Meningoencephalitis

Leptomeningeal Masses or Masquerades: A Spectrum of Diseases with Leptomeningeal Enhancement and their Mimics

Background: Leptomeningeal enhancement, visible on MRI, can indicate a variety of diseases, both neoplastic and non-neoplastic.

Objective: This comprehensive pictorial review aims to equip radiologists and trainees with a thorough understanding of the diverse imaging presentations of leptomeningeal disease.

Methods: Drawing from a retrospective analysis of MRI scans conducted between 1 January 2008 and 30 September 2022, at two tertiary teaching hospitals in Singapore, this review covers a wide range of conditions.

Results: The main neoplastic conditions discussed include leptomeningeal carcinomatosis, myelomatosis, schwannoma, CNS lymphoma, and pineal region tumors. Additionally, the review addresses non-neoplastic enhancements such as meningoencephalitis, intracranial hypotension, cerebral ischemia/infarction, epidural lipomatosis, syringomyelia, Sturge-Weber syndrome, and subarachnoid hemorrhage.

Conclusion: By highlighting the imaging features and patterns associated with these conditions, the review underscores the critical role of accurate diagnosis and timely management in improving patient outcomes. Enhanced understanding of these conditions can significantly improve patient outcomes through timely and effective therapeutic interventions.

Longitudinally Extensive Transverse Myelitis (LETM) and Meningoencephalitis Following Acute Epstein-barr Virus Infection in an Immunocompetent Male: Case Report and Review Literature

Introduction: Epstein-Barr Virus (EBV) causes heterophile-positive Infectious Mononucleosis (IM), which manifests fever, sore throat, lymphadenopathy, and atypical lymphocytosis. In the Central Nervous System (CNS), EBV can cause acute encephalitis, cerebellar ataxia, Acute Disseminated Encephalomyelitis (ADEM), myelitis, meningitis, and radiculopathy. Reports of acute transverse myelitis linked to EBV infection are limited; therefore, Longitudinally Extensive Transverse Myelitis (LETM) due to EBV infection is extremely uncommon.

Case Report: An 18-year-old male, otherwise healthy, was admitted to the medicine department with ten days of fever, headache, and vomiting and five days of altered sensorium. Subsequently, his neurological test showed bilateral upper motor neuron quadriparesis, sensory impairment, and bladder-bowel involvement. Spinal T2W MRI indicated extensive cervical, thoracic, and lumbar hyperintense lesions. Laboratory investigations supported the diagnosis, which revealed a positive IgM Antibody for EBV Viral Capsid Antigen (VCA) in serum and EBV DNA PCR in Cerebrospinal Fluid (CSF). The final diagnosis was EBVinduced acute meningoencephalitis with longitudinally extensive transverse myelitis and incidental aortic coarctation. Following methylprednisolone pulse therapy, the patient recovered significantly.

Conclusion: The present case report aims to share our experience by highlighting awareness of the rarity and treatment outcome of EBV-induced LETM.

Combating Amoebic Meningoencephalitis in Kerala and other Indian States

Concurrent Diffuse Dural and Leptomeningeal Enhancements in Brain Magnetic Resonance Imaging Following a Mild COVID-19 Infection: A Novel Case Report and Review of Literature

Introduction: During the COVID-19 pandemic, various complications have been reported in patients with this infection worldwide, including a wide range of neurological disorders. In this study, we have reported a novel neurological complication in a 46-years-old woman who was referred due to a headache following a mild COVID-19 infection. Also, we have had a quick review of previous reports of dural and leptomeningeal involvements in COVID-19 patients.

Case Report: The patient's headache was persistent, global, and compressive with radiation to the eyes. The severity of the headache was increased during the disease course and was exacerbated by walking, coughing, and sneezing but decreased with rest. The high severity of the headache disrupted the patient’s sleep. Neurological examinations were completely normal, and laboratory tests did not have abnormal findings except for an inflammatory pattern. Finally, in the brain MRI, a concurrent diffuse dural enhancement and leptomeningeal involvement were observed, which is a new finding in COVID-19 patients and has not been reported so far. The patient was hospitalized and treated with Methylprednisolone pulses. After completing the therapeutic course, she was discharged from the hospital in good condition and with an improved headache. A repeated brain MRI was requested 2 months after discharge, which was completely normal and showed no evidence of dural and leptomeningeal involvements.

Conclusion: Inflammatory complications of the central nervous system caused by COVID-19 can occur in different forms and types, and clinicians should consider them.

