Amblyopia

A Review of Current and Prospective Treatments for Channelopathies, with a Focus on Gene and Protein Therapy

Reduced cell surface expression or the malfunctioning of ion channels gives rise to a group of disorders known as channelopathies. To treat the underlying cause, the delivery and/or expression of a functional ion channel into the cell membrane of the cell of interest is required. Unfortunately, for most channelopathies, current treatment options are only symptomatic and treatments that rectify the underlying damage are still lacking. Within this context, approaches that rely on gene and protein therapy are required. Gene therapy would allow the expression of a functional protein, provided that the cellular machinery in the diseased cell could correctly fold and traffic the protein to the cell membrane. Whereas protein therapy would allow the direct delivery of a functional protein, provided that the purification process does not affect protein function and a suitable delivery vehicle for targeted delivery is used. In this review, we provide an overview of channelopathies and available symptomatic treatments. The current state of gene therapy approaches mainly using viral vectors is discussed, which is followed by the role of nanomedicine in protein therapy and how nanomedicine could be exploited for the delivery of functional ion channels to diseased cells.

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.

Choroidal Thickness Measured by Ocular Coherence Tomography (SD-OCT) and Body Mass Index in Healthy Saudi Women: A Cross-sectional Controlled Study

Background: Obesity is one of the major public health problems globally, especially among women. Obesity is associated with glaucoma, cataract, age-related macular degeneration and diabetic retinopathy. Although it is clear that the anatomy and physiologic functions of the choroid may be affected by obesity, data investigating the effect of obesity on the choroid is limited and/or unavailable for the Saudi population.

Objective: To assess Choroidal Thickness (CT) changes in a sample of healthy Saudi Arabian women with different Body Mass Index (BMI) using Spectral-domain Ocular Coherence Tomography (SD-OCT).

Methods: A total of 140 healthy women aged 18-29 years (mean age ± standard deviation SD, 24.5 ± 1.7 years) with different BMI, axial length (AL) ≤ 24 ± 1.0 mm, and spherical equivalent refraction (SER) of ≤ ±2.0 dioptres were enrolled for the study. The participants were age and refractionmatched, and grouped into underweight (BMI ≤ 18.0 kg/m2) (n = 30), normal (control group) (18.5–24.9 kg/m2) (n = 43), overweight (25.0–29.9 kg/m2) (n=37), and obese study groups (≥ 30.0 kg/m2) (n = 30). SD-OCT imaging was performed on one eye of each participant. Comparisons among groups for all locations and the associations between CT and other variables were examined.

Results: The mean CT at the subfoveal region (285 ± 31 μm, range: 203 μm to 399 μm) was significantly greater, and it was the lowest in the nasal region (248 ± 26 μm, range 154 to 304) compared with other locations, across all the groups (p < 0.05). Compared with the control, the subfoveal choroid was thinner in the obese group (mean difference: 22.6 μm, 95% Confidence Interval; CI: 8.6 μm to 36.6 μm; p = 0.02) and across all locations (p < 0.05) but thicker at the temporal location in the underweight group (12.4 μm, 95% CI: -23.7 μm to −1.04 μm; p = 0.01). No significant association of subfoveal CT with any of the measured parameters, including age (p-values ranged from 0.10 to 0.90), was found.

Conclusion: BMI may have an influence on the CT of healthy individuals and could be a cofounder in research studies on CT. It is, therefore, recommended that BMI should be evaluated in the clinical diagnosis and management of conditions associated with choroid in healthy individuals.

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.

The Importance of Citicoline in Combined Treatment in Dementia: What did the Citimem Study Teach us?

Background: Citicoline is a drug used both in degenerative and in vascular cognitive decline; memantine is a drug used for the treatment of mild to moderate Alzheimer’s disease (AD). Our hypothesis is that their combined use could have enhanced action in patients having AD and mixed dementia (MD). We report the main tips from a recent study on the use of these drugs, the CITIMEM study.

Methods: The study was retrospective and was performed on 126 patients aged 65 years old or older affected with AD or MD (mean age 80.7 ± 5.2 years old) who had been visited between 2015 and 2017 in four different centers for dementia all over Italy. Neuropsychological and functional tests were administered at baseline (T0), after 6 (T1), and 12 months (T2). The effects of combined treatment versus memantine alone on cognitive functions assessed by Mini-Mental State Examination (MMSE) and the possible onset of side effects or adverse events, as well as the influence on daily life functions and behavioral symptoms, were investigated.

Results: Patients undergoing combined treatment showed a significant increase in MMSE vs. memantine alone, both at T1 (p=0.003) and T2 (p =0.000).

Conclusion: The CITIMEM study confirms our hypothesis that the combined administration of memantine plus citicoline is safe and more effective than memantine alone on cognition in patients suffering from AD or MD.

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.

Research Progress and Prospect of Orthodontic Accelerating Device

Background: Malocclusion is a disease with a high incidence rate that is harmful to humans’ health. Fixed orthodontics is an effective method for the treatment of malocclusion. However, the orthodontic process takes a long time, requires frequent visits, causes pain, and increases the risk of complications. Since orthodontic treatment is lengthy, painful and unbearable, and even leads patients to abandon orthodontic treatment, therefore, how to shorten orthodontic treatment duration, and reduce pain is a research hotspot in the orthodontic field.

