Arachnoiditis

Prenatal Magnetic Resonance Imaging helps Discover Cerebellar Dysplasia or Malformations in Foetuses

Objective: This study aimed to characterize and assess the diagnostic value of prenatal magnetic resonance (MR) imaging in detecting fetal cerebellar hypoplasia/dysplasia and developmental malformations.

Methods: Reports of suspected intracranial abnormalities were retrospectively collected on ultrasound screening (US), and MR images of fetuses were reviewed at our institution over a 5-year period on picture archiving and communication system (PACS) servers. Two experienced radiologists recorded major abnormalities and coexisting abnormalities at the reading of the census. The results of the MRI were compared against the US in each case.

Results: For prenatal MR imaging, we enlisted a total of 121 patients (mean gestational week, 24.5 ± 4.7 weeks). This included 28 cases with normal findings of MR imaging, 62 cases with findings of cerebellar hypoplasia or dysplasia, and the remaining 31 cases with other abnormities findings. Cerebral malformations cases included agenesis of the corpus callosum, cerebral hemorrhage, hydrocephalus, holoprosencephaly, ventriculomegaly, and brainstem/gyri malformation. Cerebellar abnormalities included vermis absence, cerebellar tonsil hernia, Dandy-Walker malformation, Blake’s pouch cysts, arachnoid cysts, and intracranial hemorrhage. Other systemic malformation cases included tethered cord syndromes (9 cases), cleft lip and palate (1 case), club foot (1 case), and cardiac malformation (1 case). In 12 cases (24.5%), compared to the US, MR imaging proved the value of confirming the diagnosis and/or even yielded more findings on abnormalities.

Conclusion: Prenatal MR imaging can better visualize systemic malformations coexisting with cerebellar abnormalities. MR imaging, a complementary means to the US, can aid in prenatal counseling and treatment selection for term delivery.

Coexistence of Large Meningioma and Arteriovenous Malformation: A Case Report and Literature Review

Introduction The simultaneous presence of a giant intracranial meningioma and an arteriovenous malformation(AVM)in the same cerebral hemisphere is extremely rare. The treatment should be individualized depending on the case.

Case Presentation A 49-year-old man presented with hemiparesis. Preoperative neuroimaging revealed a giant lesion and an AVM on the left hemisphere of the brain. Craniotomy and tumour resection were performed. The AVM was not treated and needed to be followed up. The histological diagnosis was meningioma (World Health Organization grade I). The patient was in good neurological condition postoperatively.

Conclusion This case adds to the growing literature suggesting that the association between the two lesions is complex. Besides, treatment depends on the risk of neurologic function damage and hemorrhagic stroke of meningiomas and AVMs.

In-vitro and In-silico Examinations on Baicalein-loaded Solid Lipid Nanoparticles for Neurodegeneration

Background: In the current scenario, most of the population affected by neurogenerative disorders like Alzheimer's, Parkinson's, Huntington's, etc., exist among the 10% population 65 years of age group. Neurodegenerative diseases are characterised as chronic and progressive disorders that occur due to the degeneration of neurons. Baicalein is a flavonoid glycoside derived from the roots of Scutellaria baicalensis. Earlier research suggested that it could be used to treat neurodegenerative illnesses. Baicalein, which was selected for the current study, was designed into a solid lipid nanoparticle (SLN) formulation. The SLNs have low permeability across BBB and are delivered by the non-invasive route, i.e., through nasal delivery. The In-silico docking studies were performed to examine and compare the binding affinity of Baicalein to already established drugs on the two most viable targets of Alzheimer's disease, i.e., Beta- secretase and Acetylcholinesterase.

Objectives: The current work is to formulate and evaluate the Baicalein-loaded SLN for neurodegenerative disorders via a non-invasive route.

Methods: Baicalein loaded SLN was developed by solvent emulsification diffusion method, and formulation is characterised by using different parameters such as particle size analysis, zeta potential, scanning electron microscope, transverse electron microscope, X-ray diffraction, Differential scanning calorimetric, Fourier transforms -infrared radiations, drug entrapment, in-vitro drug release and in-silico docking studies.

Results: The particle size of Baicalein-loaded SLN was 755.2 ± 0.48 nm, the Polydispersity index was 0.06, and the zeta potential was -32.5 ± 0.36 mV. The drug entrapment and loading efficiency of the optimised formulation were found to be 94% ± 0.653 and 18.2% ± 0.553, respectively. Optimised formulation shows 84.6% ± 0.3% of drug release within 30 minutes, which demonstrates the sustained release of the drug.

Conclusion: Baicalein-loaded SLN is formulated and evaluated for the treatment of neurodegenerative disorders. SLN is an approach to overcome the challenge of bypassing the BBB by administering the drug via an intranasal route. Hence, when analysed together with the results of Baicalein-loaded SLN and in-silico studies, it was correlated that Baicalein proved to have a targeted moiety for neurodegeneration.

A Review on the Efficacy and Safety of Intrathecal Administration of Novel Medications for Leptomeningeal Metastases in Solid Cancers

Leptomeningeal disease (LMD) is a rare and lethal manifestation that may occur in the advanced stages of solid tumors and hematological malignancies. With advances in diagnostic techniques, the detection and confirmation of the presence of LMD have increased. Although its optimal treatment remains a challenge, the use of the intrathecal route for the delivery of novel therapeutics is now considered a promising drug delivery strategy to complement radiation and systemic-based therapies. Although methotrexate, cytarabine, and thiotepa have a long history in the treatment of LMD, other medications have also been shown to be beneficial. In this article, we have reviewed the effects of novel medications administered via the intrathecal route for the treatment of solid tumors. We have searched PubMed, Scopus, and Google Scholar databases till the end of September 2021 using the following keywords: “leptomeningeal disease”, “leptomeningeal carcinomatosis”, “leptomeningeal metastases”, “solid tumors”, “solid cancers”, and “intrathecal”. Our literature findings have uncovered that most studies on LMD, which occurs secondary to solid cancers, are available as ‘case reports’, and few clinical trials have been conducted to date. Single-drug (monotherapy) or combination drug therapy, administered via the intrathecal route, especially in metastatic breast and lung cancer, has been shown to improve patients' symptoms and overall lifespan, while exhibiting a low and acceptable prevalence of side effects. However, judgments/conclusions about the effectiveness and safety of these drugs still require further clinical evaluation.

Multi-vesicular Liposome and its Applications: A Novel Chemically Modified Approach for Drug Delivery Application

Background: This study aimed to elaborate on all the aspects of multivesicular liposomes, including structure, function, topology, etc. Liposomes are a unique drug delivery system, in which both hydrophilic and hydrophobic drug molecules can be incorporated. Particularly, multivesicular liposomes have more advantages than other liposomes because of their unique structure. This study provides an overview of several works already performed by various researchers in this field. Numerous studies have reported on preparing and evaluating multivesicular liposomes for drug delivery applications. This study summarizes the process of formulating multivesicular liposomes and their application in drug delivery systems and provides details about how to resolve the problem of limited solubility and stability of biomolecules, along with controlled drug release kinetics, with the possibility of loading various drugs. There is no doubt that multivesicular liposome opens new avenues to develop novel drug delivery system for achieving the desired functional performances and expanding the applications in the drug delivery area.

An Evolution of Bilirubin Physiology and Analysis

Bilirubin is a yellow tetrapyrrole molecule found in the gastrointestinal system, and it is produced when hemoglobin (Hb) is degraded. For treating various liver disorders like jaundice, serum bilirubin in the body is a testing marker. Jaundice develops when the serum bilirubin level is more significant than 2.0 to 2.5 mg/dl. Examining different forms of bilirubin, i.e., conjugated (direct) bilirubin, unconjugated (indirect) bilirubin, and total bilirubin, helps the physician identify the cause and metabolic disorder of jaundice. Inconsistent bilirubin production and removal results in lasting neurologic consequences (kernicterus). In this paper, we have presented a brief introduction to jaundice, the physiological mechanism of bilirubin, its types and causes, clinical approaches toward patients having jaundice, i.e., the conventional method being practiced in clinical laboratories, and various non-invasive systems in the point-of-care settings along with their advantages and disadvantages. Information on bilirubin production and elimination with tracking of bilirubin levels may help to guide the proper clinical management of jaundice. The primary focus is on the progression of established methodologies and techniques to newer ones capable of measuring bilirubin in biological materials.

Proteomic Analyses Reveal Functional Pathways and Potential Targets in Pediatric Hydrocephalus

Introduction: Hydrocephalus is a common pediatric disorder of cerebral spinal fluid physiology resulting in abnormal expansion of the cerebral ventricles. However, the underlying molecular mechanisms remain unknown.

Methods: We performed proteomic analyses of cerebrospinal fluid (CSF) from 7 congenital hydrocephalus and 5 arachnoid cyst patients who underwent surgical treatment. Differentially expressed proteins (DEPs) were identified by label-free Mass Spectrometry followed by differential expression analysis. The GO and GSEA enrichment analysis was performed to explore the cancer hallmark pathways and immune-related pathways affected by DEPs. Then, network analysis was applied to reveal the location of DEPs in the human protein-protein interactions (PPIs) network. Potential drugs for hydrocephalus were identified based on drug-target interaction.

Results: We identified 148 up-regulated proteins and 82 down-regulated proteins, which are potential biomarkers for clinical diagnosis of hydrocephalus and arachnoid cyst. Functional enrichment analysis revealed that the DEPs were significantly enriched in the cancer hallmark pathways and immunerelated pathways. In addition, network analysis uncovered that DEPs were more likely to be located in the central regions of the human PPIs network, suggesting DEPs may be proteins that play important roles in human PPIs. Finally, we calculated the overlap of drug targets and the DEPs based on drugtarget interaction to identify the potential therapeutic drugs of hydrocephalus.

Conclusion: The comprehensive proteomic analyses provided valuable resources for investigating the molecular pathways in hydrocephalus, and uncovered potential biomarkers for clinical diagnosis and therapy.

Recent Update on Pharmacokinetics and Drug Metabolism in CNS-based Drug Discovery

Despite significant advancements in CNS research, CNS illnesses are the most important and serious cause of mental disability worldwide. These facts show a tremendous unmet demand for effective CNS medications and pharmacotherapy since it accounts for more hospitalizations and extended care than practically all other disorders combined. The site-targeted kinetics of the brain and, pharmacodynamics of CNS effects are determined/regulated by various mechanisms after the dose, including blood-brain barrier (BBB) transport and many other processes. These processes are condition-dependent in terms of their rate and extent because they are dynamically controlled. For effective therapy, drugs should access the CNS “at the right place, time, and concentration”. Details on inter-species and inter-condition variances are required to translate target site pharmacokinetics and associated CNS effects between species and illness states, improving CNS therapeutics and drug development. The present review encircles a short discussion about the barriers that affect effective CNS treatment and precisely focuses on the pharmacokinetics aspects of efficient CNS therapeutics.

Review of the Chemical Composition and Biological Activities of Essential Oils from Artemisia Argyi, Artemisia Princeps, and Artemisia Montana

Background: Artemisia argyi Lévl. et Van., Artemisia princeps Pamp., and Artemisia montana Pamp., which are the sources of mugwort, have been popular across East Asian countries for nearly 2000 years now. Essential oils are the major chemical component obtained from them, exhibiting a variety of biological activities.

Objective: This review mainly focuses on the chemical composition and biological activities of A. argyi essential oil (AAEO), A. princeps essential oil (APEO), and A. montana essential oil (AMEO), with a special focus on their common and specific characteristics. The traditional use, distribution, and botany of A. argyi, A. princeps, and A. montana have also been summarized. In addition, the pharmacokinetics of AAEO was involved.

Methods: We collected literature from online and offline databases by entering the following keywords: mugwort, wormwood, A. argyi, A. princeps, A. montana, essential oil, and volatile oil. No language limitation was present in our search.

Results: A. argyi, A. princeps, and A. montana were used as traditional medicine, food, and health care products for a long time in Asia. They are widely distributed in most parts of China, Korea, and Japan. AAEO, APEO, and AMEO composed of monoterpenes, sesquiterpenes and their derivatives, alkanes, olefins, etc. Most of the specific compounds of AAEO were monoterpenoids, nearly half of the specific compounds of APEO were aliphatic hydrocarbons, and the sesquiterpenes were the typical specific compounds of AMEO. The mugwort essential oil showed multiple biological activities, such as anti-microbial, anti-inflammatory, antioxidant, antitumor, anticoagulation, sedative, and insecticide.

Conclusion: The present review provided insight into the chemical composition and biological activity of AAEO, APEO, and AMEO. The comprehensive literature showed that they possessed wide application prospects in various fields. However, they should be studied in more depth. The underlying bioactive mechanisms should be elucidated and their toxicity and quality control should be determined.

Analysis of the Causes and Experience in the Diagnosis and Treatment of Meningocele Caused by Sternberg’s Canal of the Sphenoid Sinus: Two Case Reports and a Review of the Literature

Objective: The present study aimed to improve the diagnosis and treatment outcome of cerebrospinal fluid (CSF) rhinorrhea caused by patent meningoencephalocele of Sternberg’s canal of the sphenoid sinus by analyzing the clinical data and imaging features of two rare cases of this disease and by reviewing the relevant literature for possible etiology, diagnoses, and treatments.

Methods: Together with the relevant literature, we retrospectively studied the clinical and imaging data of two patients (mother and child) with CSF rhinorrhea caused by patent meningoencephalocele of Sternberg’s canal of the sphenoid sinus, analyzed their diagnostic and treatment procedures, and proposed a potential, feasible treatment method.

Results: On the 2^nd day after surgery, the expansive sponge and iodoform gauze in the nasal cavity were removed in both patients, and the lumbar subarachnoid drainage was removed 3 days after the operation, as no nasal discharge was observed. One week after the operation, head magnetic resonance imaging (MRI) showed that the abnormal tissue in the sphenoid sinus had disappeared, and no accumulation of the CSF was observed. Both patients were discharged after 2 weeks. At the time of discharge, both patients were without nasal drip, fever, headache, and other discomforts, and they had grade 5 muscle strength in their extremities, with normal muscle tension.

Conclusion: CSF rhinorrhea is usually caused by secondary factors. Spontaneous CSF rhinorrhea caused by encephalocele of the skull base due to congenital dysplasia of the skull base is very rare and easily misdiagnosed. The presence of brain tissue or CSF signal in the sphenoid sinus on preoperative MR images is an important imaging feature of the disease. Conditional cisternography can be used to further detect CSF leaks. Endoscopic transnasal transsphenoidal repair of CSF leaks combined with short-term postoperative lumbar subarachnoid drainage is an effective treatment method. According to previous literature, the possible causes of meningoencephalocele with patent Sternberg’s canal of the sphenoid sinus include abnormal development of the sphenoid sinus or the craniopharyngeal canal and bone defects of the skull base. There are no related reports on patent meningoencephalocele caused by Sternberg’s canal in direct blood relatives, such as mother-son; therefore, the possibility of this disease having a genetic origin should be considered in future studies on its pathophysiological mechanisms.

How Do Abnormalities in the Cerebrospinal Fluid Impact Neuropsychology with Progressing Age?

The behavior of an individual changes from neonate to elderly due to the development of the central nervous system (CNS). One of the important components of the CNS is the cerebrospinal fluid (CSF), which bathes the brain and spinal cord. CSF has changing properties throughout life, including composition and volume imbalance. However, a specific age group that shows prevailing abnormality- corresponding behavior remains unclear. The objective of this article is to explore how such changes reflect on one’s psychological as well as physical processing. Production of CSF could be affected by many factors, including its flow, absorption, volume, and composition. Prenatally, congenital malformations and infections hold the greatest risk of impacting the child’s physical and mental growth. In adolescents, transmission of external substances like alcohol or drugs in the cerebrospinal fluid is known to impact severe mood changes that potentially result in suicide and depression. In the adult working population, the influence of stress levels on CSF composition causes anxiety and sleep disorders. Finally, the reduced production of CSF was found to be associated with memory deficits and Alzheimer’s disease in the aging group. From the collected evidence, it can be observed that CSF played an important role in behavioral changes and may be associated with neurodegenerations. By linking the CSF abnormalities to the clinical symptoms at different stages of life, it may provide additional information in the diagnosis of diseases that are associated with neuropsychological changes.