Neurological Manifestations of Influenza Virus and RSV Infections in Children

The most significant viral contributors to acute respiratory tract infections in children are Respiratory Syncytial Viruses (RSV) and influenza virus, causing substantial seasonal respiratory infections annually. Furthermore, severe neurological complications, notably seizures and encephalopathy, can be attributed to these viruses. Children with chronic or pre-existing neurological conditions are particularly susceptible to increased morbidity and sequelae. An active area of research to date is focused on the potential mechanisms of viral neurological invasion, which could be relevant for future therapeutic strategies. Influenza virus is frequently an important cause of epidemic or pandemic disease causing high costs of hospitalization and primary care. Furthermore, different subtypes of influenza viruses can induce various influenza-associated neurological complications, varying from mild (i.e., headache) to severe (i.e., meningoencephalitis and acute necrotizing encephalopathy), both in adults and children. While affecting the respiratory tract, RSV can also give rise to neurological manifestations, potentially resulting in long-term neurological impairment. Neurological changes associated with RSV encompass seizures, lethargy, ataxia, febrile or epileptic states, central apnea, difficulties in feeding or swallowing, tone abnormalities, strabismus, abnormalities in cerebrospinal fluid, and encephalopathy. Patients infected with RSV can also develop neuromotor difficulties or present learning impairment. In conclusion, viral respiratory infections can result in significant extrapulmonary symptoms, potentially leading to enduring health consequences in affected children. Substantial research efforts are necessary to prevent or treat these infections, particularly within the most vulnerable populations.

Recent Updates on the Development of Therapeutics for the Targeted Treatment of Alzheimer’s Disease

Alzheimer's disease (AD) is a complicated, multifaceted, irreversible, and incurable neurotoxic old age illness. Although NMDA (N-methyl D-aspartate)-receptor antagonists, cholinesterase repressors, and their pairings have been approved for the treatment, they are useful for short symptomatic relief. Researchers throughout the globe have been constantly working to uncover the therapy of Alzheimer's disease as new candidates must be determined, and newer treatment medicines must be developed. The aim of this review is to address recent advances in medication research along with new Alzheimer's disease therapy for diverse targets. Information was gathered utilizing a variety of internet resources as well as websites, such as ALZFORUM (alzforum.org) and clinicaltrials.gov. In contrast to other domains, the proposed medicines target amyloids (secretases, A42 generation, neuroinflammation, amyloid precipitation, and immunization), tau proteins (tau phosphorylation/aggregation and immunotherapy), and amyloid deposition. Despite tremendous advancement in our understanding of the underlying pathophysiology of Alzheimer's disease, the FDA (Food and Drug Administration) only approved aducanumab for diagnosis and treatment in 2003. Hence, novel treatment tactics are needed to find and develop therapeutic medicines to combat Alzheimer's disease.

Is it the Right Time to Coin the Term “Expanded COVID Syndrome (ECS)”?

Adenovirus Meningoencephalitis and Neurocysticercosis Co-infection: First Case from India

Background: Adenovirus generally causes upper and lower respiratory tract infections. It is common in children and occasionally in adults. Neurological involvement is rare, which may be mild aseptic meningitis to potentially fatal acute necrotizing encephalopathy. Recently, viruses have been reported increasingly to cause CNS infections. Viral aetiology typically varies with age.

Case Presentation: Here, we report an unusual adenovirus meningoencephalitis with a co-infection of neurocysticercosis in an immunocompetent adult patient. An 18-year-old healthy female student was admitted with fever and headache for 11 days and progressive altered behaviour for 5 days, followed by altered sensorium for 3 days. This variable and unusual presentation of adenoviral infection involving CNS provoked diagnostic difficulties, but with the help of advanced diagnostics, especially molecular, exact aetiology was detected. Even with the neurocysticercosis infection in this patient, the outcome was not adversely affected.

Conclusion: This unusual co-infection with a successful outcome is the first case of this type in literature.

Retrospective Review of Chromane Analogues as Anti-protozoal Leads: A Decade's Worth of Evolution

Tropical, vector-borne, and neglected diseases with a limited number of medication therapies include Leishmaniasis, Malaria, Chagas and Human African Trypanosomiasis (HAT). Chromones are a large class of heterocyclic compounds with significant applications. This heterocycle has long aroused the interest of scientists and the general public from biosynthetic and synthetic points of view owing to its interesting pharmacological activities. Chromones and their hybrids and isomeric forms proved to be an exciting scaffold to investigate these diseases. The in vitro activities of Chromone, Chromane, and a panel of other related benzopyran class compounds against Trypanosoma brucei rhodesiense, Trypanosoma brucei gambiense, Trypanosoma cruzi, and numerous Leishmanial and Malarial species were investigated in our previous studies. The current article briefly describes the neglected diseases and the current treatment. This review aims to attempt to find better alternatives by scrutinizing natural and synthetic derivatives for which chromones and their analogues were discovered to be a new and highly effective scaffold for the treatment of neglected diseases, including compounds with dual activity or activity against multiple parasites. Additionally, the efficacy of other new scaffolds was also thoroughly examined. This article also discusses prospects for identifying more unique targets for the disease, focusing on flavonoids as drug molecules that are less cytotoxic and high antiprotozoal potential. It also emphasizes the changes that can be made while searching for potential therapies-comparing existing treatments against protozoal diseases and the advantages of the newer chromone analogues over them. Finally, the structure- activity relationship at each atom of the chromone has also been highlighted.