Objective: The study aimed to provide an overview of the existing orthodontic accelerating device and introduce their classification, characteristics and development.

Methods: This paper reviewed various productions and patents related to the orthodontic accelerating device. The structural characteristics, differentiations, and applications of the existing orthodontic accelerating device are also introduced.

Results: The existing orthodontic accelerating devices were analyzed and compared, and the typical characteristics were concluded. The main problems in its development were analyzed, the development trend was foreseen, and the current and future research on the productions and patents related to the orthodontic accelerating device is discussed.

Conclusion: The orthodontic accelerating device is composed of a vibration device having electrical stimulation, magnetic field, a low-level laser, and an ultrasonic device according to the application of different physical loads. Orthodontic accelerating device can effectively reduce orthodontic treatment time by 30%-50%, and can reduce the risk of complications and pain. The dose of the physical load determines the effect of the device. So, an optimal loading dose should be selected . Compared with vibrating devices, other types of devices are less used in clinical practice, therefore, such products and patents should be invented in the future.

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.

Synaptic Elimination in Neurological Disorders

Synapses are well known as the main structures responsible for transmitting information through the release and recognition of neurotransmitters by pre- and post-synaptic neurons. These structures are widely formed and eliminated throughout the whole lifespan via processes termed synaptogenesis and synaptic pruning, respectively. Whilst the first process is needed for ensuring proper connectivity between brain regions and also with the periphery, the second phenomenon is important for their refinement by eliminating weaker and unnecessary synapses and, at the same time, maintaining and favoring the stronger ones, thus ensuring proper synaptic transmission. It is well-known that synaptic elimination is modulated by neuronal activity. However, only recently the role of the classical complement cascade in promoting this phenomenon has been demonstrated. Specifically, microglial cells recognize activated complement component 3 (C3) bound to synapses targeted for elimination, triggering their engulfment. As this is a highly relevant process for adequate neuronal functioning, disruptions or exacerbations in synaptic pruning could lead to severe circuitry alterations that could underlie neuropathological alterations typical of neurological and neuropsychiatric disorders. In this review, we focus on discussing the possible involvement of excessive synaptic elimination in Alzheimer’s disease, as it has already been reported dendritic spine loss in post-synaptic neurons, increased association of complement proteins with its synapses and, hence, augmented microglia-mediated pruning in animal models of this disorder. In addition, we briefly discuss how this phenomenon could be related to other neurological disorders, including multiple sclerosis and schizophrenia.

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.

Leber's Hereditary Optic Neuropathy: Novel Views and Persisting Challenges

Background & Objective: Leber's hereditary optic neuropathy is an inherited form of optic neuropathy, genetically and pathophysiologically based on mitochondrial insufficiency causing bilateral loss of central vision mostly amongst young adults. Despite being one of the most common mitochondrial diseases, the explanation for its pathophysiological background and effective clinical solutions remain elusive. Widening the scope in the search for pathological findings beyond the optic system has yielded several non-ophthalmologic findings, which might imply that Leber's hereditary optic neuropathy is in fact a multi-systemic disease.

Conclusion: The aim of this review is to provide an overview of literature regarding the epidemiology, etiology, pathogenesis, clinical features, diagnostics and possible treatment options and drug targets, as well as presenting challenges related to the disease and proposing a diagnostic algorithm based on current clinical experience.

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.

Therapeutic, Molecular and Computational Aspects of Novel Monoamine Oxidase (MAO) Inhibitors

Background Due to the limited number of MAO inhibitors in the clinics, several research efforts are aimed at the discovery of novel MAO inhibitors. At present, a high specificity and a reversible mode of inhibition of MAO-A/B are cited as desirable traits in drug discovery process. This will help to reduce the probability of causing target disruption and may increase the duration of action of drug.

Aim: Most of the existing MAO inhibitors lead to side effects due to the lack of affinity and selectivity. Therefore, there is an urgent need to design novel, potent, reversible and selective inhibitors for MAO-A/B. Selective inhibition of MAO-A results in the elevated level of serotonin and noradrenaline. Hence, MAO-A inhibitors can be used for improving the symptoms of depression. The selective MAO-B inhibitors are used with L-DOPA and/or dopamine agonists in the symptomatic treatment of Parkinson's disease. The present study was aimed to describe the recently developed hits of MAO inhibitors.

Method: At present, CADD techniques are gaining an attention in rationale drug discovery of MAO inhibitors, and several research groups employed CADD approaches on various chemical scaffolds to identify novel MAO inhibitors. These computational techniques assisted in the development of lead molecules with improved pharmacodynamics / pharmacokinetic properties toward MAOs. Further, CADD techniques provided a better understanding of structural aspects of molecular targets and lead molecules.

Conclusions: The present review describes the importance of structural features of potential chemical scaffolds as well as the role of computational approaches like ligand docking, molecular dynamics, QSAR and pharmacophore modeling in the development of novel MAO inhibitors.

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.

The Fall in Older Adults: Physical and Cognitive Problems

Background: The aging of posture and balance function alters the quality of life in older people and causes serious problems in terms of public health and socio-economic costs for our modern societies.

Method: This article reviews the various causes of imbalance and dizziness in the elderly, and considers how to prevent falls, and how to rehabilitate a faller subject in order to regain a good quality of life. Two effective ways of intervention are discussed, emphasizing the crucial role of physical activity and cognitive stimulation, classic or using the latest technical advances in virtual reality and video games.