Distinguishing Intramedullary Spinal Cord Neoplasms from Non-Neoplastic Conditions by Analyzing the Classic Signs on MRI in the Era of AI

Intramedullary lesions can be challenging to diagnose, given the wide range of possible pathologies. Each lesion has unique clinical and imaging features, which are best evaluated using magnetic resonance imaging. Radiological imaging is unique with rich, descriptive patterns and classic signs-which are often metaphorical. In this review, we present a collection of classic MRI signs, ranging from neoplastic to non-neoplastic lesions, within the spinal cord. The Differential Diagnosis (DD) of intramedullary lesions can be narrowed down by careful analysis of the classic signs and patterns of involvement in the spinal cord. Furthermore, the signs are illustrated memorably with emphasis on the pathophysiology, mimics, and pitfalls. Artificial Intelligence (AI) algorithms, particularly deep learning, have made remarkable progress in image recognition tasks. The classic signs and related illustrations can enhance a pattern recognition approach in diagnostic radiology. Deep learning can potentially be designed to distinguish neoplastic from non-neoplastic processes by pattern recognition of the classic MRI signs.

Mucoadhesive Nanosystems for Nose-to-Brain Drug Delivery in the Treatment of Central Nervous System Diseases

The diseases affecting the Central Nervous System (CNS) can have varied etiopathology, but they have in common silent progression, global incidence, and significant impacts on the quality of life of patients and public health systems. With the advance of biomedicine and pharmaceutical technology, new and more modern diagnostic methods and treatments were developed, repurposing the use of drugs currently available for the treatment of CNS diseases. An attractive approach is the use of alternative drug delivery platforms, such as nanocarriers, and less invasive administration routes, such as the noseto- brain, extensively explored for the delivery of drugs into the CNS. Despite many promising results, the nose-to-brain route has some physiological limitations that make it difficult to deliver drugs satisfactorily to exert therapeutic activity in the CNS. To overcome these limitations, nanostructured systems with mucoadhesive properties have stood out over the last few years in pharmaceutical R&D. In this review; we discuss how the noseto- brain route limitations can influence the delivery of drugs to the CNS and highlight the benefits that mucoadhesion can bring to these nanostructured systems. The main findings in the literature are brought together and discussed critically, focusing on how mucoadhesion can improve the biopharmaceutical properties of molecules used in the clinic, as well as their biological performance. Finally, conclusions are drawn about the points of strength of mucoadhesive nanosystems and the points that still need attention to successfully use the nose-to-brain route for the treatment of diseases that affect the CNS.

Recent Advances in Neuromyelitis Optica Spectrum Disorder: Pathogenesis, Mechanisms and Potential Treatments

Neuromyelitis optica spectrum disorder (NMOSD) is an acute or subacute demyelinating disease that affects mainly the optic nerve and spinal cord. A major proportion of NMOSD cases have a relationship with autoimmunity to aquaporin 4 (AQP4) found on the central nervous system. NMOSD can occur repeatedly, causing symptoms such as decreased vision and weakness of limbs. The main goal of the current therapy is to relieve acute symptoms and prevent recurrence of the disease. Without timely and appropriate treatment, the recurrence and disability rates are high. In the present work, we review recent advances in the diagnosis and treatment of patients with NMOSD, as well as the pathogenesis and mechanisms of AQP4-IgG-seropositive NMOSD.

Imaging and Clinical Features of Neurocutaneous Melanosis in the Pediatric Population

Background: Neurocutaneous Melanosis (NCM) is a rare nonfamilial phakomatosis characterized by the presence of congenital melanocytic nevi and abnormal melanocyte infiltration of the leptomeninges.

Objective and Methods: This paper shows the importance of early diagnosis and the most important imaging features of the disease on CT and MR scans. PubMed database was searched from January 1972 to September 2020. Papers including imaging findings of NCM, clinical, follow-up, and treatment features were collected, selecting only 89 studies.

Discussion: NCM is a term used for the first time by van Bogaert in 1948. It refers to a condition caused by an error during morphogenesis and migration leading to leptomeningeal melanocytic accumulation. Although histological findings are the gold standard for diagnosis confirmation, neuroimaging and clinical features strongly support the suspect of NCM. Localization and extension of the lesions are predictive of neurological manifestations related to increased intracranial pressure, mass lesions, or spinal cord compression. CT demonstrates sites of increased density in the anterior temporal lobe, mainly the amygdala, thalami, cerebellum, and frontal lobes base. However, MRI is the best imaging method to diagnose central nervous system lesions, often appearing as T1-short signal areas of the cerebral parenchyma, indicative of central nervous system melanosis. MRI can also reveal associated intracranial and intraspinal abnormalities.

Conclusion: Early imaging, when available, is helpful if NCM suspect is raised and may be of guidance in comparing later studies. NCM requires a multidisciplinary approach since it is a multisystem disease with a genetic component.

Polyphenols as Potential Therapeutics for Pain and Inflammation in Spinal Cord Injury

Spinal cord injury (SCI) and associated pain and inflammation caused by trauma or infection are serious health care issues world-wide. The various inflammatory, redox-sensitive and apoptotic events are contributing factors, but altered neuronal function, axonal degeneration, activated microglia, endothelial cells, astrocytes, fibroblasts, pericytes, Schwann cells, and meningeal cells are major players in its pathogenesis. Further, monocytes and neutrophil infiltration get recruited and facilitate the release of chemokines, cytokines, and other mediators of inflammation. This event leads to the production of different amino acids, neuropeptides kinin, prostaglandins, prostacyclin, thromboxane, leukotrienes, bradykinin, histamine, matrix metal proteinases, and serotonin that stimulate nerve endings and manifest the inflammation and pain processes, etc. Arachidonic acid (AA), NF-kB, NLRP3 inflammasome, and nitric oxide pathways along with P2X7 receptor and ion channel transient receptor potential (TRP) vanilloid are some of the recently explored targets for modulation of pain and inflammation in SCI. Till now, NSAIDs, opioids, antidepressants, anticonvulsants, NMDA antagonists, α2-adrenergic agonists, and GABA-receptor agonists are used for the management of these pathological conditions. However, these drugs are associated with various side effects. Additionally, the number of available animal models for SCI has enhanced the understanding of the complex pathological mechanisms involved in the generation of chronic inflammatory pain in SCI. These findings enable us to identify and validate several potent natural analgesic-anti-inflammatory drug candidates with minimal side effects. However, these compounds have been studied in preclinical models and shown promising results, but no clinical studies have been performed. Therefore, a detailed exploration of these natural compounds is important for bringing them from bench to bedside.

Artificial Intelligence for Epigenetics: Towards Personalized Medicine

Epigenetics is a field of biological sciences focused on the study of reversible, heritable changes in gene function, not due to modifications of the genomic sequence. These changes are the result of a complex cross-talk between several molecular mechanisms that is in turn orchestrated by genetic and environmental factors. The epigenetic profile captures the unique regulatory landscape and the exposure to environmental stimuli of an individual. It thus constitutes a valuable reservoir of information for personalized medicine, which is aimed at customizing health-care interventions based on the unique characteristics of each individual.

Nowadays, the complex milieu of epigenomic marks can be studied at the genome-wide level thanks to massive, high-throughput technologies. This new experimental approach is opening up new and interesting knowledge perspectives. However, the analysis of these complex omic data requires to face important analytic issues.

Artificial Intelligence, and in particular Machine Learning, are emerging as powerful resources to decipher epigenomic data. In this review, we will first describe the most used ML approaches in epigenomics. We then will recapitulate some of the recent applications of ML to epigenomic analysis. Finally, we will provide some examples of how the ML approach to epigenetic data can be useful for personalized medicine.

Body Mass Index and Waist Hip Ratio as a Risk Factor for Meningioma Incidence

Background: Meningioma is a pathological condition in the central nervous system (CNS), while obesity is defined as excess fat accumulation in the body, which is associated with adverse effects on health. Obesity is characterized by an increase in the Body Mass Index (BMI) and Waist Hip Ratio (WHR). Research on the relationship of BMI, and WHR with meningioma has been widely carried out in various countries of Europe, however, it has not been done much in the Asian countries, especially in Indonesia.

Objective: To prove BMI and WHR as risk factors for the incidence of meningioma after being controlled by confounding variables of age and sex.

Methods: This is a case-control research involving 44 meningioma patients and 44 family members as controls. The study was conducted at the outpatient clinic at Kariadi Doctors Hospital from May 2019 to June 2019. We collected data including age, sex, BMI, and WHR. Bivariate analysis using the Chi-square test and multivariate analysis with logistic regression was performed.

Results: Bivariate test results showed a significant relationship between meningioma and BMI (p < 0.001), WHR (p < 0.001), and sex (p < 0.001). Multivariate test results found that the variables that influence the incidence of meningioma the most were BMI, WHR, and sex.

Conclusion: Besides BMI, the increase of WHR and female sex are risk factors for meningioma incidence.

The Pathogenesis of Neurotrauma Indicates Targets for Neuroprotective Therapies

The spinal cord injury (SCI) initiates an extraordinarily protracted disease with 3 phases; acute, inflammatory, and resolution that are restricted to the cavity of injury (COI) or arachnoiditis by a unique CNS reaction against the severity of destructive inflammation. While the severity of inflammation involving the white matter is fueled by a potently immunogenic activity of damaged myelin, its sequestration in the COI and its continuity with the cerebrospinal fluid of the subdural space allow anti-inflammatory therapeutics infused subdurally to inhibit phagocytic macrophage infiltration and thus provide neuroprotection. The role of astrogliosis in containing and ultimately in eliminating severe destructive inflammation post-trauma appears obvious but is not yet sufficiently understood to use in therapeutic neuroprotective and neuroregenerative strategies. An apparent antiinflammatory activity of reactive astrocytes is paralleled by their active role in removing excess edema fluid in blood-brain barrier damaged by inflammation. Recently elucidated pathogenesis of neurotrauma, including SCI, traumatic brain injury (TBI), and stroke, calls for the following principal therapeutic steps in its treatment leading to the recovery of neurologic function: (1) inhibition and elimination of destructive inflammation from the COI with accompanying reduction of vasogenic edema, (2) insertion into the COI of a functional bridge supporting the crossing of regenerating axons, (3) enabling regeneration of axons to their original synaptic targets by temporary safe removal of myelin in targeted areas of white matter, (4) in vivo, systematic monitoring of the consecutive therapeutic steps. The focus of this paper is on therapeutic step 1.

Intracranial Cerebrospinal Fluid Volume Evaluation in Healthy People and Hydrocephalus Patients using SPACE Sequence

Introduction: Cerebrospinal Fluid (CSF) is produced mainly by the choroid plexus but with a substantial influence by the ependymal lining of the ventricles in the brain. Hydrocephalus occurs as a result of discrepancy in the production as well as circulation of CSF as a result of congenital and acquired conditions. Nevertheless, studies on the differences between CSF dynamics according to age and gender are still insufficient. Thus, this study evaluated the volume of intracranial CSF in healthy people and hydrocephalus patients taking into account the differences between CSF dynamics according to age and gender using Sampling Perfection with Application optimised Contrast using different flip-angle Evolution (SPACE) sequence.

Methods: 120 healthy volunteers and 60 patients with hydrocephalus were included in this study. SPACE sequence was used to evaluate intracranial CSF with a 3.0T magnetic resonance machine. The total volume of intracranial CSF and the amount of CSF in the ventricle were obtained using a software, and the volume ratio of CSF in the subarachnoid space, the ventricle and the subarachnoid space were calculated.

Results: The mean volume of intracranial CSF, ventricular CSF, and subarachnoid CSF of male volunteers were (206.9±47.7) cm3, (33.0±10.7) cm3, (173.9±37.9) cm3 respectively. The average volume of intracranial CSF, ventricular CSF, and subarachnoid CSF of female volunteers were (199.7±44.9) cm3, (30.8±9.4) cm3, and (168.9±37.0) cm3, respectively. Thus, no significant statistically (P>0.05) difference between males and females was found. (3) The mean values of intracranial CSF, ventricle CSF and subarachnoid CSF, ventricle and subarachnoid CSF volume ratio in patients with hydrocephalus were significantly greater than health volunteers. Thus, the difference between the two groups was statistically significant (P<0.05).

Conclusion: SPACE sequence can quantitatively determine the content of CSF. The change of CSF volume has nothing to do with gender but with age. It is feasible to use SPACE sequence to evaluate the spatial distribution and volume of intracranial CSF.

Importance of Pre-treatment Fractional Anisotropy Value in Predicting Volumetric Response in Patients with Meningioma Treated with Gamma Knife Radiosurgery

Background: The importance of pre-treatment Diffusion Tensor Imaging (DTI) parameters in determining the response to treatment after radiosurgery in patients with meningioma has not yet been clearly revealed.

Objective: This study was conducted to determine tumor volume changes in terms of radiological response in patients with meningioma treated with Gamma Knife Radiosurgery (GKR) and to analyze the relationship between Total Tumor Volume (TTV) and Diffusion Tensor Imaging (DTI) parameters. In addition, we investigated whether the response to treatment can be predicted by pre-radiosurgery DTI findings.

Methods: Fifty-four patients were assessed using MRI and DTI before and after GKR. Mean Diffusivity (MD), Fractional Anisotropy (FA), Radial Diffusivity (RD), and TTV of tumour were determined. Patients with 10% or more decrease in TTV after GKR were classified as group 1 and those with less than 10% decrease in volume or increase in volume were considered group 2. The relationships between MD, RD, and FA values and TTV were investigated.

Results: A decrease of 46.34% in TTV was detected in group 1 after GKR, while TTV increased by 42.91% in group 2. The lowest pre-treatment FA value was detected in group 1. In addition, after GKR, FA values showed a significant increase in group 1. MD and RD values increased in both groups after radiosurgery. There was a negative correlation between pre-treatment FA, RD, and MD values after radiosurgery.

Conclusion: Detection of low FA values due to the poor fiber content in meningioma before radiosurgery may be a guide in predicting the response to treatment. Further studies are required to have a better understanding of the relationship between pre- and post-treatment follow-up FA values and tumor volume in determining the efficacy of GKR in patients with meningioma.

G-Lymphatic, Vascular and Immune Pathways for Aβ Clearance Cascade and Therapeutic Targets For Alzheimer’s Disease

Alzheimer's disease is an age-related neurodegenerative disease. The factors causing Alzheimer's disease are numerous. Research on humans and rodent models predicted various causative factors involved in Alzheimer's disease progression. Among them, neuroinflammation, oxidative stress, and apoptosis play a major role because of the accumulation of extracellular amyloid-beta peptides. Here, the clearance of amyloid beta-peptide plays a major role because of the imbalance in the production and clearance of the amyloid beta-peptide. Additionally, neuroinflammation by microglia, astrocytes, cytokines, chemokines, and the complement system also has a major role in Alzheimer's disease. The physiological clearance pathways involved in amyloid beta-peptide are glymphatic, vascular, and immune pathways. Amyloid precursor protein, low-density lipoprotein receptor-related protein 1, receptor for the advanced glycation end product, apolipoprotein E, clusterin, aquaporin 4, auto-antibodies, complement system, cytokines, and microglia are involved in amyloid beta-peptide clearance pathways across the blood-brain barrier. The plaque formation in the brain by alternative splicing of amyloid precursor protein and production of misfolded protein results in amyloid-beta agglomeration. This insoluble amyloid-beta leads to a neurodegenerative cascade and neuronal cell death occurs. Studies had shown that disturbed sleep may be a risk factor for dementia and cognitive decline. In this review, the therapeutic targets for Alzheimer'sdisease via focusing on pathways for amyloid-beta clearance are discussed.

Distinct Forms of Spinal Cysticercosis: A Vietnamese Case Series

Introduction: Neurocysticercosis (NCC), a major contributor to the burden of seizure disorders and epilepsy in the world, is one of the most common parasitic infections of the central nervous system, which is usually located in the brain. Medical therapy for NCC should initially cover appropriate symptom control and then the use of antiparasitic agents should be considered. Antiparasitic treatment is of benefit in most cases of viable and degenerating NCC. Nevertheless, cysticercosis of the spinal cord is very uncommon.

