclusively rather than amidated gastrins, may be more effective for treating GI cancers. Since GI cancers at advanced stages are largely responsive to autocrine and intracrine progastrins, down-regulation of intracellular progastrins will likely be more effective at this stage.

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.