Results: Fall in the elderly result from aging mechanisms acting on both the sensorimotor and cognitive spheres. The structural and functional integrity of the peripheral sensory receptors and the musculoskeletal system deteriorate with age. The brain ages and the executive functions, memory, learning, cortical processing of information, sharing of attentional resources and concentration, are modified in the elderly. Psychological affective factors such as depression, anxiety and stress contribute also to speed up the sensorimotor and cognitive decline. The rehabilitation of the postural balance in the elderly must take into account all of these components.

Conclusion: The aging of the population and the increased of lifespan are a challenge for our modern societies regarding the major health and socio-economic questions they raise. The fall in the elderly being one of the dramatic consequences of the aging equilibration function, it is therefore imperative to develop rehabilitation procedures of balance.

Smoking and Eye Pathologies. A Systemic Review. Part I. Anterior Eye Segment Pathologies

Background: Tobacco smoking has detrimental influence on human health and is one of the leading causes of preventable mortality worldwide, associated with lung cancer, chronic obstructive lung disease and cardiovascular disease.

Aim: The analysis of the influence of tobacco smoking on pathology of the anterior segment of the eye in adults and children.

Methods: A comprehensive review of the literature performed through MEDLINE and PubMed searches, was published during the period 2000-2016.

Results: In adults, tobacco smoking is associated with hyperopia, delayed corneal epithelial healing and progression of Fuchs’ endothelial corneal dystrophy. Smoking is a strong risk factor for age-related nuclear cataract. However, smoking is not associated with pterygium, and its influence on dry eye symptoms, central corneal thickness and progression of primary open glaucoma remains controversial. Smoking during pregnancy increases risk of convergent or divergent strabismus or poor stereo acuity, however, its influence on anophtalmia, microphtalmia, amblyopia and hyperopic refractive error is controversial.

Conclusion: Tobacco smoking plays an important role in the pathogenesis of many diseases of anterior eye segment leading to visual impairment in adults and children.

Ziconotide Monotherapy: A Systematic Review of Randomised Controlled Trials

Introduction: Chronic neuropathic pain is difficult to treat and is often refractory to most modalities of treatment. Ziconotide is a novel, potent, non-opioid, calcium channel blocking agent which has been shown in clinical trials to be effective in treating chronic neuropathic pain.

Methods: EMBASE, MEDLINE, CINAHL Plus and Web of Science electronic databases were searched for English language studies. Reference sections of articles were examined for further papers and the manufacturer of ziconotide was contacted for further unpublished data. Three randomised controlled trials in ziconotide monotherapy were included and subjected to a random effects meta-analysis.

Results: All three studies used the similar main outcome measure (visual analogue scale of pain intensity; VASPI) and were therefore comparable. A Jadad score was performed for each paper. Frequent serious adverse events (SAEs) were observed which resulted in two of the studies revising the protocol. The metaanalysis revealed a pooled odds ratio (responders on ziconotide vs. placebo) of 2.77 (95% CI, 1.37 to 5.59).

Discussion: The results suggest that ziconotide is beneficial for pain reduction in chronic neuropathic pain. However, there remain some methodological issues that may call into question the validity of the results. It is evident that more work needs to be conducted to further validate the efficacy of ziconotide and to discover new areas of use.

Development of a Registry for Down Syndrome in the Gulf Area of the Middle East

Systems for organizing specific data about large groups of people have been in existence for many years; their structures depend greatly on their purposes and goals. This paper describes the creation of a registry and database detailing demographics and co-occurring conditions of a population with Down syndrome living in the United Arab Emirates. The Gulf Down Syndrome Registry-Abu Dhabi seeks to describe the population’s demographics and associated co-occurring conditions, bringing attention to their unique needs through description of findings.

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.

Non-Antidepressant Treatment of Generalized Anxiety Disorder

Introduction: Generalized anxiety disorder (GAD) is a prevalent and very disabling anxiety disorder. First-line medications are antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and selective serotonin and noradrenalin reuptake inhibitors (SNRIs). However, a substantial number of patients do not reach remission while on antidepressants and they may develop troublesome side effects, which highlights the necessity of new therapeutic options for GAD.

Methods: The purpose of this review is to discuss all non-antidepressant treatments studied in GAD. We searched MedLine for English articles published between 1980 and 2012, containing the following keywords: “generalized (or generalised) anxiety disorder” OR “anxiety disorder”, AND “drug therapy” OR “herbal medicine”. 76 articles were finally selected.

Results: Pregabalin is the anticonvulsant with the most robust level of evidence in GAD. It rapidly reduces anxiety, has a safe side effect profile and presents a low potential for abuse. Among antipsychotics, quetiapine is the one of choice in GAD, with similar efficacy to SSRIs in low dosages, yet with lower overall tolerability. Benzodiazepines, buspirone and hydroxyzine are Food and Drugs administration (FDA) approved for GAD and have relatively good evidence of efficacy. Other drugs (betablockers, zolpidem, riluzole, etc.) and natural remedies (e.g. Piper methysticum) could be potential treatment options, yet additional research is warranted.

Conclusion: Pregabalin and quetiapine are the two most promising non-antidepressant treatments for GAD.