Case Series: In this article, we recorded 5 cases of extramedullary-intradural lumbar spinal cysticercosis, in which one case displayed cystic lesions in both brain and spine, one case showed an independent cystic lesion in the spine, and three remaining cases showed diffuse lesions in the spinal canal.

Conclusion: Thus, in any case of single or numerous cystic lesions or dispersed lesions entering the spinal canal, spinal cysticercosis should be considered.

Nanotherapeutics in Neuropathologies: Obstacles, Challenges and Recent Advancements in CNS Targeted Drug Delivery Systems

Neurology and associated nanotherapeutics are a complex field in terms of therapeutics and neurological disorder complexity. The brain is an intricate appendage and requires more precise embattled treatment for the particular diseases and hence it is a broad scale for developing more targeted drug deliveries. The brain is one of the most inaccessible tissues of the body due to the existence of the blood-brain barrier (BBB), thus delivery of drugs inside the brain is a striking dare and it is also tricky to treat central nervous system (CNS) complications pharmacologically. The therapeutic aspiration is to accomplish the lowest drug meditation in the brain tissues so as to gain favoured therapeutic results. To devastate this obstacle, nanotechnology is engaged in the field of targeted brain drug delivery and neuropathology targeting. These carriers hold myriad abilities as they may augment the drug delivery into the brain by shielding them from degradation and prolonging their transmission in the blood, as well as promoting their transport through the BBB. Nanopharmaceuticals are quickly sprouting as a new avenue that is engaged with the drug-loaded nanocarriers to demonstrate unique physicochemical properties and tiny size range for penetrating the central nervous system. The enchantment behind their therapeutic achievement is the condensed drug dose and inferior toxicity, whereby restricting the therapeutic compound to the specific site. Therefore, in this article, we have tried to recapitulate the advances of the novel scopes for the brain targeted drug delivery for complex neurological disorders.

Mass Spectrometric (MS) Analysis of Proteins and Peptides

The human genome is sequenced and comprised of ~30,000 genes, making humans just a little bit more complicated than worms or flies. However, complexity of humans is given by proteins that these genes code for because one gene can produce many proteins mostly through alternative splicing and tissue-dependent expression of particular proteins. In addition, post-translational modifications (PTMs) in proteins greatly increase the number of gene products or protein isoforms. Furthermore, stable and transient interactions between proteins, protein isoforms/proteoforms and PTM-ed proteins (protein-protein interactions, PPI) add yet another level of complexity in humans and other organisms. In the past, all of these proteins were analyzed one at the time. Currently, they are analyzed by a less tedious method: mass spectrometry (MS) for two reasons: 1) because of the complexity of proteins, protein PTMs and PPIs and 2) because MS is the only method that can keep up with such a complex array of features. Here, we discuss the applications of mass spectrometry in protein analysis.

Organic Lesions in the Brain MRI of Children with Febrile Seizure

Objective: Seizure is the most common neurological disorders in children, where 4-10% of the cases experience at least one seizure before the age of 16. The most frequent causes of seizures in children are fever, epilepsy, infection and brain damage. The aim of this study was to investigate the frequency of organic lesions in MRI of children with seizures unrelated to fever.

Materials and Methods: This cross-sectional study included children presented with fever-unrelated seizures. The MRI was examined by a radiologist to identify abnormal findings in each patient. A researcher-made questionnaire including general information, history of head trauma, obstructed labor and the history of seizure was completed for the patients.

Results: Of 287 children with fever-related seizure, 127 (45.7%) were male and 151 (54.3%) were female. History of seizure, history of obstructed labor, abnormal MRI, complete delay, use of antiepileptic drug and history of trauma were 22(9.9%), 1 (0.4%), 11(4%), 5(1.8%), 259(93.2%) and 12 (4.3%), respectively. Of 11 patients with abnormal MRI, 4 had MTS lesions, 2 had tumor lesions, 2 had scarring trauma, 1 had an epidural abscess and 1 had meningitis. The frequency of organic lesions had no significant differences based on gender, use of antiepileptic drug and traumatic history, but it had a significant relation with obstructed labor andthehistory of seizure.

Conclusion: The results showed that organic brain lesions in children with fever-unrelated seizure had a significant relationship with the history of seizure and obstructed maternal labor.

Dural Venous Sinuses: What We Need to Know

Background: The dural venous sinuses (DVS), in general, are frequently asymmetrical and display far more anatomical variations than arterial systems. A comprehensive study of the anatomy and variants of the DVS can help surgeons in the preoperative evaluation and management as well as minimizing possible complications in the following treatment.

Methods: The current review was designed to provide a general overview of the normal anatomy and notable variants of the cerebral venous system as surveyed from the available literature. The pros and cons of different multimodal imaging methods for investigating DVS are also outlined. Finally, cases of various pathological entities are illustrated from our clinical practice.

Conclusion: There are many anatomical variations and lesions involving the DVS. MRI examination can provide essential information both on anatomical variation and morphological or functional change of the offending DVS in most circumstances. Multimodal non-invasive venography protocols may become a feasible alternative to the classical digital subtraction angiography and would improve the diagnostic accuracy in future studies.

The Updated Role of the Blood Brain Barrier in Subarachnoid Hemorrhage: From Basic and Clinical Studies

Subarachnoid hemorrhage (SAH) is a type of hemorrhagic stroke associated with high mortality and morbidity. The blood-brain-barrier (BBB) is a structure consisting primarily of cerebral microvascular endothelial cells, end feet of astrocytes, extracellular matrix, and pericytes. Post-SAH pathophysiology included early brain injury and delayed cerebral ischemia. BBB disruption was a critical mechanism of early brain injury and was associated with other pathophysiological events. These pathophysiological events may propel the development of secondary brain injury, known as delayed cerebral ischemia. Imaging advancements to measure BBB after SAH primarily focused on exploring innovative methods to predict clinical outcome, delayed cerebral ischemia, and delayed infarction related to delayed cerebral ischemia in acute periods. These predictions are based on detecting abnormal changes in BBB permeability. The parameters of BBB permeability are described by changes in computed tomography (CT) perfusion and magnetic resonance imaging (MRI). K_ep seems to be a stable and sensitive indicator in CT perfusion, whereas K^trans is a reliable parameter for dynamic contrast-enhanced MRI. Future prediction models that utilize both the volume of BBB disruption and stable parameters of BBB may be a promising direction to develop practical clinical tools. These tools could provide greater accuracy in predicting clinical outcome and risk of deterioration. Therapeutic interventional exploration targeting BBB disruption is also promising, considering the extended duration of post-SAH BBB disruption.

Coexistence of Ectopic Posterior Pituitary and Sellar/Suprasellar Arachnoid Cyst: A Case Report

Background: The ectopic posterior pituitary (EPP) is a rare condition characterized by the ectopic location of the posterior pituitary lobe associated with varying degrees of stalk anomalies. The arachnoid cysts (AC) are benign lesions of the arachnoid, which account for 1% of all intracranial space-occupying lesions. Sellar/suprasellar ACs account for approximately 1% of all ACs. This is the first case of coexistence EPP with sellar/suprasellar AC.

Case Report: A 67-year-old woman presented with 6 months history of fatigue. Her medical history was positive for irregular menstruation. Her endocrine examinations indicated low free thyroxine level with low TSH level, low oestradiol with low gonadotrophin level, slightly elevated prolactin level. Her Insulin-like growth factor-1 was below the normal levels. Dynamic contrast hypophysis MRI revealed a sellar cystic lesion with a dimension of 18 × 14 × 14 mm, extending from the suprasellar cistern, traversing the diaphragma sellae and reaching the level of the floor of the 3rd ventricle, consistent with sellar/suprasellar AC. There was no wall enhancement. The optic chiasm was compressed. The precontrast T1-weighted magnetic resonance images did not demonstrate the characteristic bright spot of posterior pituitary within the sella, which was higher in position, in the region of the median eminence. The pituitary stalk was not present.

Conclusion: Although speculative, we have a hypothesis to explain how the EPP and sellar/- suprasellar AC coexist in this patient. Due to the absence of stalk, CSF may enter the sella tursica from the central aperture of the diaphragma sellae through which normally the stalk passes.

Clinical and Translational Research Challenges in Biliary Tract Cancers

Background: Biliary Tract Cancers (BTC) are rare malignancies with a poor prognosis. There are many challenges encountered in treating these patients in daily practice as well as in clinical, translational and basic research.

Objective: This review summarises the most relevant challenges in clinical and translational research in BTCs and suggests potential solutions towards an improvement in quality of life and outcomes of patients diagnosed with such malignancies.

Findings: The main challenge is the low number of patients with BTCs, complicated by the aggressive natural behaviour of cancer and the lack of funding sources for research. In addition, the clinical characteristics of these patients and the specific cancer-related complications challenge clinical research and clinical trial recruitment. It is worth highlighting that BTCs are a group of different malignancies (cholangiocarcinoma, gallbladder cancer and ampullary cancer) rather than a unique homogeneous disease. These subgroups differ not only in molecular aspects, but also in clinical and demographic characteristics. In addition, tailored imaging and quality of life assessment are required to tackle some of the issues specific to BTCs. Finally, difficulties in tissue acquisition both in terms of biopsy size and inclusion of sufficient tumour within the samples, may adversely impact translational and basic research.

Conclusion: Increasing awareness among patients and clinicians regarding BTC and the need for further research and treatment development may address some of the main challenges in BTC research. International collaboration is mandatory to progress the field.

Sam Domains in Multiple Diseases

Background: The sterile alpha motif (Sam) domain is a small helical protein module, able to undergo homo- and hetero-oligomerization, as well as polymerization, thus forming different types of protein architectures. A few Sam domains are involved in pathological processes and consequently, they represent valuable targets for the development of new potential therapeutic routes. This study intends to collect state-of-the-art knowledge on the different modes by which Sam domains can favor disease onset and progression.

Methods: This review was build up by searching throughout the literature, for: a) the structural properties of Sam domains, b) interactions mediated by a Sam module, c) presence of a Sam domain in proteins relevant for a specific disease.

Results: Sam domains appear crucial in many diseases including cancer, renal disorders, cataracts. Often pathologies are linked to mutations directly positioned in the Sam domains that alter their stability and/or affect interactions that are crucial for proper protein functions. In only a few diseases, the Sam motif plays a kind of "side role" and cooperates to the pathological event by enhancing the action of a different protein domain.

Conclusion: Considering the many roles of the Sam domain into a significant variety of diseases, more efforts and novel drug discovery campaigns need to be engaged to find out small molecules and/or peptides targeting Sam domains. Such compounds may represent the pillars on which to build novel therapeutic strategies to cure different pathologies.

Curcumin Prevents Brain Damage and Cognitive Dysfunction During Ischemic-reperfusion Through the Regulation of miR-7-5p

Objective: This study was to investigate the potential protective effects of curcumin in cerebral ischemia-reperfusion (CIR) and its regulation of miR-7.

Methods: Rats were occluded by middle cerebral artery occlusion (MCAO) for 1.5 h and reperfused for 2 h to establish a local CIR model. After 24 hours of model establishment, MCAO rats were given curcumin for 3 days by intragastric administration. PC12 cells were cultured for 6 h in oxygen-glucose deprivation medium and then reoxygenated for 24 h to establish an oxygenglucose deprivation/reoxygenation (OGD/R) model. The OGD/R model cells were treated with curcumin for 48 h.

Results: Curcumin inhibited the decrease of miR-7-5p expression and an increase of RelA p65 expression induced by CIR and ODG/R. RelA p65 was a target of miR-7-5p. MiR-7-5p antagonists were able to counteract the effect of curcumin on the expression of RelA p65 in ischemic brain tissue of MCAO rats and OGD/R model cells. Curcumin improved OGD/R-induced inhibition of cell activity, necrosis and apoptosis. Curcumin significantly reduced the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, reactive oxygen species (ROS) and malondialdehyde (MDA) and increased the activity of superoxide dismutases (SOD) and catalase (CAT) in OGD/R-induced cells. Curcumin may inhibit OGD/R-induced cell damage by regulating miR-7-5p. Curcumin improved cerebral infarction, nerve damage and cognitive dysfunction in rats with CIR, which may be related to the regulation of miR-7-5p/RelA p65 axis.

Conclusion: Curcumin exerts cerebral protection by attenuating cell necrosis and apoptosis, inflammatory response and oxidative stress following CIR, which may be related to its regulation of the miR-7/RELA p65 axis.

A Brief Review of Cardiovascular Diseases, Associated Risk Factors and Current Treatment Regimes

Cardiovascular diseases (CVDs) are the leading cause of premature death and disability in humans and their incidence is on the rise globally. Given their substantial contribution towards the escalating costs of health care, CVDs also generate a high socio-economic burden in the general population. The underlying pathogenesis and progression associated with nearly all CVDs are predominantly of atherosclerotic origin that leads to the development of coronary artery disease, cerebrovascular disease, venous thromboembolism and, peripheral vascular disease, subsequently causing myocardial infarction, cardiac arrhythmias or stroke. The aetiological risk factors leading to the onset of CVDs are well recognized and include hyperlipidaemia, hypertension, diabetes, obesity, smoking and, lack of physical activity. They collectively represent more than 90% of the CVD risks in all epidemiological studies. Despite high fatality rate of CVDs, the identification and careful prevention of the underlying risk factors can significantly reduce the global epidemic of CVDs. Beside making favorable lifestyle modifications, primary regimes for the prevention and treatment of CVDs include lipid-lowering drugs, antihypertensives, antiplatelet and anticoagulation therapies. Despite their effectiveness, significant gaps in the treatment of CVDs remain. In this review, we discuss the epidemiology and pathology of the major CVDs that are prevalent globally. We also determine the contribution of well-recognized risk factors towards the development of CVDs and the prevention strategies. In the end, therapies for the control and treatment of CVDs are discussed.

Crossing the Blood-Brain Barrier: A Review on Drug Delivery Strategies for Treatment of the Central Nervous System Diseases

Many drugs have been designed to treat diseases of the central nervous system (CNS), especially neurodegenerative diseases. However, the presence of tight junctions at the blood-brain barrier has often compromised the efficiency of drug delivery to target sites in the brain. The principles of drug delivery systems across the blood-brain barrier are dependent on substrate-specific (i.e. protein transport and transcytosis) and non-specific (i.e. transcellular and paracellular) transport pathways, which are crucial factors in attempts to design efficient drug delivery strategies. This review describes how the blood-brain barrier presents the main challenge in delivering drugs to treat brain diseases and discusses the advantages and disadvantages of ongoing neurotherapeutic delivery strategies in overcoming this limitation. In addition, we discuss the application of colloidal carrier systems, particularly nanoparticles, as potential tools for therapy for the CNS diseases.

Patterns of Acute Intracranial Hemorrhage in Adult Patients with Bilateral and Unilateral Moyamoya Disease

Background: Moyamoya disease (MMD) is a rare cerebrovascular disease. The difference of hemorrhagic patterns in adult patients with bilateral and unilateral MMD is still unclear.

Objective: For a better understanding of their characteristics, we compared the patterns of acute intracranial hemorrhage in adult patients with bilateral and unilateral MMD.

Methods: Adult MMD patients with acute intracranial hemorrhage were retrospectively included. Clinical and radiological characteristics of adult patients with bilateral and unilateral MMD were collected and analyzed. Chi-square test, t-test, or rank sum test were used for statistical analyses.

Results: A total of 107 patients were included. Among 74 patients with bilateral MMD, 9 (12.2%) were at Suzuki Stage 2, 48 (64.9%) were at Stage 3, 16 (21.6%) were at Stage 4, and another (1.4%) was at Stage 5. However, in patients with unilateral MMD, 8 (24.2%) were at Stage 2, 23 (69.7%) were at Stage 3, and 2 (6.1%) were at Stage 4. Intraparenchymal hemorrhage was found in 40 (54.1%) patients with bilateral MMD and 16 (48.5%) patients with unilateral MMD (P=0.594). Intraventricular hemorrhage was shown in 65 (87.8%) patients with bilateral MMD and 19 (57.6%) patients with unilateral MMD (P<0.001). Subarachnoid hemorrhage was observed in 17 (23.0%) patients with bilateral MMD and 18 (54.5%) patients with unilateral MMD (P=0.001).

Conclusion: Unilateral MMD patients with acute intracranial hemorrhage are at the earlier Suzuki stage than the bilateral MMD patients. Intraventricular hemorrhage occurs more frequently in bilateral MMD, while subarachnoid hemorrhage is more frequent in unilateral MMD.

New Advanced Strategies for the Treatment of Lysosomal Diseases Affecting the Central Nervous System

Lysosomal Storage Disorders (LSDs), also known as lysosomal diseases (LDs) are a group of serious genetic diseases characterized by not only the accumulation of non-catabolized compounds in the lysosomes due to the deficiency of specific enzymes which usually eliminate these compounds, but also by trafficking, calcium changes and acidification. LDs mainly affect the central nervous system (CNS), which is difficult to reach for drugs and biological molecules due to the presence of the blood-brain barrier (BBB). While some therapies have proven highly effective in treating peripheral disorders in LD patients, they fail to overcome the BBB. Researchers have developed many strategies to circumvent this problem, for example, by creating carriers for enzyme delivery, which improve the enzyme’s half-life and the overexpression of receptors and transporters in the luminal or abluminal membranes of the BBB. This review aims to successfully examine the strategies developed during the last decade for the treatment of LDs, which mainly affect the CNS. Among the LD treatments, enzyme-replacement therapy (ERT) and gene therapy have proven effective, while nanoparticle, fusion protein, and small molecule-based therapies seem to offer considerable promise to treat the CNS pathology. This work also analyzed the challenges of the study to design new drug delivery systems for the effective treatment of LDs. Polymeric nanoparticles and liposomes are explored from their technological point of view and for the most relevant preclinical studies showing that they are excellent choices to protect active molecules and transport them through the BBB to target specific brain substrates for the treatment of LDs.

Biomarkers for Alzheimer’s Disease

Alzheimer´s disease (AD) and related forms of dementia are increasingly affecting the aging population throughout the world, at an alarming rate. The World Alzheimer´s Report indicates a prevalence of 46.8 million people affected by AD worldwide. As population ages, this number is projected to triple by 2050 unless effective interventions are developed and implemented. Urgent efforts are required for an early detection of this disease. The ultimate goal is the identification of viable targets for the development of molecular markers and validation of their use for early diagnosis of AD that may improve treatment and the disease outcome in patients. The diagnosis of AD has been difficult to resolve since approaches for early and accurate detection and follow-up of AD patients at the clinical level have been reported only recently. Some proposed AD biomarkers include the detection of pathophysiological processes in the brain in vivo with new imaging techniques and novel PET ligands, and the determination of pathogenic proteins in cerebrospinal fluid showing anomalous levels of hyperphosphorylated tau and low Aβ peptide. These biomarkers have been increasingly accepted by AD diagnostic criteria and are important tools for the design of clinical trials, but difficulties in accessibility to costly and invasive procedures have not been completely addressed in clinical settings. New biomarkers are currently being developed to allow determinations of multiple pathological processes including neuroinflammation, synaptic dysfunction, metabolic impairment, protein aggregation and neurodegeneration. Highly specific and sensitive blood biomarkers, using less-invasive procedures to detect AD, are derived from the discoveries of peripheric tau oligomers and amyloid variants in human plasma and platelets. We have also developed a blood tau biomarker that correlates with a cognitive decline and also with neuroimaging determinations of brain atrophy.

Recent Advances in Rational Diagnosis and Treatment of Normal Pressure Hydrocephalus: A Critical Appraisal on Novel Diagnostic, Therapy Monitoring and Treatment Modalities

Background: Normal pressure hydrocephalus (NPH) is a critical brain disorder in which excess Cerebrospinal Fluid (CSF) is accumulated in the brain’s ventricles causing damage or disruption of the brain tissues. Amongst various signs and symptoms, difficulty in walking, slurred speech, impaired decision making and critical thinking, and loss of bladder and bowl control are considered the hallmark features of NPH.

Objective: The current review was aimed to present a comprehensive overview and critical appraisal of majorly employed neuroimaging techniques for rational diagnosis and effective monitoring of the effectiveness of the employed therapeutic intervention for NPH. Moreover, a critical overview of recent developments and utilization of pharmacological agents for the treatment of hydrocephalus has also been appraised.

Results: Considering the complications associated with the shunt-based surgical operations, consistent monitoring of shunting via neuroimaging techniques hold greater clinical significance. Despite having extensive applicability of MRI and CT scan, these conventional neuroimaging techniques are associated with misdiagnosis or several health risks to patients. Recent advances in MRI (i.e., Sagittal-MRI, coronal-MRI, Time-SLIP (time-spatial-labeling-inversion-pulse), PC-MRI and diffusion-tensor-imaging (DTI)) have shown promising applicability in the diagnosis of NPH. Having associated with several adverse effects with surgical interventions, non-invasive approaches (pharmacological agents) have earned greater interest of scientists, medical professional, and healthcare providers. Amongst pharmacological agents, diuretics, isosorbide, osmotic agents, carbonic anhydrase inhibitors, glucocorticoids, NSAIDs, digoxin, and gold-198 have been employed for the management of NPH and prevention of secondary sensory/intellectual complications.

Conclusion: Employment of rational diagnostic tool and therapeutic modalities avoids misleading diagnosis and sophisticated management of hydrocephalus by efficient reduction of Cerebrospinal Fluid (CSF) production, reduction of fibrotic and inflammatory cascades secondary to meningitis and hemorrhage, and protection of brain from further deterioration.

Current Limitations in the Treatment of Parkinson’s and Alzheimer’s Diseases: State-of-the-Art and Future Perspective of Polymeric Carriers

Alzheimer’s and Parkinson’s diseases are the most common neurodegenerative diseases worldwide and their incidence is increasing due to the aging population. At the moment, the available therapies are not disease modifying and have several limitations, some of which are discussed in this review. One of the main limitations of these treatments is the low concentration that drugs reach in the central nervous system after systemic administration. Indeed, the presence of biological barriers, particularly the blood-brain barrier (BBB), hinders the effective drug delivery to the brain, reducing the potential benefit coming from the administration of the medication. In this review, the mechanisms of transport across the BBB and new methods to improve drug passage across the BBB are discussed. These methods include non-invasive solutions such as intranasal and intravitreal administration, and the use of nanotechnology solutions based on polymeric carriers when the drug is intravenously injected, orally taken for intestine adsorption or delivered through the dermal mucosa. Also, it provides an analysis of more invasive solutions that include intracranially injected hydrogels and implanted devices for local drug delivery. Efforts in finding new therapeutic drugs blocking neurodegenerative disease progression or reverting their course should be coupled with efforts addressed to efficient drug delivery systems. Hence, new pharmacology discoveries together with advancements in nanotechnologies and biomaterials for regenerative medicine are required to effectively counteract neurodegenerative diseases.

Current Updates on Bone Grafting Biomaterials and Recombinant Human Growth Factors Implanted Biotherapy for Spinal Fusion: A Review of Human Clinical Studies

Background: Owing to their great promise in the spinal surgeries, bone graft substitutes have been widely investigated for their safety and clinical potential. By the current advances in the spinal surgery, an understanding of the precise biological mechanism of each bone graft substitute is mandatory for upholding the induction of solid spinal fusion.

Objective: The aim of the present review is to critically discuss various surgical implications and level of evidence of most commonly employed bone graft substitutes for spinal fusion.

Method: Data was collected via electronic search using “PubMed”, “SciFinder”, “ScienceDirect”, “Google Scholar”, “Web of Science” and a library search for articles published in peer-reviewed journals, conferences, and e-books.

Results: Despite having exceptional inherent osteogenic, osteoinductive, and osteoconductive features, clinical acceptability of autografts (patient’s own bone) is limited due to several perioperative and postoperative complications i.e., donor-site morbidities and limited graft supply. Alternatively, allografts (bone harvested from cadaver) have shown great promise in achieving acceptable bone fusion rate while alleviating the donor-site morbidities associated with implantation of autografts. As an adjuvant to allograft, demineralized bone matrix (DBM) has shown remarkable efficacy of bone fusion, when employed as graft extender or graft enhancer. Recent advances in recombinant technologies have made it possible to implant growth and differentiation factors (bone morphogenetic proteins) for spinal fusion.

Conclusion: Selection of a particular bone grafting biotherapy can be rationalized based on the level of spine fusion, clinical experience and preference of orthopaedic surgeon, and prevalence of donor-site morbidities.

Cerebrospinal Fluid, Brain Electrolytes Balance, and the Unsuspected Intrinsic Property of Melanin to Dissociate the Water Molecule

Background & Objective: Regulation of composition, volume and turnover of fluids surrounding the brain and damp cells is vital. These fluids transport all substances required for cells and remove the unwanted materials. This regulation tends to act as barrier to prevent free exchange of materials between the brain and blood. There are specific mechanisms concerned with fluid secretion of the controlled composition of the brain, and others responsible for reabsorption eventually to blood and the extracellular fluid whatever their composition is. The current view assumes that choroidal plexuses secrete the major part of Cerebrospinal Fluid (CSF), while the Blood-Brain Barrier (BBB) has a much less contribution to fluid production, generating Interstitial Fluid (ISF) that drains to CSF. The skull is a rigid box; thereby the sum of volumes occupied by the parenchyma with its ISF, related connective tissue, the vasculature, the meninges and the CSF must be relatively constant according to the Monroe-Kellie dogma. This constitutes a formidable challenge that normal organisms surpass daily. The ISF and CSF provide water and solutes influx and efflux from cells to these targeted fluids in a quite precise way. Microvessels within the parenchyma are sufficiently close to every cell where diffusion areas for solutes are tiny. Despite this, CSF and ISF exhibit very similar compositions, but differ significantly from blood plasma. Many hydrophilic substances are effectively prevented from the entry into the brain via blood, while others like neurotransmitters are extremely hindered from getting out of the brain. Anatomical principle of the barrier and routes of fluid transfer cannot explain the extraordinary accuracy of fluids and substances needed to enter or leave the brain firmly. There is one aspect that has not been deeply analyzed, despite being prevalent in all the above processes, it is considered a part of the CSF and ISF dynamics. This aspect is the energy necessary to propel them properly in time, form, space, quantity and temporality.

Conclusion: The recent hypothesis based on glucose and ATP as sources of energy presents numerous contradictions and controversies. The discovery of the unsuspected intrinsic ability of melanin to dissociate and reform water molecules, similar to the role of chlorophyll in plants, was confirmed in the study of ISF and CSF biology.

Inflammatory Events Following Subarachnoid Hemorrhage (SAH)

Acute SAH from a ruptured intracranial aneurysm contributes for 30% of all hemorrhagic strokes. The bleeding itself occurs in the subarachnoid space. Nevertheless, injury to the brain parenchyma occurs as a consequence of the bleeding, directly, via several well-defined mechanisms and pathways, but also indirectly, or secondarily. This secondary brain injury following SAH has a variety of causes and possible mechanisms. Amongst others, inflammatory events have been shown to occur in parallel to, contribute to, or even to initiate programmed cell death (PCD) within the central nervous system (CNS) in human and animal studies alike.

Mechanisms of secondary brain injury are of utmost interest not only to scientists, but also to clinicians, as they often provide possibilities for translational approaches as well as distinct time windows for tailored treatment options.

In this article, we review secondary brain injury due to inflammatory changes, that occur on cellular, as well as on molecular level in the various different compartments of the CNS: the brain vessels, the subarachnoid space, and the brain parenchyma itself and hypothesize about possible signaling mechanisms between these compartments.

Transcranial Near-infrared Laser Therapy in Improving Cognitive Recovery of Function Following Traumatic Brain Injury

Traumatic brain injury (TBI) has turned into a major health and socioeconomic problem affecting young people and military personnel. Numerous TBI patients experienced the sequela of brain injury called cognitive impairment, which reduced functions in attention, working memory, motivation, and execution. In recent years, transcranial near-infrared laser therapy (tNiRLT) as a possible therapy has been gradually applied in treating cognitive impairment post-TBI. In the present review, the biological mechanisms of transcranial tNiRLT for TBI are synthesized mainly based on the photonic impact of chronic mild TBI. Various exciting molecular events possibly occur during the procedure, such as stimulation of ATP production, regional cerebral blood flow, acupoint, neurogenesis and synaptogenesis, as well as a reduction in anti-inflammatory effect. Some animal experiments and clinical studies of tNiRLT for TBI are outlined. Several labs have displayed that tNiRLT is effective not only in improving neurological functions but also in increasing memory and learning capacity in rodent animals’ model of TBI. In a 2 patients case report and a 11-case series, cognitive functions were ameliorated. Efficacy on cognitive and emotional effects was also observed in a double-blind, controlled clinical study. Several Randomized, parallel, double blind, sham-controlled trials are underway, aiming to evaluate the efficacy of tLED on cognitive functions and neuropsychiatric status in participants post-TBI. Therefore, tNiRLT is a promising method applied to cognitive impairment following TBI.

Recent Advances in Pathophysiology of Traumatic Brain Injury

Background: Traumatic brain injury (TBI) constitutes the primary reason for mortality and morbidity in persons worldwide below 45 years of age. 1.7 million Traumatic events occur yearly in the United States alone, considering for 50,000 deaths. In severe traumatic brain injury sufferers, a considerable achievement attained in treating short-term consequences; but till date, huge failures are occurring in researcher’s capability to render severe traumatic brain injury sufferers to an elevated degree of performing.

Methods: Initial damage force results in Primary brain injury, causing tissue destruction and distortion in the early post-injury period. These secondary injuries from TBI cause changes in cell performance and dissemination of trauma via activities like free-radical generation, depolarization, and formation of edema, excitotoxicity, and disruption of blood brain barrier, calcium homeostasis, and intracranial hematoma. The expectation for developing effect in TBI sufferers is the best knowledge of these activities and enhancement of remedies that restrict secondary brain damage.

Results: The focal point of this study is on knowing the complex outburst of secondary impairments and studying the pathophysiology of TBI which provides alternative treatment benefits.

Conclusion: While injured persons demonstrate dissimilar levels of harm and every case is novel with specific recovery profiles, this article strengthens the recent pathophysiological sight of TBI mainly attention on oxidative stress, excitotoxicity, cerebral oxygenation and cerebral blood flow (CBF), development of edema, and inflammatory activities. For initial research acknowledgment of these recurring factors could permit clarification of possible beneficial targets.

Peptide Mediated Brain Delivery of Nano- and Submicroparticles: A Synergistic Approach

The brain is a complex, regulated organ with a highly controlled access mechanism: The Blood-Brain Barrier (BBB). The selectivity of this barrier is a double-edged sword, being both its greatest strength and weakness. This weakness is evident when trying to target therapeutics against diseases within the brain. Diseases such as metastatic brain cancer have extremely poor prognosis due to the poor permeability of many therapeutics across the BBB. Peptides can be designed to target BBB receptors and gain access to the brain by transcytosis. These peptides (known as BBB-shuttles) can carry compounds, usually excluded from the brain, across the BBB. BBB-shuttles are limited by poor loading of therapeutics and degradation of the peptide and cargo. Likewise, nano- submicro- and microparticles can be fine-tuned to limit their degradation and with high loading of therapeutics. However, most nano- and microparticles’ core materials completely lack efficient targeting, with a few selected materials able to cross the BBB passively. Combining the selectivity of peptides with the high loading potential of nano-, microparticles offers an exciting strategy to develop novel, targeted therapeutics towards many brain disorders and diseases. Nevertheless, at present the field is diverse, in both scope and nomenclature, often with competing or contradictory names. In this review, we will try to address some of these issues and evaluate the current state of peptide mediated nano,-microparticle transport to the brain, analyzing delivery vehicle type and peptide design, the two key components that must act synergistically for optimal therapeutic impact.

Frontier View on Nanotechnological Strategies for Neuro-therapy

Background: Nanotechnology exploits materials and devices with a functional organization that has been engineered at the nanometre scale. The application of nanotechnology in neuroscience involves specific interactions with neurons and glial cells. This property is used for delivering drugs and other small molecules (such as genes, oligonucleotides and contrasting agents) across the blood brain barrier (BBB), an important requirement for delivering the drug successfully to the brain.