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.

Genetic Basis of Mitochondrial Optic Neuropathies

Over two decades have elapsed since the first mtDNA point mutation was associated with Leber’s hereditary optic neuropathy (LHON) in 1988. We have subsequently witnessed a substantial understanding of the molecular basis of hereditary optic neuropathies, as well as of their clinical features and pathogenic mechanisms. It became clear that the large majority of genetic optic neuropathies have a primary or an indirect involvement of mitochondrial functions, justifying the definition of “mitochondrial optic neuropathies”. Despite this progress many unsolved features remain to be understood, such as incomplete penetrance and variable clinical expressivity in LHON and dominant optic atrophy (DOA), gender prevalence in LHON, and complex gene/environment interactions in both LHON and DOA. The most recent advancement in our understanding of the molecular basis of mitochondrial optic neuropathies is the topic of this review. In particular, we analyze the role that mitochondrial biogenesis may play in the compensatory mechanisms that underlie incomplete penetrance and clinical expressivity, a scenario relevant for the possible design of future therapeutic approaches.

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.

Signaling with Homeoprotein Transcription Factors in Development and Throughout Adulthood

The concept of homeoprotein transduction as a novel signaling pathway has dramatically evolved since it was first proposed in 1991. It is now well established in several biological systems from plants to mammals. In this review, the different steps that have led to this unexpected observation are recalled and the developmental and physiological models that have allowed us (and a few others) to consolidate the original hypothesis are described. Because homeoprotein signaling is active in plants and animals it is proposed that it has predated the separation between animals and plants and is thus very ancient. This may explain why the basic phenomenon of homeoprotein transduction is so minimalist, requiring no specific receptors or transduction pathways beside those offered by mitochondria, organelles present in all eukaryotic cells. Indeed complexity has been added in the course of evolution and the conservation of homeoprotein transduction is discussed in the context of its synergy with bona fide signaling mechanism that may have added robustness to this primitive cell communication device. The same synergy possibly explains why homeoprotein signaling is important both in embryonic development and in adult functions fulfilled by signaling entities (e.g. growth factors) themselves active throughout development and in the adult. The cell biological mechanism of homeoprotein transfer is also discussed. Although it is clear that many questions are still in want of precise answers, it appears that the sequences responsible both for secretion and internalization are in the DNA-binding domain and very highly conserved among most homeoproteins. On this basis, it is proposed that this signaling pathway is likely to imply as many as 200 proteins that participate in a myriad of developmental and physiological pathways.

Adverse Drug Reaction Labelling for Atomoxetine, Methylphenidate and Modafinil: Comparison of Product Information for Oral Formulations in Australia, Denmark and the United States

Medical product information contains information about efficacy and safety for marketed pharmaceuticals. Three studies have compared safety labelling for different therapeutic categories in different countries and detected large variations in a number of reported adverse drug reactions (ADRs). The rapid increase in use of medications for treatment of ADHD symptoms has created concern due to lack of information about effects from long-term use. The aim of this study was to compare ADR information in product information (PI)/summary of product characteristics (SPC) for oral formulations of atomoxetine, methylphenidate and modafinil marketed by the same pharmaceutical companies in Australia, Denmark and the United States. Discrepancies in listed ADRs were defined as types of ADRs (system organ class) not listed in all countries. For ADRs where discrepancies were detected, we extracted information about study design (clinical trials, spontaneous report). Discrepancies in ADR labelling for the medications were found across the three countries. A total of 75 ADR categories were listed for atomoxetine and 80% of these were listed in all three countries. For methylphenidate, totally 101 ADR categories and for modafinil 115 ADR categories were listed. For both substances approximately 60% of listed ADRs were found in all three countries. Discrepancies were primarily detected for ADRs information based on clinical trials. For methylphenidate, many ADRs labelled in Australia and Denmark were not mentioned in PIs issued in the United States. In conclusion, information about possible ADRs associated with the use of a specific product should be made available worldwide, as the prescriber information about medicines’ safety profile should not depend on the country in which the medication is licensed.

Giant Cell Arteritis – A Series of Cases and Review of Literature

Giant cell arteritis is the most frequently occurring primary vasculitis in European and North American adults over the age of 50 years. It usually presents with constitutional symptoms like fatigue, malaise and fevers with a temporal headache. We present a series of three interesting cases of the disease, discuss the differential diagnosis and review the literature on the same.

Coated with Nanomaterials Intraocular Lenses, Ophthalmic and Human Body Implantable Devices with High Catalytic Antioxidant Activities: A New Nanotechnology Strategy of Peroxidase Cellular Enzyme Mimics Increasing the Biocompatibility and Therapeutic Deployment of the Medical Prosthetic Device

While cataract surgery is generally recognized as being one of the safest operations, there is still a significant complication rate. From 30 to 50% of all patients in the United States having cataract extraction develop opacification of the posterior lens capsule within two years and require laser treatment with its own significant risk of complications. Of the patients having cataract surgery, 0.8% develop retinal detachments, from 0.6% to 1.3% were rehospitalized for corneal edema or required corneal transplantation and about 0.1% presented with endophthalmitis . Thus, aside from secondary cataract, about 2% of 1.3 million people, or 26,000 individuals in the United States annually develop serious complications as a result of cataract surgery.

The aim of this investigation was to increase the safety and effectiveness of an individual intraocular lens (IOL) preventing an impairment in peroxide metabolism of the mature human cataractous lenses compared to normal lenses employing the specific nanotechnology coating which substitutes the inhibitory effect of the implantable device towards the active species of oxygen and the ability of IOL to regulate the H2O2 and lipid hydroperoxides levels in the surrounding medium.

The implantation of IOLs with metabolic activity improves the capability of the surrounding ocular tissues to withstand oxidative stress induced in ocular humors by the photochemical and other metabolic reactions. The coated implantable medical device with thin film of platinum applied with magnetron sputtering, reacts as a body enzyme with deleterious peroxide compounds and free radical oxygen species in body fluids and tissue when said device is implanted into human body. The IOL having haptics coated with thin film of platinum, catalyzes the reduction of peroxide compounds to decrease their levels within the aqueous humor. Further, the coatings also scavenge toxic free radicals of oxygen, thus preventing cellular dysfunction resulting from oxidative attack.

Coated IOLs according to the patented nanotechnology can address the vast majority of cataract surgery-induced complications, such as secondary cataract, intraocular inflammation (endophthalmitis) and foreign body reactions, cystoid macular oedema , corneal edema . The nanotechnology offers physicians and surgeons to develop and commercialize costeffective therapeutic medical implantable devices, products and support systems with metabolic activities for the treatment of ophthalmic diseases and of a wide range of pathological states and disorders which are treated by insertion of the implantable and prosthetic (polymeric) devices.

Current Updates in the Medical Management of Obesity

Obesity is a chronic medical condition that is expected to become an indirect but leading cause of mortality and morbidity. Obesity results in type 2 diabetes mellitus, insulin resistance, hypertension, dyslipidemia, coronary heart disease. These factors contribute to cardiovascular disease that is a leading cause of death. Therefore, the approach to obesity therapy should be designed to reduce cardiovascular disease risk and mortality. Diet and lifestyle changes remain the cornerstones of therapy for obesity, but the resultant weight loss is often small. For more effective weight loss, individuals have shown to benefit from anti-obesity medications. Anti-Obesity therapy is considered for individuals with a body mass index greater than 30 kg/m2 or ranging from 25 to 30 kg/m2, or individuals with co-morbid conditions. Recent anti-obese medications affect biological mechanisms that suppress appetite and absorb nutrients to regulate body weight. In this review, we discuss the FDA approved anti-obesity drugs and recent patents which include phentermine/topiramate, pramlintide, lorcaserin, AOD9604, oleoyl-estrone, trk-beta antagonists and melanin concentrating hormone that can reduce adiposity at the molecular level.

Treatment of Central Nervous System Tuberculosis Infections and Neurological Complications of Tuberculosis Treatment

Tuberculosis (TB) with central nervous system (CNS) manifestation is a form of TB with a high mortality and morbidity. Tuberculous meningitis (TM) is the most common form of CNS-TB. Although diagnosis of CNS-TB can be challenging, early treatment of CNS-TB is related to a better outcome. If CNS-TB is suspected, even though the clinical picture is not specific, it should be immediately treated.

For the treatment of CNS-TB, knowledge of the penetration across the blood-brain barrier of the various antituberculosis agents used in TB treatment is important. These will be described here in order to serve as a guide in choosing a treatment for CNS-TB. Corticosteroids have an evidence-based value in the treatment of TM and so are recommended. As for thalidomide use in CNS-TB, sound evidence is still lacking. We will also include a description of the adverse neurotoxic effects of the various other agents including their psychiatric, ototoxic and ophthalmic adverse effects.

Depot Based Drug Delivery System for the Management of Depression

Depression is a common mental disorder discerns with depressed mood, loss of interest, the primary treatment methods are drug therapy, electroconvulsive therapy, psychotherapy, light therapy, vagus nerve stimulation, etc. A number of innovative delivery systems have been developed to address suboptimal therapy outcomes by enhancing drug delivery, assuring efficacy of treatment, reducing side effects, improving compliance and drug targeting specific locations resulting in a higher efficiency. Depot delivery offers the advantage of a very high loading, controlled release of drug for an extended period of time and reduces frequency of dosing. The increase in AUC and decrease in Cmax reflects that the depot formulations could reduce the toxic complications and limitations of conventional and oral therapies. Products at preclinical and clinical stages include formulations of naltrexone and buprenorphine for alcoholism/drug abuse, GLP-1 peptides for diabetes, r-hFSH for fertility, dopamine for nerve growth, dexamethasone for ocular treatment, melanotan for cancer prevention, plasmid DNA for cancer prevention, a variety of vaccines, octreotide generics, etc. Most depot formulations are comprised of biodegradable polymer-excipients that control the rate of drug release and resorbs during/after drug release. The major advantage of depot antipsychotics over oral medication was facilitation of compliance in medication taking. One class of biodegradable polymers that has gained wide acceptance and still attractive today is lactide/ glycolide polymers. The greatest advantage of these degradable polymers is that they are broken down into biologically acceptable molecules that are metabolized and removed from the body via normal metabolic pathways. This versatile delivery system offers the advantage of a very high loading and controlled release of various drug for an extended period of time compared with plain delivery system. New formulations of depression can offer advantages over older formulations in terms of convenience, side effect profiles, efficacy, and/or a fast onset of action.