Objective: Nanotechnology based approaches (NBA) favours transcytosis-mediated delivery of nanoparticles to the brain by crossing the BBB. The last five years have witnessed the successful applications of NBA to treat neurological disorders. It is expected that the development of novel NBA will result in important insights on the brain mechanisms, and eventually provide better medical care to patients suffering from neurological disorders.

Conclusion: This review introduces the emerging work in this area and summarizes the successful NBA used in recent past for treating various neurological disorders ike Alzheimer’s disease, Parkinson's disease, amyotrophic lateral sclerosis, meningitis and glioblastoma.

Advances in Drug Delivery from Nose to Brain: An Overview

Brain targeting has always been challenging due to the presence of various physiological barriers resulting in low bioavailability via the oral and parenteral route. Altering the integrity of these barriers so as to permit the drugs to enter into the brain could severely damage the Central Nervous System by also allowing the entrance of toxic substances, bacteria and viruses into the brain. This problem can be tackled by delivering drugs via the intranasal route which bypasses the blood brain barrier and reaches different parts of the brain primarily via the olfactory and trigeminal neural pathways. This route offers several advantages over the oral and parenteral route and has shown potential for targeting drugs to the brain for treating various central nervous system disorders such as Psychosis, Parkinson's and Alzheimer's disease. In spite of several advantages, the intranasal route faces many challenges. Hence, a complete understanding of every aspect related to nose to brain delivery is of utmost importance. This article reviews the mechanism of nose to brain drug transport, challenges and approaches for nose to brain drug delivery, a few specialized olfactory delivery devices and some applications of this novel route of brain targeting.

Antiepileptic Drugs for Preventing Seizures in Patients with Chronic Subdural Hematoma

Chronic subdural hematoma (CSH) is an accumulation of blood within the intracranial subdural space. It is associated with minor traumatic events and affects mostly the elderly. CSH can be effectively treated surgically with good outcomes, although the recurrence rate is high. Epileptic seizures are one of the major complications associated with CSH, either in the pre or postoperative period. The incidence rate of new onset seizures after CSH diagnosis ranges between 3% and 23%. However, the benefit of using prophylactic antiepileptic drugs in these patients is controversial with significant variations in clinical practice. It ranges from routine to total absence of use in this clinical context. The best current evidence does not allow any firm conclusion on whether such prophylactic treatment is effective, that is if it prevents the development of epileptic seizures. Furthermore, these drugs are associated with important adverse events. A systematic literature review found no controlled randomized trials evaluating the risk/benefit of the prophylactic use of anticonvulsants for people with CSH and retrospective studies showing contradictory results. Moreover, these observational studies are outdated and do not evaluate new generation drugs. Herein, we discuss the evidence for the use of antiepileptic drugs for preventing seizures in patients with CSH, with a particular focus on the subgroup of people most likely to benefit (such as the elderly and alcohol abusers), as well as the possible safety advantages of the new antiepileptic drugs.

A Case Presentation of Atypical X-linked Adrenoleukodystrophy: Initial Experience with ASL Technique

Background: A 7-year-old boy with an atypical form of X-linked adrenoleukodystrophy is reported, predominantly involving frontal, occipital and temporal lobes, corticospinal tracts and cerebellar lobes.

Methods: The disease has been well documented previously with Magnetic Resonance Imaging (MRI).

Discussion: However, there isn't enough data on Magnetic Resonance Perfusion Imaging (MRPI) and non-contrast Arterial Spin Labeling (ASL) technique in current literature.

Conclusion: We presented initial and follow up MRI and multiphase ASL perfusion MRI findings.

Prepontine Chordoma Presenting with MRI Features of an Epidermoid Cyst: Case Presentation and a Mini-Review

Background: We report a patient with a prepontine chordoma, presented with MRI features of an Epidermoid Cyst (EC) including hypointensity on T1-weighted image, hyperintensity on T2- weighted image, hyperintensity on DWI, and no contrast enhancement. We also presented a concise review of the relevant clinical data, since such cases were rarely reported in the English medical literature.

Results & Conclulsion: To avoid delays in the management of patients with this locally aggressive tumor, clival chordoma should be taken into consideration as a differential diagnosis of tumors residing in close proximity to the clivus even in the absence of a bony erosion.

Nano-Delivery in Pediatric Tumors: Looking Back, Moving Forward

Recent advances in the treatment of pediatric tumors led to an improvement of survival in this population. As a result, many pediatric survivors experience long-term effects that impact their quality of life. Therefore, it is extremely important to identify new treatment approaches that may target the tumor minimizing the drug-related side effects. Over the past 10 years, remarkable advances in nanomedicine have provided several potential tools for cancer treatment. Recently, there has been a growing interest towards therapeutic nanocarriers in the pediatric field, since they represent a new strategy to enhance the drug efficacy and reduce the toxicity. Various nanoformulations have been developed to improve the targeting and the release of antitumor compound to cancer cells in pediatric tumors and clinical trials have been conducted or are ongoing. Exosomes are nanometer-sized vesicles that play a crucial role in mediating intercellular communication. Thanks to to their intrinsic cell targeting properties, stability in the circulation, and bio-compatibility, they are emerging as new promising vehicles both for drugs and biological therapeutics. Moreover, these nanovesicles are a reservoir of potential diagnostic and prognostic markers. In this review, we describe recent advances in the treatment of pediatric tumors through nanodelivery system with particular attention to neuroblastoma, soft-tissues/bone sarcomas and pediatric brain tumors. Furthermore, we explore the potential role of exosomes as an effective option of nanodelivery providing insights into their characteristics in pediatric tumors and their use in adult clinical trials.

The Updated Role of Oxidative Stress in Subarachnoid Hemorrhage

Background: Subarachnoid hemorrhage (SAH) is considered as a violent disease with high rate of morbidity and mortality. Early brain injury (EBI) and delayed vasospasm are the two aspects of this disease that are becoming research hotspots.

Objective: We aim to update the role of oxidative stress in the development of EBI and delayed cerebral vasospasm after SAH.

Method: We reviewed early researches, and mainly discussed three aspects of contents: reactive oxygen species (ROS) production, the role of oxidative stress in early brain injury and delayed vasospasm, and clinical implications.

Results: There are several sources for the excessive generation of oxidants after SAH such as disrupted mitochondrial respiration, upregulated enzymatic pathways, extracellular hemoglobin degradation and depressed intrinsic antioxidant systems. Neuron apoptosis induced by ROS is one vital mechanism of EBI. And extracellular hemoglobin degradation and nitric oxide synthases up-reputation are involved in the pathogenesis of delayed cerebral vasospasm. Some antioxidants show significant neuroprotection in researches.

Conclusion: ROS production increases in SAH via mitochondria, hemoglobin or enzymatic pathway, and it plays a vital important role in SAH. It seems that antioxidant therapy will be most effective as one component in a treatment regime that attempts to address all the different pathways to EBI and vasospasm following SAH.

Current Therapeutic Drugs Against Cerebral Vasospasm after Subarachnoid Hemorrhage: A Comprehensive Review of Basic and Clinical Studies

Background: Cerebral vasospasm (CVS) is well known as a major complication in subarachnoid hemorrhage (SAH) patients, and research has long been focused on improving morbidity and mortality. As CVS commonly develops from day 4 to day 14 after SAH onset, SAH patients require therapies with drugs for preventing CVS after surgical treatment for the source of hemorrhage, mostly ruptured intracranial aneurysms. It is thought that the pathogenesis of CVS is initiated by prolonged smooth muscle contraction, and the subsequent hypoperfusion and cytotoxic responses induce cerebral ischemia. Although therapeutic investigations have historically focused on morphological improvement, the improvement of outcome is limited by the reversal of arterial narrowing. Therefore, it might be important to look back at evidence from long-lasting studies of CVS and to determine a highroad to effective drugs, including combination therapy.

Objective: In this review, we introduce current candidate beneficial drugs against CVS in clinical SAH, including nimodipine and other Ca2+ channel antagonists, magnesium sulfate, clazosentan, statins, cilostazol, eicosapentaenoic acid, fasudil hydrochloride, milrinone, and edaravone, all of which have been frequently studied in recent years.

Intraventricular Recombinant Tissue Plasminogen Activator in Treatment of Aneurysmal Intraventricular Hemorrhage: A Meta-Analysis

Objective: Intraventricular hemorrhage (IVH) is deemed to result in poor outcomes in patients with aneurysmal subarachnoid hemorrhage (SAH). The aim of this study was to explore the efficacy and safety of intraventricular injections of recombinant tissue plasminogen activator (rt-PA).

Methods: We searched MEDLINE, EMBASE, and Cochrane Library from January 1980 to March 2015 for studies in English. The primary outcome was good functional improvement. The secondary outcomes were angiographic vasospasm, acute obstructive hydrocephalus, hemorrhage rate, and mortality.

Results: Three observational studies and 3 randomized controlled trials (RCTs) with 217 patients were included in the present study. There is a significant difference in angiographic vasospasm (RR 0.58, 95% CI 0.16 to 0.85, P = 0.01). In the subgroup analysis, angiographic vasospasm (RR 0.37, 95% CI 0.38 to 0.88, P = 0.02) and acute obstructive hydrocephalus (RR 0.48, 95% CI 0.27 to 0.84, P = 0.01) showed significant differences in the observational studies. High dosage of rt-PA showed a significant difference in angiographic vasospasm (RR 0.60, 95% CI 0.38 to 0.97, P = 0.04). Sensitivity analysis showed that no significant differences were observed in all the outcomes after the Ramakrishna 2010 trial was excluded.

Conclusion: Intraventricular rt-PA has no significant efficacy on the long-term functional recovery after aneurysmal SAH with IVH. However, high dosage of rt-PA might reduce the incidence of angiographic vasospasm. A feasible, large-scale, multi-center, placebo RCT is needed to confirm the present findings.

Aligning Animal Models of Clinical Germinal Matrix Hemorrhage, From Basic Correlation to Therapeutic Approach

Background: Germinal matrix hemorrhage is a leading cause of mortality and morbidity from prematurity. This brain region is vulnerable to bleeding and re-bleeding within the first 72 hours of preterm life. Cerebroventricular expansion of blood products contributes to the mechanisms of brain injury. Consequences include lifelong hydrocephalus, cerebral palsy, and intellectual disability. Unfortunately little is known about the therapeutic needs of this patient population.

Objectives: This review discusses the mechanisms of germinal matrix hemorrhage, the animal models utilized, and the potential therapeutic targets.

Conclusion: Potential therapeutic approaches identified in pre-clinical investigations include corticosteroid therapy, iron chelator administration, and transforming growth factor-β pathway modulation, which all warrant further investigation. Thus, effective preclinical modeling is essential for elucidating and evaluating novel therapeutic approaches, ahead of clinical consideration.

Personalized Nanoparticles for Cancer Therapy: A Call for Greater Precision

Nanotechnology has brought about the advent of personalized medicine in the era of targeted therapeutic strategies for cancer therapy. The ability to exploit tumor features for therapeutic gain has made it possible to manufacture more effective nanomedicines for cancer treatment. However, known obstacles, including the inability to overcome pathophysiological barriers of tumors, have impeded disease management. In spite of this, recent efforts have been made to develop more functionalized nanosystems that utilize the active-targeting approach. This article reviews the FDA-approved cancer drug delivery systems in the general framework of personalized nanomedicine. We discuss the latest efforts in the development of functionalized nano-systems, and summarize relevant ongoing preclinical and clinical trials.

An Uncommon Case of Symptomatic Multiple Meningiomas with Bilateral Compressive Optic Neuropathy Rapidly Induced under Cyprotero ne Acetate Treatment

Introduction: Multiple meningiomas growth in patients under cyproterone acetate (CPA) is now well known. However, time between initial CPA intake and diagnosis remains unclear.

Methods: The exposure time differs in each reported case: from 2 to 10 years. We present the case of an old man with acute visual impairment caused by an unusual bilateral optic nerve compression by three likely planum sphenoidale meningiomas rapidly induced by the admistration of CPA for prostatic adenocarinoma.

Results and Conclusion: This case is the first reported with a short exposure time (7 months) to CPA treatment before diagnosis of multiple meningiomas and stabilization on clinical follow-up after CPA treatment discontinuation.

Tauopathies – Focus on Changes at the Neurovascular Unit

In the past, the blood-brain barrier (BBB) has been characterized mainly as a layer of endothelial cells forming the vessel/capillary wall of the brain. More recently, the BBB is considered to be a part of a highly dynamic and interactive system called the neurovascular unit (NVU), consisting of vascular cells, glial cells, and neurons.

The list of central nervous system (CNS) pathologies involving BBB dysfunction is rapidly growing. The opening of the BBB and subsequent infiltration of serum components to the brain can lead to a host of processes resulting in progressive synaptic and neuronal dysfunction and loss. Such processes have been implicated in different diseases, including vascular dementias, stroke, Alzheimer´s disease (AD), Parkinson´s disease, multiple sclerosis, amyotrophic lateral sclerosis, hypoxia, ischemia, and diabetes mellitus.

Tauopathies represent a heterogeneous group of around 20 different neurodegenerative diseases characterized by abnormal deposition of microtubule-associated protein tau in cells of the nervous system.

Increased microvascular permeability has been more typically related to cerebrovascular deposition of amyloid-β (Aβ), but in contrast very little is known about the connection between functional impairment of the BBB and the misfolded tau proteins. Here, we review what is known about tauopathies, the BBB, and the NVU.

Long-Term Extensions of Randomized Vaccination Trials of ACC-001 and QS-21 in Mild to Moderate Alzheimer’s Disease

Objectives: Long-term safety and tolerability of ACC-001 (vanutide cridificar), an antiamyloid- beta therapeutic vaccine, was evaluated in subjects with mild to moderate Alzheimer’s disease.

Design: Phase 2a extension studies of randomized parent trials were conducted in the United States, European Union, and Japan.

Methods: Four immunizations of ACC-001 were administered at the same 3 dose levels (3, 10, and 30 μg) to subjects randomized in the parent studies; ACC-001 was administered with QS-21 adjuvant. Safety, tolerability, and immunogenicity were assessed during active treatment and 6-month follow-up.

Results: ACC-001 + QS-21 was well tolerated in the United States (N=110) and European Union (N=50), and Japan (N=53) extension studies; safety profile was similar to that observed in the parent studies, and no new safety signals were identified. Overall, injection site reactions were the most common adverse event in these studies. Anti-amyloid antibody titers were elicited in all groups, with the highest titers observed in subjects who received ACC-001 + QS-21 in both the parent and extension studies.

Conclusions: Long-term exposure to ACC-001 + QS-21 was well tolerated in subjects with Alzheimer’s disease, suggesting that side effects do not pose a principal limitation for anti-amyloid active immunotherapy. The highest anti-amyloid-beta IgG titers are elicited during long-term therapy with ACC-001 + QS-21 compared with other regimens.

Polyphenols Beyond Barriers: A Glimpse into the Brain

Background: Ageing can be simply defined as the process of becoming older, which is genetically determined but also environmentally modulated. With the continuous increase of life expectancy, quality of life during ageing has become one of the biggest challenges of developed countries. The quest for a healthy ageing has led to the extensive study of plant polyphenols with the aim to prevent age-associated deterioration and diseases, including neurodegenerative diseases. The world of polyphenols has fascinated researchers over the past decades, and in vitro, cell-based, animal and human studies have attempted to unravel the mechanisms behind dietary polyphenols neuroprotection.

Methods: In this review, we compiled some of the extensive and ever-growing research in the field, highlighting some of the most recent trends in the area.

Results: The main findings regarding polypolyphenols neuroprotective potential performed using in vitro, cellular and animal studies, as well as human trials are covered in this review. Concepts like bioavailability, polyphenols biotransformation, transport of dietary polyphenols across barriers, including the blood-brain barrier, are here explored.

Conclusion: The diversity and holistic properties of polypolyphenol present them as an attractive alternative for the treatment of multifactorial diseases, where a multitude of cellular pathways are disrupted. The underlying mechanisms of polypolyphenols for nutrition or therapeutic applications must be further consolidated, however there is strong evidence of their beneficial impact on brain function during ageing. Nevertheless, only the tip of the iceberg of nutritional and pharmacological potential of dietary polyphenols is hitherto understood and further research needs to be done to fill the gaps in pursuing a healthy ageing.