The Newborn Individualized Developmental Care and Assessment Program (NIDCAP) with Kangaroo Mother Care (KMC): Comprehensive Care for Preterm Infants

State-of-the-art Newborn Intensive Care Units (NICUs), instrumental in the survival of high-risk and everearlier- born preterm infants, often have costly human repercussions. The developmental sequelae of newborn intensive care are largely misunderstood. Developed countries eager to export their technologies must also transfer the knowledgebase that encompasses all high-risk and preterm infants' personhood as well as the neuro-essential importance of their parents. Without such understanding, the best medical care, while assuring survival jeopardizes infants' long-term potential and deprives parents of their critical role. Exchanging the womb for the NICU environment at a time of rapid brain growth compromises preterm infants' early development, which results in long-term physical and mental health problems and developmental disabilities. The Newborn Individualized Developmental Care and Assessment Program (NIDCAP) aims to prevent the iatrogenic sequelae of intensive care and to maintain the intimate connection between parent and infant, one expression of which is Kangaroo Mother Care. NIDCAP embeds the infant in the natural parent niche, avoids over-stimulation, stress, pain, and isolation while it supports self-regulation, competence, and goal orientation. Research demonstrates that NIDCAP improves brain development, functional competence, health, and life quality. It is cost effective, humane, and ethical, and promises to become the standard for all NICU care.

Uveitis in Rheumatic Diseases

Uveitis is a common extra-articular manifestation of many rheumatic diseases and can be associated with considerable morbidity, both in terms of vision loss and the need for systemic immunosuppression. Anterior uveitis is symptomatic in adults, presenting as a red, painful eye with photophobia, and is most commonly associated with HLAB27 disease. In contrast, chronic anterior uveitis can be silent in children with juvenile idiopathic arthritis, necessitating regular screening to detect its presence. Posterior segment inflammation carries a worse prognosis for vision, and usually manifests as floaters and visual impairment. This article reviews the pathophysiology and clinical features of uveitis occurring in association with systemic inflammatory disease, as well as discussing the current and emerging therapies available for treating its various manifestations.

Manufacturing and Regulatory Strategies for Clinical AAV2-hRPE65

Recombinant adeno-associated virus (AAV) -based vectors expressing therapeutic gene products have shown great promise for human gene therapy. A recent milestone has been the safety and efficacy observed using recombinant AAV2 expressing retinal pigment epithelial associated 65KDa protein for Leber Congenital Amaurosis. This review summarizes manufacturing and characterization of ‘AAV2-hRPE65v2’, the vector used in one completed Phase I/II clinical trial. Regulatory challenges and strategies that were successfully used for this groundbreaking trial are described.

Dorsal Stream Dysfunction in Children. A Review and an Approach to Diagnosis and Management

The classical model of how the human visual system works is that image data are transferred from the eyes to the occipital cortex where the picture is “seen”. Damage to the parts of the brain serving vision causes visual field impairment and reduced visual acuities. However, additional impairment of higher visual processing is common and may go unrecognised. Two higher visual pathways have recently been described, the dorsal and ventral streams. The dorsal stream connects the occipital lobes and posterior parietal lobes. It serves to appraise the whole scene, and perceive elements within the scene. It facilitates visual guidance of movement, by interacting with area V5 of the middle temporal lobes, or motion perception centre. It is automatic, immediate and unconscious. It is ‘on line’ and is not memory based. Damage impairs visual guidance of movement (optic ataxia) and visual search. The ventral stream links the occipital and temporal lobes, which contain the “image libraries”. Recognition of faces, shapes, objects and routes, is attained by matching incoming data with “library data”. Dorsal stream dysfunction results from posterior parietal damage and is associated with cerebral palsy, periventricular white matter injury, premature birth, hydrocephalus and Williams syndrome, and similar visual difficulties are becoming apparent in children with autistic spectrum disorder. Ventral stream dysfunction is less frequent and usually accompanies dorsal stream dysfunction. It is not uncommon in children with hydrocephalus. A specific disorder of dorsal stream dysfunction is emerging, comprising difficulty handling the complexity of a visual scene (of varying degree) with impaired visual guidance of the limb movement (optic ataxia). Commonly, but not always this is associated with reduced visual acuities and visual field impairment, and occasionally with impaired recognition of people (which could be called “dorsal stream dysfunction plus”).

Current Ocular Drug Delivery Challenges for N-acetylcarnosine: Novel Patented Routes and Modes of Delivery, Design for Enhancement of Therapeutic Activity and Drug Delivery Relationships

This review article explores the functional activity and development aspects of N-acetylcarnosine for the visual system as revealed by the use of a variety of biophysical, physiological and therapeutic ophthalmic methods. It is designed for pharmacists and more advanced ophthalmology, optometry and pharmacology researchers who wish to gain a basic understanding of the biological effects of N-acetylcarnosine for vision and to share in the excitement of the latest developments in this field. Topics under the consideration include: ophthalmic drug delivery of N-acetylcarnosine eye drops and challenging endeavors facing the pharmaceutical scientist; clinical and functional types of activity of the developed and patented N-acetylcarnosine lubricant eye drops designed as 1% N-acetylcarnosine prodrug of L-carnosine containing a mucoadhesive cellulose-based compound combined with corneal absorption promoters in a drug delivery system; management of age-related serious or disabling eye diseases in humans with N-acetylcarnosine eye drop therapeutic platform (age-related cataracts, ocular inflammation, age-related macular degeneration , macular dystrophies, ocular manifestations of diabetes , hypertonic retinopathy, primary open angle glaucoma , vitreous lesions) ; development and molecular mechanisms of ocular therapeutic activities of carnosine derivatives in the visual system. Through this article we can perceive some helpful recent patents according to the title of the issue. The biologically significant applications of carnosine mimetics including those in ophthalmology were patented by Dr. Babizhayev and the alliance Groups (WO2004028536A1; WO9419325; WO9512581; WO2004064866A1).