Nanotechnology in Neuroscience and its Perspective as Gene Carrier

Gene therapy has a strong potential in neuroscience by suppressing or replacing abnormalities in genetic materials. The employment of nano-gene carrier for neurological disorders is comparatively young and restricted since the aim to effectively deliver therapeutic agents into the central nervous system (CNS) commonly has confronted difficulties of several natural occurring barriers in the body and unfavorable characteristics of pharmaceutical agents. Two major anatomical and biochemical barriers are blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB), which significantly prevent permeation of most drugs and genes to brain parenchyma. In this concern, nanotechnology emerges as an innovative method for transporting therapeutics to the CNS. Diverse nano-systems have been closely investigated, some of which have demonstrated initial success for in vivo studies. The perspectives of nanotechnology for gene therapy would be a promising field to be further explored in the near future.

HTLV-1 Associated Neurological Disorders

Human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus which is endemic to certain regions of the world and infects around 10-20 million people. HTLV-1 is the etiologic agent of Adult T cell leukemia/lymphoma and HTLV-1 associated neurological disorders including mainly HTLV-1 associated myelopathy/Tropical spastic paraparesis. The involvement of the central nervous diseases occurs among: HTLV-1 infected patients from endemic areas, HIV positive individuals and drug users. The ability of HTLV-1 to cause associated neuropathies starts with the virus crossing the blood brain barrier (BBB), then entering and infecting the cells of the central nervous system. As a consequence, to the viral attack, HTLV-1 infected lymphocytes produce pro-inflammatory cytokines like tumor necrosis factor alpha, Interleukin 1 beta and interleukin 6 which further disrupts the BBB. Different serological tests have been used in the diagnosis of HTLV-1. These include: ELISA, Western Blotting (WB), Immunofluorescence, Particle Agglutination and Polymerase Chain Reaction which is used as a confirmatory test. Danazol, pentoxifylline, azathioprine and vitamin C have been used in the treatment of the HTLV-1 associated neurological disorders. Other antiviral drugs (lamivudine, zidovudine), monoclonal antibodies (Daclizumab) and therapeutic agents (valporic acid, interferons) have also been evaluated. No known drug, so far, has been shown to be efficacious. The aim of this review is to present the complexities of HTLV-1 associated neurological disorders and their current ongoing treatment. In addition to discussing future possible therapeutic strategies, by targeting HTVL-1 viral components and gene/s products, for the treatment of those neurological conditions.

Nanomedicine and its Potential for the Treatment of Alzheimer’s Disease

Background: CNS disorders have reached a concerning number globally. While a lot of research is being encouraged, there are not many drugs in the market to combat the severity of Alzheimer’s or Parkinson’s diseases. Most of the drugs used for the management of these diseases have poor solubility, low hydrophilcity and cannot reach the target owing to the Blood-Brain-Barrier (BBB). Due to these problems, science involving nanotechnology is now being used to formulate drug delivery systems to permeate through the barrier and deliver the drug at the target.

Methods: This mini review analyses the work of various scientists and research groups in this field and discusses the significance of nanoparticles for drug delivery across the BBB. Formulations that have demonstrated high potential for penetration through the bloodbrain- barrier include Solid Lipid Nanoparticles (SLNs), Polymeric Nanoparticles (PNs), Liposomes and Dendrimers. Along with these formulations, quantum dots have also demonstrated their ability to be used as a diagnostic platform.

Results: The management of these conditions at a global level requires efforts from multiple research disciplines along with a diagnostic platform, formulation development and drug delivery techniques. ‘Theranostics’ as an approach for the diagnosis and treatment of the condition and the use of appropriate in vitro/in vivo models have also been discussed to highlight on the importance of multi-disciplinary approach for better understanding of the subject.

Conclusion: This mini review discusses the future of some of the most potent nano-sized formulations for the treatment of Alzheimer’s disease. It also reviews the theranostic platforms that can be potentially incorporated in the health care system for the diagnosis and treatment of the condition. The significance of an appropriate animal/3D model for a better understanding of the condition has also been discussed. In a nut shell, this mini review focuses on the nano-particulate systems and the future of nano-medicines for delivering drugs through the barrier for Alzheimer’s Disease (AD).

Analysis of Adverse Events Related to 720 Cases of Neural Progenitor Cell Transplantation

Background: Cell therapies have shown to be able to improve neurological functions to some extent for patients with refractory central nervous system (CNS) diseases or damages. Meanwhile, increasing attention has been drawn to the operation-related and (or) cell-related adverse events when performing cell therapy. Our study is to explore the safety issue from 720 cases of neural progenitor cell (NPC) transplantation based on clinic manifestations and examinations.

Method: A retrospective analysis of all adverse events associated with 720 cases of NPC transplantation by administering the cells into the ventricles was done.

Results: One hundred and sixty-six cases had postoperative crying and irritability, 69 with vomiting and 84 with fever. None of them had CNS infection, but 4 cases presented intracranial hemorrhage. One month after cell therapy, 568 cases did EEG test, in which 153 patients showed improvement, 74 had abnormal changes in and 341 cases had no changes in; two patients developed new-onset convulsions and 3 had recurrent convulsions; 6 cases had intracranial hemorrhage, but no other CNS sequelae left from the primary diseases. 180 patients were able to follow-up for their clinical evaluation and head MRI or CT examination 2 years after transplantation. All patients didn’t show signs of tumorigenesis and no serious and irreversible operation- or cell-related adverse events.

In Conclusion: there are mild adverse reactions and reversible adverse events following cell transplantation, our study indicated that NPC transplantation is a safe therapy in clinical treatment. Further clinical trials are necessary to establish the safety of this therapy.

The Gut Microbiota and the Emergence of Autoimmunity: Relevance to Major Psychiatric Disorders

Background: Autoimmune phenotypes are prevalent in major psychiatric disorders. Disequilibria of cellular processes occurring in the gastrointestinal (GI) tract likely contribute to immune dysfunction in psychiatric disorders. As the venue of a complex community of resident microbes, the gut in a homeostatic state equates with a functional digestive system, cellular barrier stability and properly regulated recognition of self and non-self antigens. When gut processes become disrupted as a result of environmental or genetic factors, autoimmunity may ensue.

Methods: Here, we review the issues pertinent to autoimmunity and the microbiome in psychiatric disorders and show that many of the reported immune risk factors for the development of these brain disorders are in fact related and consistent with dysfunctions occurring in the gut. We review the few human microbiome studies that have been done in people with psychiatric disorders and supplement this information with mechanistic data gleaned from experimental rodent studies.

Results: These investigations demonstrate changes in behavior and brain biochemistry directly attributable to alterations in the gut microbiome. We present a model by which autoantigens are produced by extrinsicallyderived food and microbial factors bound to intrinsic components of the gut including receptors present in the enteric nervous system.

Conclusion: This new focus on examining activities outside of the CNS for relevance to the etiology and pathophysiology of psychiatric disorders may require new modalities or a re-evaluation of pharmaceutical targets found in peripheral systems.

Beyond the Synapse and Hebb's Rule: Is the Rest of the Neuron More Important for Psychiatric Disorders?

The neuronal synaptic action potential is still considered the basic unit of signaling in the brain underlying mental states, behavior and psychiatric disorders. However, exponentially deepening and mind boggling progress has been made during the last 30 years in the molecular and cellular understanding of what drives action potentials. The classical “synaptic relay model” of the action potential is now considered to be a special, minor case, most relevant to “machine-like” mentation and behavior. Volume transmission, not involving synapses, but certainly driving neuronal action potentials, is now understood to be far more prevalent, complex, and more relevant to “soul-like” mentation and behavior. Only a few very brief or highly technical accounts of this scientific revolution have been published specifically for psychiatrists despite the fact that psychiatry is the discipline most likely to gain in the short term, with neurology following more in the long term. We review here what we think are the most relevant aspects of extrasynaptic signaling for psychiatry in a manner we hope is most useful and enlightening for practicing psychiatrists.

ABC Transporters and Drug Resistance in Patients with Epilepsy

Resistance to antiepileptic drugs (AED) remains a major problem in clinical epileptology. This pharmacoresistance is independent of the choice of AEDs. Different hypotheses have been proposed to explain the neurobiological basis for pharmacoresistance in epilepsy. The transporter hypothesis is the mostly investigated theory. Hereby, overexpression of multidrug efflux transporters, such as P-glycoprotein (Pgp), at the blood-brain-barrier (BBB) is thought to be involved in pharmacoresistance in epilepsy by extruding AEDs from their target site. Accumulating evidence supports an overexpression of Pgp in pharmacoresistant epilepsy. Molecular Imaging studies provide unique opportunities for the in-vivo study of the transporter hypothesis in the central nervous system (CNS). Several studies demonstrated that positron emission tomography (PET) with [¹¹C]-radiolabled Pgp substrates is a promising tool for in vivo investigation of Pgp function at the rat, monkey and human BBB. Quantification of Pgp over activity in epilepsy patients by in vivo imaging could be highly useful because altered treatment strategies or novel AED could then be applied.

Pharmaceutical Targeting of the Brain

Besides being indispensable for the protection and nutrition of the central nervous system (CNS), blood-brain barrier (BBB)-forming cerebral endothelial cells (CECs) have a major role in hampering drugs to reach therapeutically relevant concentrations in the brain. In this respect, the most important defense systems of CECs are tight junctions (TJs) sealing the paracellular way of transport, efflux pumps (ABC transporters) and metabolic enzymes. Here we review current strategies aiming at overcoming the BBB with the purpose of effectively delivering drugs to the CNS. Besides chemical modification of drug candidates to improve CNS availability, the main strategies include: bypassing the BBB (intracranial or nasal routes), reversible opening of TJs (using hyperosmotic mannitol, ultrasounds, peptides and other physical methods or chemical agents), vector-mediated drug delivery systems (nanocarriers, exploitation of receptor- and carrier-mediated transport) and inhibition of efflux transporters. We discuss the main advantages, disadvantages and clinical relevance of each strategy. Special emphasis will be given to the description of the chemical characteristics of nanoparticles (lipidic, polymeric, inorganic, etc.) and the main strategies of targeting them to the CNS.

Potential Pathways for CNS Drug Delivery Across the Blood-Cerebrospinal Fluid Barrier

The blood-brain interfaces restrict the cerebral bioavailability of pharmacological compounds. Various drug delivery strategies have been developed to improve drug penetration into the brain. Most strategies target the microvascular endothelium forming the bloodbrain barrier proper. Targeting the blood-cerebrospinal fluid (CSF) barrier formed by the epithelium of the choroid plexuses in addition to the blood-brain barrier may offer addedvalue for the treatment of central nervous system diseases. For instance, targeting the CSF spaces, adjacent tissue, or the choroid plexuses themselves is of interest for the treatment of neuroinflammatory and infectious diseases, cerebral amyloid angiopathy, selected brain tumors, hydrocephalus or neurohumoral dysregulation. Selected CSF-borne materials seem to reach deep cerebral structures by mechanisms that need to be understood in the context of chronic CSF delivery. Drug delivery through both barriers can reduce CSF sink action towards parenchymal drugs. Finally, targeting the choroid plexus-CSF system can be especially relevant in the context of neonatal and pediatric diseases of the central nervous system. Transcytosis appears the most promising mechanism to target in order to improve drug delivery through brain barriers. The choroid plexus epithelium displays strong vesicular trafficking and secretory activities that deserve to be explored in the context of cerebral drug delivery. Folate transport and exosome release into the CSF, plasma protein transport, and various receptor-mediated endocytosis pathways may prove useful mechanisms to exploit for efficient drug delivery into the CSF. This calls for a clear evaluation of transcytosis mechanisms at the blood-CSF barrier, and a thorough evaluation of CSF drug delivery rates.

Strategies that Target Tight Junctions for Enhanced Drug Delivery

Ions and molecules move across epithelial barriers by two pathways, the transcellular and the paracellular. The former is taken by lipophilic compounds, or by ions and molecules that move across the plasma membrane through pumps, carriers or exchangers. The second route is regulated by the tight junction (TJ) that through paracellular channels, allows the transport of ions across epithelial barriers. Since, a wide variety of bioactive molecules like peptides, proteins and oligonucleotides cannot use the transcellular route, due to their hydrophilic nature, interest has arisen in devising procedures to open the TJ in a reversible manner for paracellular drug delivery. Here, we describe how different strategies have been devised to enhance the paracellular intestinal absorption of drugs; to open the blood-brain barrier (BBB) to allow the penetration of drugs for the treatment of disorders and tumors of the central nervous system; or to deliver antigens into the subjacent mucosa associated lymphoid tissues, for the development of mucosal vaccines. The strategies described, include the use of peptides, antibodies and miRNAs that target proteins of the apical junctional complex, as well as toxins derived from microorganisms that open the TJ by inducing the contraction of the cortical actomyosin ring. Also, we describe how paracellular absorption, is enhanced by drugs that extract cholesterol from the plasma membrane, surfactants, fatty acids, oligosaccharides, cationic polymers, nitric oxide donors and calcium chelators. Likewise, we explain how the BBB has been opened by employing tumor necrosis factor-α, bradykinin, short chain alkylglycerols, hyperosmotic mannitol and focused ultrasound.

Brain-metastatic Breast Cancer: Clinical Considerations and Pharmacological Approaches

Despite constant advances on breast cancer knowledge, the metastatic disease resulting from the spreading of this disease is still a challenge. This scenario is particularly critical in the more aggressive subtypes, as HER2-amplified and triple negative breast cancers, when often occurs the invasion of central nervous system (CNS) structures. In this situation, the survival of patients is drastically reduced, and the number of sequels and functional impairment is huge due to the small therapeutic arsenal available. In this context, it is necessary to understand the mechanisms involved in the process of metastasis of breast cancer to CNS, and how this process affects anatomically important structures for its functioning. This review aims to point out some mechanisms enrolled in the spread of breast cancer to CNS, discuss the clinical impact of such metastatisation and address the critical aspects related to the treatment of this condition.

Merging Transport Data for Choroid Plexus with Blood-Brain Barrier to Model CNS Homeostasis and Disease More Effectively

Robust modeling of CNS transport integrates molecular fluxes at the microvascular blood-brain barrier and epithelial choroid plexus blood-cerebrospinal fluid (CSF) barrier. Normal activity of solute transporters, channels and aquaporins, in the cerebral endothelium and choroidal epithelium, sets the microenvironment composition for neurons and glia. Conversely, perturbed transport/permeability at the barrier interfaces causes interstitial fluid dyshomeostasis (e.g. edema) arising in neural disorders. Critically-important transependymal solute/water distribution between brain and CSF needs more attention. This treatise encourages procuring transport data simultaneously for blood-brain barrier, blood-CSF barrier and CSF. In situ perfusion and multicompartmental analyses (tracers, microdialysis) provide dynamic assessments of molecular transfer among various CNS regions. Diffusion, active transport and convection are distorted by disease- and age-associated alterations in barrier permeability and CSF turnover (sink action). Clinical complications result from suboptimal conveyance of micronutrients (folate), catabolites (β-amyloid) and therapeutic agents (antibiotics) within the CNS. Neurorestorative therapies for stroke, traumatic brain injury, multiple sclerosis and brain tumors are facilitated by insight on molecular and cellular trafficking through the choroid plexus-CSF nexus. Knowledge is needed about fluxes of growth factors, neurotrophins, hormones and leukocytes from ventricular CSF into the hippocampus, subventricular zone and hypothalamus. CSF and brain removal of potentially toxic catabolites and neuropeptides merits further investigation to manage the degeneration of Alzheimer’s disease and normal pressure hydrocephalus. Novel therapies will rely on delineating peptide and drug distributions across the blood-brain barrier and choroid plexus-CSF, and how they modulate the intervening neural-glial networks and neurogenic sites. Multicompartmental transport modeling is key to devising specific pharmacologic targeting and thus impactful CSF translational research for CNS disorders.

An Unusual Case of Reversible Empty Sella

Context: An empty sella is a relatively common condition, often being an incidental finding at MRI or CT scan. It can develop because of the intrasellar herniation of Cerebro-spinal Fluid (CSF) and arachnoid membrane through an absent or rudimentary diaphragm sellae in concomitance of a sudden and even transient increment of intracranial pressure, leading to a picture in which the pituitary is flattened along the floor of the sella.