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.

Intraocular Lens and Biocompatibility - A Review

Enormous work and research have been done so far for improving and developing new biocompatible biomaterials. Still, the need for better biocompatible materials is there for implants like Intraocular lens (IOL). IOLs are used for correcting eye vision. They are placed inside eye after surgery. Besides quality and performance of material, biocompatibility is an important aspect for implants. Advances in the field of IOLs still require the material of high quality which meets the stringent norms of performance. Scientists are working on the development of materials for IOL targeting the needs arising out of the developing countries. The challenge includes not only bringing down the cost of the material but also increases biocompatibility of IOLs. To aid in knowledge of material and biomedical scientists, we are presenting here a review article with compilation of work done so far along with recent patents in relation to IOLs and biocompatibility.

Abnormal Head Posture due to Ocular Problems- A Review

An abnormal head posture (AHP), or torticollis, is a common condition in children, with an estimated incidence of 1.3%. This condition is encountered commonly by primary care family pediatricians. AHP can be congenital or acquired. The cause of the AHP can be ocular, orthopedic and neurologic. The orthopedic causes of AHP include congenital muscular torticollis due to tightness of the sternocleidomastoid muscle, Klippel- Feil anomaly and brachial plexus injury. Neurologic causes of AHP are mainly related to brain tumors, postinflammatory central nervous system conditions, psychomotor delay and focal dystonia. Other less common reasons for AHP are: Sandifer syndrome (hiatal hernia associated with gastro- esophageal reflux) and unilateral hearing loss. Numerous ocular conditions can cause AHP or “ocular torticollis”. Among them: superior oblique muscle palsy, lateral rectus muscle palsy, nystagmus, vertically incomitant horizontal strabismus (A or V patterns), Browns syndrome, Duanes syndrome, refractive errors and DVD. The AHP can take the form of head tilt, face turn, chin up, chin down or combined, depending on the specific etiology. However, there are many variations and the type of the head posture cannot reliably predict the underlying cause. Since the etiology is not always obvious, these patients must be carefully evaluated, and sometimes a multidisciplinary approach is needed, including examinations by ophthalmologist, neurologist and orthopedist. Ocular AHP is usually an attempt to improve visual acuity or binocularity. Some patients adopt the head posture to avoid diplopia caused by incomitant strabismus, those with nystagmus adopt a head position that brings the eyes to the null point (where the oscillations dampen or markedly diminish). Ocular AHP is usually a binocular phenomenon. Rarely, abnormal head position can be acquired following visual loss in one eye. The majority of these ocular conditions require eye muscle surgery. Different ocular etiologies of AHP require different surgical strategy, for this reason careful etiological diagnosis is important. The purpose of this article is to review the ocular conditions that cause AHP, their relative frequency, indication for surgery and the appropriate surgical treatment.

State of the Art Clinical Efficacy and Safety Evaluation of N-Acetylcarnosine Dipeptide Ophthalmic Prodrug. Principles for the Delivery, Self-Bioactivation, Molecular Targets and Interaction with a Highly Evolved Histidyl-Hydrazide Structure in the Treatment and Therapeutic Management of a Group of Sight-Threatening Eye Diseases

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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.

Review of Pediatric Uveitis

Uveitis is a significant cause of blindness and vision loss in children and encompasses a diverse group of disease processes. It is important that physicians become familiar with presenting symptoms and signs of uveitis. Early recognition and referral to a uveitis specialist is key in preventing irreversible vision loss. Aggressive management with antiinflammatory medications and immunosuppressive agents may be necessary. This chapter will provide an introduction to common causes of pediatric uveitis, as well as a discussion of classification, etiologies, work-up, and management.

The Contrast Sensitivity Test in Early Detection of Ocular Changes in the Relation to the Type I Diabetes Mellitus Compensation in Children,Teenagers, and Young Adults