Case Description: A young female with headache, nausea, dizziness, diplopia and visual impairment showed an empty sella on MRI and increased CSF pressure at the lumbar puncture. After an initial improvement, there was a progressive worsening of the headache, especially in orthostatic position, with transient relief after bed rest and hydration. At MRI the empty sella was no longer evident, cerebellar tonsils were displaced in the occipital foramen and there was an impregnation of the meninges after contrast medium, a picture of CSF hypotension, probably due to the previously performed lumbar puncture causing a fistula with leak of CSF and consequent disappearance of the empty sella. The patient gradually improved after being submitted to epidural blood patch.

Conclusions: The case here reported demonstrates that an empty sella can be a reversible condition in rare cases. Its disappearance can be due to the reduction in intracranial pressure caused by the lumbar puncture itself. The changes in the characteristics of the headache, in particular its worsening in the orthostatic position, should lead to the suspicion of CSF leak through a fistula and consequent intracranial hypotension, a dangerous and sometimes life-threatening condition.

Nanosized Drug Delivery Systems for Direct Nose to Brain Targeting: A Review

Background: Drug targeting to brain has always been problematic due to Blood-Brain Barrier (BBB), which, does not allow most of the drugs to pass through it as they are hydrophilic and macromolecular drugs. So, in order to bypass the BBB, alternative modes of administration were searched and nasal to brain delivery route was tried by many workers. Such studies yielded patented nano-formulations with the ability to cross blood brain barrier.

Methods: Nanoparticles being smaller in size and large surface area help in increasing the rate of drug permeation to the brain. In this review work, emphasis has been laid on discussion on various works done in the field of nasal delivery of drugs to brain over the last decade.

Results: The works that are discussed in this paper show better drug targeting of brain when given through nasal route as nanoparticles. Experiments performed in animal models have clearly exhibited that nano-sized formulations are able to facilitate the delivery of drugs to brain through nose in comparison to tantamount drug solutions.

Conclusion: However, it is not yet confirmed whether the drug is freed from the formulation in the nasal cavity and then absorbed or the nanoparticles themselves are absorbed and then the drug is released in the CNS. Furthermore, the toxicity studies were not carried out extensively in suitably designed model, which should be considered before going for further studies and application.

An Intelligent Three-dimensional Ultrasound Program for Rapidly Imaging of the Fetal Cranial Mid-sagittal Plane

This paper described a novel intelligent technique for rapid visualization of the fetal cranial mid-sagittal view to allow for the differentiation of fetal midline anomalies. Two hundred consecutive normal singleton pregnancies and twenty abnormal fetuses with cranial midline anomalies were imaged to display the mid-sagittal view using this new intelligent three-dimensional imaging program developed by our team. The cranial transverse plane was used as starting plane to acquire the threedimensional volumes and then scanned with this new program. The three-dimensional median planes were also evaluated by other two doctors. The reference landmarks of the mid-sagittal plane were that the falxs of fetal head on Plane A and Plane B were parallel to the X-axis and the reference dot was put on the falx. If one doctor thought it was not the median plane or the structure of corpus callosum or cerebellar vermis was not clearly visualized, the case was labelled as failed case. The cranial mid-sagittal view was successfully visualized in 190 normal cases (95%) and 18 abnormal cases (90%) by Smart MSP program. The failed 12 cases becuase the cerebral falxs of these fetuses were unable to be recognized by the program. In conclusion, this new intelligent three-dimensional program is a feasible method for quick visualization of fetal cranial mid-sagittal plane and may become a potential tool for routinely screening the fetal midline anomalies.

Drug Delivery to CNS: Challenges and Opportunities with Emphasis on Biomaterials Based Drug Delivery Strategies

The current epoch has witnessed a lifestyle impregnated with stress, which is a major cause of several neurological disorders. High morbidity and mortality rate due to neurological diseases and disorders have generated a huge social impact. Despite voluminous research, patients suffering from fatal and/or debilitating CNS diseases such as brain tumors, HIV, encephalopathy, Alzheimer’s, epilepsy, Parkinson’s, migraine and multiple sclerosis outnumbered those suffering from systemic cancer or heart diseases. The brain being a highly sensitive neuronal organ, has evolved with vasculature barriers, which regulates the efflux and influx of substances to CNS. Treatment of CNS diseases/disorders is challenging because of physiologic, metabolic and biochemical obstacles created by these barriers which comprise mainly of BBB and BCFB. The inability of achieving therapeutically active concentration has become the bottleneck level difficulty, hampering the therapeutic efficiency of several promising drug candidates for CNS related disorders. Parallel maturation of an effective CNS drug delivery strategy with CNS drug discovery is the need of the hour. Recently, the focus of the pharmaceutical community has aggravated in the direction of developing novel and more efficient drug delivery systems, giving the potential of more effective and safer CNS therapies. The present review outlines several hurdles in drug delivery to the CNS along with ideal physicochemical properties desired in drug substance/formulation for CNS delivery. The review also focuses on different conventional and novel strategies for drug delivery to the CNS. The article also assesses and emphasizes on possible benefits of biomaterial based formulations for drug delivery to the CNS.

Immune-Regulatory Mechanisms of Classical and Experimental Multiple Sclerosis Drugs: A Special Focus on Helminth-Derived Treatments

Multiple sclerosis (MS) is the most prevalent autoimmune disease affecting the central nervous system (CNS). Its pathophysiology is centered on neuron myelin sheath destruction in a manner largely dependent upon CD4+/CD8+ T-cell autoreactivity against myelin antigens, inducing Th1/Th17 pathogenic responses with the resulting production of free radicals and soluble mediators that exhibit the effector mechanisms of neurodegeneration. The immune response responsible for this disease is complex and challenges modern medicine. Consequently, many experimental therapies have been proposed in addition to the classical array of immunoregulatory/ immunosuppressive drugs that are normally used to treat MS. In this review, we will describe the effects and mechanisms of action of widely used disease-modifying MS drugs as well as those of select treatments that are currently in the experimental phase. Special emphasis is placed on helminth-derived immunoregulators, as some of them have shown promising results. Additionally, we will compare the mechanisms of action of both the MS drugs and the helminth-derived treatments to discuss the potential importance of some signaling pathways in the control of MS.

Adoptive Regulatory T-cell Therapy Attenuates Subarachnoid Hemor-rhage-induced Cerebral Inflammation by Suppressing TLR4/NF-B Signaling Pathway

Inflammation is one major cause of poor outcomes of subarachnoid hemorrhage (SAH). The recent evidence suggested that adoptive regulatory T-cell (Treg) therapy conferred potential neuroprotection by suppressing cerebral inflammation against cerebral ischemia. Therefore, we proposed that Treg transfer might protect the brain against SAH by decreasing cerebral inflammation. In this study, we injected the autologous blood into cisterna magna twice to make the SAH model and administrated Tregs by vein to SAH rats. Intriguingly, adoptive transfer of Tregs significantly ameliorated SAH-induced brain edema and increased cerebral blood flow. Moreover, Treg-afforded cerebral protection was accompanied by suppressing SAH-induced cerebral inflammation. Concurrently, administration of Tregs attenuated the activation of the toll-like receptor 4 and nuclear factor-kappa B (TLR4/NF-κB) signaling pathway, which should be involved in the suppression of SAH-induced cerebral inflammation. Altogether, our study suggested that Treg adoptive transfer could attenuate SAH-induced cerebral inflammation by suppressing the activation of the TLR4/NF-κB signaling pathway, and thus provided new insights into the potent Treg cells-based therapy specifically targeting on post-SAH inflammatory dysregulation.

Therapeutic Nucleic Acids

Gene therapy strategies have become involved in methods for the treatment of inherited or acquired diseases with the aim to correct the faulty genetic code or to modify gene expression. In order to develop safe and effective therapeutic methods for applying in humans, different nucleic acids, termed as vectors, have been engineered, as therapeutic molecules in addition to classical drugs. In this review we included an overview of recent research and patents on therapeutic nucleic acids, designed for use on safe and effective gene therapy protocols for the treatment of diseases, whose results have been obtained in animal models, and which suggests that the use of nucleic acids as therapeutics molecules holds great promise for the future of disease control or cure.

The Unbiased Search of Biomarkers in Neurodegenerative Diseases

A clear link exists between the extension of life expectancy throughout the world and the increased incidence of age-related neurodegenerative disorders. Diseases like Alzheimer’s and Parkinson’s are chronic diseases with devastating consequences for patients and their families. They also represent a major economic cost for society. Therapeutic progress has been made mainly by alleviating some of the symptoms of these diseases, but currently no cure is available. Attempts to develop new therapies have been hampered mainly because of gaps in our current knowledge about the pathogenic mechanism underlying neurodegeneration, making difficult the identification of targets for new drug development, and also because of the lack of biomarkers essential for early diagnosis, patient stratification and follow up of treatment. Taking advantage of the latest technical developments, proteomics and peptidomics based approaches are being used to identify new cellular pathophysiological pathways as well as biomarkers in biological fluids. Here we will review the results, mainly published in the last five years, of unbiased proteomics and peptidomics approaches for biomarker research using biological fluids of Alzheimer’s, Parkinson’s and Amyotrophic Lateral Sclerosis patients.

Blood-Based Biomarkers of Alzheimer´s Disease: Diagnostic Algorithms and New Technologies

New concepts about Alzheimer's disease (AD), considered as a clinical-biological entity, make essential the definition of biomarkers that could be used for the in vivo diagnosis of the disorder before dementia develops. Different types of genetic, biochemical and neuroimaging markers have been described, highlighting some of the changes that occur in the brain during the course of the disease, yet there is little proof of their pathognomonic and diagnostic value. Furthermore, many of the assays used are difficult to perform, the equipment/reagents are expensive or potentially hazardous (e.g.; use of radioactive compounds, CSF extraction). Thus, there is a need to define more suitable and convenient approaches, such as the determination of blood parameters that are easy to obtain and that can be repeated as necessary without contraindications. These data can be used by algorithms that combine specific and non-specific changes to classify patients at different stages of AD and/or distinguish AD from other related diseases with a greater specificity and reliability (> 80%). The blood parameters considered in this review are varied, including: β-amyloid, tau, apolipoproteins and proteins, as well as the metabolic behavior of blood cells, etc. Among the proteins, cytokines/chemokines and other cell factors related to both neuro-inflammatory and peripheral-inflammatory processes in AD are of prime importance. New technologies to detect and quantify these substances, reasonably priced such as the vibrational spectroscopy, panels of parameters and algorithms to assess the results, would be fundamental for the early AD diagnosis and to define new potential therapies.

Vasculogenic and Angiogenic Pathways in Moyamoya Disease

Background. Moyamoya disease (MMD) is a slowly progressing steno-occlusive cerebrovascular disease. The typical moyamoya vessels, which originate from an initial stenosis of the internal carotid, highlight that increased and/or abnormal angiogenic, vasculogenic and arteriogenic processes are involved in the disease pathophysiology. Objective. Herein, we summarize the current knowledge on the most important signaling pathways involved in MMD vessel formation, particularly focusing on the expression of growth factors and function of endothelial progenitor cells (EPCs). Methods and Results. Higher plasma concentrations of vascular endothelial growth factor, matrix metalloproteinase, hepatocyte growth factor, and interleukin-1β were reported in MMD. A specific higher level of basic fibroblast growth factor was also found in the cerebrospinal fluid of these patients. Finally, the number and the functionality of EPCs were found to be increased. In spite of the available data, the approaches and findings reported so far do not give an evident correlation between the expression levels of the aforementioned growth factors and MMD severity. Furthermore, the controversial results provided by studies on EPCs, do not permit to understand the true involvement of these cells in MMD pathophysiology. Conclusion. Further studies should thus be implemented to extend our knowledge on processes regulating both the arterial stenosis and the excessive formation of collateral vessels. Moreover, we suggest advances of integrated approaches and functional assays to correlate biological and clinical data, arguing for the development of new therapeutic applications for MMD.

Cyclooxygenase-2 and Prostaglandin E2 are Associated with Middle Cerebral Artery Occlusion and Hemorrhage in Patients with Moyamoya Disease

Some inflammatory proteins, such as cyclooxygenase (COX)-2 and prostaglandin (PG) E2 are hypothesized to be implicated in the development of moyamoya disease (MMD). However, the functional roles of COX-2/PGE2 in the pathogenesis of MMD remain elusive. In this study, tiny pieces of middle cerebral artery (MCA) and superficial temporal artery (STA) were surgically harvested from 18 adult MMD patients and 5 surgical control patients. The expression levels of COX-2 and microsomal prostaglandin E2 synthase-1 (mPGES-1) in the vascular walls were immunohistochemically detected. With additional 10 healthy controls, the plasma levels of PGE2 were also measured by enzyme-linked immunosorbent assay (ELISA). Obvious intimal thickening was observed in both STA and MCA of MMD patients, but not in the controls. However, the MCA had a thicker intima than the STA (P < 0.01). Although plasma concentrations of PGE2 had no differences among the MMD patients, surgical controls and healthy controls, MCA of most MMD patients (15/18, 83.3%) were stained positively for COX-2 and all patients for mPGES-1. Staining of both COX-2 and mPGES-1 was more abundant in the MCA of hemorrhagic patients than those in their ischemic counterparts (P = 0.001 and 0.029, respectively). The expression levels of COX-2 were positively correlated with those of mPGES-1 (r = 0.647, P = 0.004). Positive COX-2 and mPGES-1 expressions were detected neither in the MCA samples from the surgical controls nor in all STA specimens. Our findings indicate that COX-2/PGE2 may be associated with the MCA occlusion and the hemorrhagic stroke in patients with MMD.

Use Of External Intrathecal Infusion Pumps In The Management Of Septic Complications: A Case Report

Spasticity is a motor disorder with an increased muscle tone, typically associated with spasms, weakness and lack of coordination. It is an invalidating and debilitating pathology, characterized by pain, limited autonomy in activities of daily living, development of severe lesions. Spasticity can be adequately treated with physiotherapy, muscle relaxants drugs or topical treatment with botulinic toxin type A. Intrathecal baclofen therapy is very effective in the treatment of severe and generalized spasticity. Sometimes, soft tissues adjacent to the implant intrathecal infusion become infected; removing intrathecal infusion and systemic antibiotic therapy are best solution for clinical cure. However, removing intrathecal baclofen therapy could increase muscle spasticity with enhancement of pain and clonus that can worsen quality of life. In this study, we evaluated clinical improvement after complete healing of the septic focus and implantation of a new infuser

Tyrosine Kinase Inhibitor as a new Therapy for Ischemic Stroke and other Neurologic Diseases: is there any Hope for a Better Outcome?

The relevance of tyrosine kinase inhibitors (TKIs) in the treatment of malignancies has been already defined. Aberrant activation of tyrosine kinase signaling pathways has been causally linked not only to cancers but also to other non-oncological diseases. This review concentrates on the novel plausible usage of this group of drugs in neurological disorders, such as ischemic brain stroke, subarachnoid hemorrhage, Alzheimer’s disease, multiple sclerosis. The drugs considered here are representatives of both receptor and non-receptor TKIs. Among them imatinib and masitinib have the broadest spectrum of therapeutic usage. Both drugs are effective in ischemic brain stroke and multiple sclerosis, but only imatinib produces a therapeutic effect in subarachnoid hemorrhage. Masitinib and dasatinib reduce the symptoms of Alzheimer’s disease. In the case of multiple sclerosis several TKIs are useful, including apart from imatinib and masitinib, also sunitinib, sorafenib, lestaurtinib. Furthermore, the possible molecular targets for the drugs are described in connection with the underlying pathophysiological mechanisms in the diseases in question. The most frequent target for the TKIs is PDGFR which plays a pivotal role particularly in ischemic brain stroke and subarachnoid hemorrhage. The collected data indicates that TKIs are very promising candidates for new therapeutic interventions in neurological diseases.