An alteration of contrast sensitivity (CS) might be connected with structural and functional changes in foveolar and perifoveolar regions caused by different etiologies. We tested the hypothesis, that disturbances of CS can precede the typical changes in macular area in nonproliferative diabetic retinopathy (NPDR) in young patients with diabetes type 1 (T1DM). Material and methods: One hundred and twenty one (121) patients (63 girls and young women and 58 boys and young men) were included in the study; their age ranged 7 to 36 years, (median: 17.6 years). The T1DM duration was 6 to 21 years (median: 9.8 years), and it was diagnosed at the age from 2 to 30 years (median: 10.5 years). CS was examined in all patients repeatedly after one year (range, 11 - 15 months, median: 12.5 months) by means of CSV-1000 instrument in 3, 6, 12, and 18 cycles/degree (c/deg) respectively. In 42 patients older than 18 years of age, the simultaneous CS and fluorescein angiography (FA) were performed; in all of them, the T1DM duration was longer than 10 years. The compensation of the metabolic state was evaluated from average yearlong values of the glycolysated hemoglobin (Hb1Ac). Results: The value of pathologically decreased CS in most of the cases was found in four spatial frequencies and the difference increased depending on the T1DM duration and was from 5 % to 8 % between 6 and 10 years of diabetes duration and from 17 % to 25 % after 15 years of diabetes duration. The total decrease of CS, especially in middle and higher frequencies (6, 12, and 18 c/deg), was determined by the increase of changes at the posterior pole. The early changes at the fundus related to the alteration of CS were of two types: (1) the dilatation of the capillaries with their possible obliteration and tortuosity (DCT) and (2) the changes of the macular structure (CMS) by means of the irregularity of the foveolar reflex and relative retinal thickening without significant macular edema and with increased pigmentation of this region. The combination of these two findings was considered as diabetic preretinopathy (DpR) with preserved visual acuity and decrease of CS in 65 % of cases. The authors also compared the decrease in every single space frequency marked on the CS curvature for NPDR and DpR (distinguished by means of FA). Comparing the NPDR with the norm, the authors found important and fundamental pathological defect of the CS (p = 0.0058). Comparing the DpR with the norm showed significant defect of the CS (p = 0.0197). Comparing NPDR and DpR, the difference was found in more noticeable pathological defect of the CS (p = 0.0228). The T1DM metabolic status during study (actual blood sugar and one year level of Hb1Ac) did not affected the CS positively nor negatively. The regressive study concerning the average Hb1Ac level (norm: 6.5 - 7.5 % by DCCT) during the 10 years period found, that in NPDR patients the Hb1Ac level was pathologically increased during three quarters (7.5 years) of the follow up period and in DpR patients during one half of the same period (5 years). Conclusions: The CS test by means of the CSV - 1000 device can already detect the first retinal changes in patients with normal visual acuity and is positive in patients with still normal ophthalmologic macular finding.

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.

Fragile X Syndrome and Autism: Common Developmental Pathways?

Identifying atypical trajectories that distinguish children with differing developmental disorders from each other and from typically developing children is a potentially powerful tool for early ascertainment and treatment of syndrome specific proficiencies and deficiencies. The past decade has seen unparalleled advances in the fields of molecular genetics, pediatrics, developmental cognitive neuroscience and brain imaging. Collaboratively, these advances have facilitated our understanding of how genes can impact upon early development, through the identification of specific patterns of cognitive and behavior processing and the deficits in these domains that are typical to a specific developmental disorder. These advances have also made early diagnoses possible for many developmental disorders, including those for which genetic etiology has yet to be determined, such as is the case for most individuals with autism, or disorders such as fragile X syndrome that result from the silencing of a single gene. This early identification necessitates thorough investigation of the impact of a condition across the lifespan beginning in early childhood when interventions are most likely to have significant benefit. This is especially relevant for disorders that at first glance appear to share overlapping behavioral and clinical symptomology. In the case of autism and fragile X syndrome, commonalties in social and communication profiles are now well documented in early childhood. However, to what degree symptom overlap implies common developmental pathways or etiologies remains unclear. The focus of this review will be to critically evaluate whether so called commonalities in phenotypic outcomes actually reflect very different developmental pathways that diverge over developmental time and across syndromes. More detailed knowledge of these profiles will facilitate early timing of tailored interventions that will promote optimal development resulting in significant educational, clinical, and adaptive benefits across a childs lifespan.

Insights in Specific Cerebellar and Cerebral Activations in Blind Subjects

In the past, many aspects concerning specific cerebral activation patterns and cross-modal plasticity in blind subjects have been reported. Experimental data on cortical reorganization in blind subjects, using positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), has revealed activation of the visual cortex related to Braille reading and tactile discrimination tasks in congenitally and early blind subjects. In addition to the cortical activity in sensorimotor and visual areas, an increased global activation of the cerebellum has been shown during Braille reading in blind subjects. Our studies addressed the two aspects mentioned above: early blind and normal sighted subjects were studied with fMRI during Braille reading, tactile discrimination of nonsense dots, sensory electrical stimulation and finger tapping to reveal specific cerebral and cerebellar activation and further insights into cross modal plasticity. Findings of specific cortical and cerebellar activation during Braille reading in normal volunteers and blind subjects are discussed in light of the current literature concerning cross modal plasticity and the hypothesis of cerebellar involvement in language processing.

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.

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.

Prospects for Rational Development of Pharmacological Gap Junction Channel Blockers

Connexin-null mice and human genetic gap junction diseases illustrate the important roles that gap junction channels play under normal conditions, and the neuro- and cardioprotective effects of gap junction blocking agents demonstrate that closure of these channels may be beneficial in certain pathological situations. This overview summarizes studies in which gap junction modifying reagents have been characterized, highlighting examples of agents for which selectivity for gap junction subtypes has been demonstrated. In addition, strategies for targeting connexin domains through peptide inhibitors are outlined, which may ultimately provide agents that are not only connexin-selective in their actions, but also affect only a subset of a gap junction channels gating responses.