Nose to Brain Delivery: New Trends in Amphiphile-Based “Soft” Nanocarriers

The aim of the present paper is to highlight the potential of nasal mucosa as an administration route for targeting the central nervous system, in particular, the brain. Among the formulation strategies for enhance nose to brain drug delivery, the use of colloidal carriers has became a revolutionary approach. These systems should be able to entrap drugs in the desired amount, to penetrate through anatomical barriers, to efficiently release the loaded drugs in the site of action and moreover to show a good physicochemical, biological stability and good biocompatibility. The use of vesicular systems (liposomes and niosomes) together with the use of micelles, in nose to brain delivery are here presented. Vesicle structure is characterized by the presence of a hydrophobic bilayer and an aqueous core that is absent in micelles. Amphiphilic molecules are responsible for soft nanocarriers formation, in particular: liposomes are formed by phospholipids, while niosomes by non-ionic surfactant and micelles by amphiphilic polymers.

Coccidioidomycosis Involving the Cranium: A Case Report and Review of Current Literature

We report a case of Coccidioidomycosis of the cranium that presented as a cystlike structure with adjoining bone destruction in a 40-year-old patient with underlying rheumatoid arthritis that was treated with a combination of lipid amphotericin B and longterm fluconazole. We also discuss the common risk factors and presentations of this unusual extra-pulmonary form of Coccidioidomycosis.

Neuroimaging of Non-Accidental Injury

Deliberate inflicted trauma to children has irrefutably occurred for centuries but the notion of non-accidental injury (NAI) as a distinct clinical entity has only relatively recently been described. Awareness and understanding of this syndrome of abuse has increased greatly in recent decades, although many alternative names have been given to the condition and uncertainty remains as to what exactly comprises the syndrome.

What is not in question, however, is the role of imaging; the radiologist is often at the front line in terms of raising the spectre of NAI and in assessing the probability given the objective imaging features available.

Non-accidental head injury (NAHI) encompasses a broad spectrum of manifestations, ranging from trivial superficial injuries to potentially fatal severe brain trauma. In this review, we aim to introduce the epidemiological, historical and legal aspects of NAI. Focussing specifically on NAHI, current biomechanical theories and neuropathological aspects will be discussed. Finally, the patterns of injury and prognosticating features with respect to the various imaging modalities will be covered, with careful consideration given to differential diagnoses and syndrome mimics.

Is there a Role for Bevacizumab in Non-Glial Tumors?

Angiogenesis is one of the hallmarks of cancer, including brain tumors. The vascular endothelial growth factor (VEGF) family and their receptors are of utmost importance in the complex interaction between pro- and anti-angiogenic factors, and have a crucial role in tumor angiogenesis. Up to date, targeting the VEGF pathway with specific drugs has yielded interesting results in oncology. In particular bevacizumab (Bev), a humanized monoclonal antibody against VEGF-A, has been approved by the Food and Drug Administration (FDA) for use in recurrent glioblastomas failing standard radiochemotherapy. Bevacizumab is now being extensively investigated in several non-glial brain tumors, such as vestibular schwannomas, meningiomas, ependymomas, medulloblastomas and miscellaneous histotypes. The aim of this review is to reevaluate the literature on the use of Bev in non-glial brain tumors.

Emerging Use of Nanotechnology in the Treatment of Neurological Disorders

Neurological disorders represent one of the major health concerns worldwide. Yet currently employed treatment strategies have not been very successful in the treatment of many of these disorders. One of the root causes of this lack of success is that many pharmaceutically active compounds are unable to reach their target sites of action inside the body. The delivery of substances from systemic circulation to the desired site of action, namely central nervous system (CNS), is hindered by CNS extracellular and intracellular barriers. One promising approach to circumvent these barriers is the use of nanoscaled drug delivery systems. These nanosized drug carriers display various advantages over other conventional drug delivery methods such as high drug loading capacity, targeted action, reduced toxicity, and increased therapeutic effect. Nano-neuroscience is thereby emerging as an exciting field of study and a promising future direction for the delivery of therapeutics to their targeted site of action inside the CNS for the treatment of various neurological and psychiatric disorders. Here, we will first discuss the general pharmacokinetics of therapeutics depending on the route of administration, drawbacks of conventional drug delivery systems and challenges for CNS drug delivery, namely CNS barriers. Next, a short overview of the strategies to circumvent these barriers will be given. Finally, nanotechnology and its emerging use as drug delivery systems will be discussed. This includes the advantages of nanoparticles over other conventional drug delivery systems; production of nanoparticles and their designing as an effective drug carrier; various types of nanoparticles; and some examples of their efficient use in the delivery of bioactive substances, and in the treatment of neurological disorders mainly Alzheimer’s disease, brain tumors and neuroAIDS. Lastly, a future perspective on the use of nanotechnology in CNS drug delivery will be highlighted.

Lipoproteins, Stroke and Statins

Dyslipidemia represents one of the major risk factors for atherosclerosis affecting the arteries of large and medium caliber and consequently causing ischemia in the brain, heart, or legs. Coronary artery disease and cerebral stroke represent the major causes of morbidity and mortality among the elderly and middle aged subjects. The change of lifestyle can reduce the risk of cardiovascular disease but available drug therapy (in particular statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase) is effective in modifying hyperlipidemia and consequently reducing cardiovascular events. The hypolipemic drugs can prevent, slow the progression and sometimes determine the regression of atherosclerotic plaques, therefore significantly reducing the clinical complications of atherosclerotic cardiovascular disease. In this review, we want to point out the role of the different lipoproteins, such as triglycerides, HDL-C, LDLC, Lp(a), in the pathogenesis of stroke and the role of statins in reducing both lipid fractions and stroke risk.

Cerebrovascular and Blood-Brain Barrier Morphology in Spontaneously Hypertensive Rats: Effect of Treatment with Choline Alphoscerate

Cholinergic precursors increasing choline availability and acetylcholine synthesis/release may represent a therapeutic approach for countering cognitive impairment occurring in adult-onset dementia disorders. Choline alphoscerate (alpha-gliceryl-phosphoryl-choline, GPC) is among cholinergic precursors the most effective in enhancing acetylcholine biosynthesis and release in animal models. This study was designed to assess if a long-term treatment with GPC modify cerebrovascular components [perivascular astrocytes, blood-brain barrier (BBB) and microvessels] and endothelial inflammatory markers expression in spontaneously hypertensive rats (SHR) used as a model of brain vascular injury. Male SHR aged 32 weeks and age-matched normotensive Wistar-Kyoto rats were treated for 4 weeks with GPC (150 mg/kg/day) or a vehicle. Intracerebral arteries of different brain areas, perivascular astrocytes, BBB and endothelial inflammatory markers were assessed by quantitative morphological and immunohistochemical techniques. No significant changes in the size of perivascular astrocytes were observed in SHR versus normotensive Wistar-Kyoto rats, whereas the expression of the BBB marker aquaporin-4 increased in SHR. This phenomenon was countered by GPC treatment. On the contrary, GPC has no vasodilator effect on brain micro-vessels. Endothelial markers and vascular adhesion molecules expression were not homogeneously affected by hypertension and GPC treatment in intracerebral vessels. The observation that treatment with GPC reversed BBB changes and countered to some extent micro-vessels changes occurring in SHR could explain data of clinical trials reporting an improvement of cognitive function in subjects suffering from cerebrovascular disorders and treated with GPC. These preclinical data suggest that the compound could have a cerebrovascular protective effect deserving a further characterization.

Is There A Pulse Wave Encephalopathy Component To Multiple Sclerosis?

The dominant hypothesis in multiple sclerosis is that it is an autoimmune disease; however, there is considerable evidence that the immune attack on myelin may be secondary to a cytodegenerative event. Furthermore, the immune modulating therapies longest in clinical use, although modulating the frequency and severity of exacerbation, do not affect long-term progression towards disability. Clearly alternative perspectives on the etiology of multiple sclerosis are warranted. In this paper I outline the commonalities between idiopathic normal pressure hydrocephalus and multiple sclerosis. These include decreased intracranial compliance as evidenced by increased cerebrospinal fluid volume and velocity of cerebrospinal fluid flow through the cerebral aqueduct; increased ventricular volume; periventricular demyelination lesions; increase in size of Virchow-Robin spaces; presence of Hakim’s triad comprised of locomotory disabilities, cognitive problems and bladder control problems. Furthermore, multiple sclerosis is associated with decreased arterial compliance. These are all suggestive that there is a pulse wave encephalopathy component to multiple sclerosis. There are enough resemblances between normal pressure hydrocephalus and multiple sclerosis to warrant further investigation. Whether decreases in intracranial compliance is a consequence of multiple sclerosis or is a causal factor is unknown. Effective therapies can only be developed when the etiology of the disease is understood.

Neonatal Brain Hemorrhage (NBH) of Prematurity: Translational Mechanisms of the Vascular-Neural Network

Neonatal brain hemorrhage (NBH) of prematurity is an unfortunate consequence of preterm birth. Complications result in shunt dependence and long-term structural changes such as posthemorrhagic hydrocephalus, periventricular leukomalacia, gliosis, and neurological dysfunction. Several animal models are available to study this condition, and many basic mechanisms, etiological factors, and outcome consequences, are becoming understood. NBH is an important clinical condition, of which treatment may potentially circumvent shunt complication, and improve functional recovery (cerebral palsy, and cognitive impairments). This review highlights key pathophysiological findings of the neonatal vascular-neural network in the context of molecular mechanisms targeting the posthemorrhagic hydrocephalus affecting this vulnerable infant population.

Ion Transporters in Brain Tumors

Ion transporters are important in regulation of ionic homeostasis, cell volume, and cellular signal transduction under physiological conditions. They have recently emerged as important players in cancer progression. In this review, we discussed two important ion transporter proteins, sodiumpotassium- chloride cotransporter isoform 1 (NKCC-1) and sodium-hydrogen exchanger isoform 1 (NHE-1) in Glioblastoma multiforme (GBM) and other malignant tumors. NKCC-1 is a Na⁺- dependent Cl^- transporter that mediates the movement of Na⁺, K⁺, and Cl^- ions across the plasma membrane and maintains cell volume and intracellular K⁺ and Cl^- homeostasis. NHE-1 is a ubiquitously expressed cell membrane protein which regulates intracellular pH (pH_i) and extracellular pH (pH_e) homeostasis and cell volume. Here, we summarized recent pre-clinical experimental studies on NKCC-1 and NHE-1 in GBM and other malignant tumors, such as breast cancer, hepatocellular carcinoma, and lung cancer cells. These studies illustrated that pharmacological inhibition or down-regulation of these ion transporter proteins reduces proliferation, increases apoptosis, and suppresses migration and invasion of cancer cells. These new findings reveal the potentials of these ion transporters as new targets for cancer diagnosis and/or treatment.

Nanoparticles in the Treatment of Mental Disorders: A New Tool in the Psychiatric Medication

The use of the nanotechnology in the development of new drugs has had in the last years a very widespread presence in the pharmaceutical industry. Diverse diseases that are treated by means of conventional administration systems as capsules, covered tablets or injectable not always have the therapeutic effect expected due to its bioavailability, solubility in aqueous medium and the stability of the excipients that they accompany to the drug. It is for this reason that the formation of nanoparticles either from organic sources as natural polymers like chitosan or synthetic like poly-ε-caprolactone (PCL) affording the inclusion of diverse liposoluble active compounds, they have given excellent results in the incipient treatment of behavior disorders that are necessary drugs that should remain close of active sites at the time. Thus, this review shows the formation of nanoparticles for a direct application of the psychiatric medication, may be considered as a new pharmacological tool by its low cytotoxicity and high efficiency.

The Heart and Brain Imaging in Lone Atrial Fibrillation – Are We Surprised?

“Lone” atrial fibrillation (AF) is generally used to refer to patients with AF in the absence of structural heart disease. When the decision for oral anticoagulation is discussed, “lone” AF refers to patients who do not have established stroke risk factors. Imaging is often used to rule out structural heart disease, e.g. coronary artery disease, peripheral vascular disease, mitral stenosis or left ventricular (LV) dysfunction. Imaging of the heart has a central role in establishing the “lone” aspect in patients with “lone”AF, similar to the measurement of blood glucose and blood pressure: Patients with structural heart disease, defined as e.g. reduced LV ejection fraction, clinical evidence for heart failure, or evidence for coronary artery disease, will not be considered as patients with “lone” AF. The search for these conditions requires some cardiac imaging, often done by echocardiography and non-invasive tests for coronary artery disease or ischemia.

Increasingly, brain imaging is used to define the clinical diagnosis of a stroke, thus also contributing to the detection of stroke risk factors. Cerebral imaging in AF patients without competing causes for silent strokes or microbleeds (“lone” AF, rather used in the context of anticoagulation, i.e. clinical absence of structural heart disease) would allow to better understand the contribution of AF to these brain lesions. The assumption that silent strokes are likely drivers of cognitive dysfunction, and the fact that microbleeds put patients at risk for intracerebral hemorrhage, illustrates the need to collect information on brain imaging.

In this review article, we summarize current data on heart and brain imaging in patients with “lone” AF and discuss their clinical implications for risk assessment and management of patients with “lone” AF.

Intrathecal Rituximab Therapy in Multiple Sclerosis: Review of Evidence Supporting the Need for Future Trials

Rituximab has demonstrated a major effect in B-cell lymphoma and in a wide range of autoimmune disorders. Unfortunately, the blood-brain-barrier excludes the disorders restricted to the central nervous system (CNS) from the action of rituximab. The progressive phase of multiple sclerosis (MS) is a prototypical CNS autoimmune disorder characterized by an intrathecal compartmentalization of inflammation resisting all the available immunosuppressive treatments. As a consequence, intrathecal therapeutics are promising new approach in progressive MS. We first review data gathered from animal models and human off-label intrathecal rituximab use in CNS lymphomas, then summarize the recent evidence supporting the need for trials based on the intrathecal use of rituximab in multiple sclerosis. The experience obtained in these settings offers valuable preliminary data for future studies in CNS autoimmunity.

Relationship Between Na⁺, K⁺-ATPase and NMDA Receptor at Central Synapses

Specific receptors for classical neurotransmitters and neuropeptides, as well as the Na⁺, K⁺-ATPase, are all molecular entities inserted into synaptic region membranes and localized contiguously. Herein, available experimental evidence showing close interactions between the activity of the Na⁺, K⁺-ATPase and the N-methyl-D-aspartate (NMDA) ionotropic glutamate receptor was reviewed, supporting a functional link between these macromolecules. The Na⁺, K⁺- ATPase and NMDA receptor are involved in ion movements through membranes. The former acts as an ion transporter, whereas the latter acts as an ion channel. The modulation of their activity plays a critical role in controlling neuronal function. Examples were taken from studies performed with specific agonists or antagonists of the NMDA receptor. Regarding the Na⁺, K⁺-ATPase, its involvement was postulated after observing its inhibition by ouabain or related cardiac glycosides. Additionally, experimental conditions known to prevent normal Na⁺, K⁺-ATPase (i. e., sodium pump functioning) led to similar valuable information. These findings indicate potential cross-talk between this enzyme and the NMDA receptor. The Na⁺, K⁺-ATPase and NMDA play very important roles in the regulation of learning and memory in the hippocampus. The fact that important changes here described were recorded in the hippocampus indicate a different vulnerability of this area to toxicity induced by the Na⁺, K⁺-ATPase inhibitor ouabain. Some interesting relationships include calcineurin actions, the participation of ERK or Src family kinases, and signaling cascades initiated by calcium. At present, many other examples of signaling related to the NMDA receptor cannot be correlated with Na+, K⁺-ATPase activity. It is desirable that the development of future research offer new clues for the relationship between Na⁺, K⁺-ATPase and NMDA receptor activation.

Novel Agents in CNS Myeloma Treatment

Central nervous system localization of multiple myeloma (CNS-MM) accounts for about 1% of all MM. Treatment is still unsatisfactory. Many treatments have been described in the literature: chemotherapy (CHT), intrathecal therapy (IT), and radiotherapy (RT), with survivals reported between one month and six months. Recent drugs such as the immunomodulatory drugs (IMiDs) and proteasome inhibitors (bortezomib) have changed the treatment of patients with MM, both younger and older, with a significant improvement in response and survival. The activity of new drugs in CNSMM has been reported but is still not well known. Bortezomib does not cross the blood brain barrier (BBB), and IMID’s seem to have only a minimal crossover. The role of novel agents in CNS MM management will be discussed as well as the potential role of other new immunomodulatory drugs (pomalidomide) and proteasome inhibitors that seem to cross the BBB and hold promise into the treatment of this rare and still incurable localization of the disease.