A Case of Cerebral Toxoplasmosis and Cryptococcosis Preferred Therapy Associated Adverse Drug Reactions in a Patient Newly Co-diagnosed with Acquired Immune Deficiency Syndrome

Purpose: The simultaneous occurrence of cerebral toxoplasmosis and cryptococcosis is rare. The infections continue to be treated with sulfadiazine and amphotericin-B-based regimens (preferred therapy), respectively. Both these drugs are linked to some serious adverse drug reactions (ADRs). We report such a unique instance of both; the CNS co-infections and adverse drug reactions to the preferred therapy.

Case Presentation: A 44-year-old Asian-Indian female was diagnosed with cerebral toxoplasmosis, impending cryptococcal meningoencephalitis, and acquired immune deficiency syndrome (AIDS). The preferred therapy of opportunistic CNS co-infections commenced. Within a week, she had an occurrence of fall in hemoglobin concentrations (11.3 g/dL to 5.6 g/dL; grade IV), reticulocytosis (1% to 3.2%), and indirect hyperbilirubinemia (0.5 mg/dL to 2.8 mg/dL; grade IV) after sulfadiazine administration. The drug was discontinued and the patient was treated with hematocrit transfusions. After amphotericin-B deoxycholate (AmBd) administration, the patient developed hypokalemia (serum potassium; 4.5 mmol/L to 2.7 mmol/L) and increased serum creatinine (1.0 to 2.2 mg/dL; stage-I) levels. Hence, AmBd was discontinued and potassium correction was given. The patient got diagnosed with sulfadiazine induced hemolytic anemia and AmBd induced acute renal failure. He was switched to alternative therapy regimens for the treatment of cerebral toxoplasmosis and cryptococcosis. Radiological investigations were followed up to confirm the clinical outcomes of alternative therapy. Complete recovery from the ADRs and opportunistic infections was observed.

Conclusion: The preferred therapy regimens for toxoplasmosis and cryptococcosis are accompanied by potential adverse drug reactions, thus continuous monitoring is vital, especially in the initial phases of therapy. Discontinuation of the treatment should be the preliminary intervention in the management. Having said that, alternative therapy regimens had an optimal clinical response in the present case.

Current Status on 1,4-Dihydropyridine Derivatives against Human Pathogenic Parasites

Infections provoked by parasites are among the most prevalent diseases worldwide and generate important health and socioeconomic problems. Despite the enormous amount of work done, the chemotherapy for most of them remains unsolved. Usually, treatments are based on no specific drugs associated, in several cases, with long-term treatments and severe side effects. In addition, drug resistance and different strains' susceptibility are further drawbacks of the existing chemotherapy. Considering that 1,4-dihydropyridines derivatives constitute an important class of compounds for new drug development, we present in this review an in-depth overview of the work done so far on 1,4-dihydropyridines and their antiparasitic activities. The development of new derivatives or the application of known drugs used for other diseases is described in terms of their potential usefulness for drug design.

Antifungal Activity of Plant Secondary Metabolites on Candida albicans: An Updated Review

Fungal infections have been increasing continuously worldwide, especially in immunocompromised individuals. Fungi, regarded as eukaryotic pathogens, have many similarities to the host cells, which inhibit anti-fungal drug development progress. Various fungal model systems have been studied, and it was concluded that Candida spp. is the most common disease-causing fungus. Candida species are well known to cause infections not only in our mouth, skin, and vagina, but they are also a frequent cause of life-threatening hospital bloodstream infections. The morphological and developmental pathways of Candida have been studied extensively, providing insight into the fungus development. Candida albicans is known to be the most pathogenic species responsible for a variety of infections in humans. Conventional anti-fungal drugs, mainly azoles drugs available in the market, have been used for years developing resistance in C. albicans. Hence, the production of new anti-fungal drugs, which require detailed molecular knowledge of fungal pathogenesis, needs to be encouraged. Therefore, this review targets the new approach of \"Green Medicines\" or the phytochemicals and their secondary metabolites as a source of novel anti-fungal agents to overcome the drug resistance of C. albicans, their mechanism of action, and their combined effects with the available anti-fungal drugs.

Disseminated Cryptococcosis in Idiopathic CD4+ Lymphocytopenia

Introduction: Idiopathic CD4+ Lymphocytopenia (ICL) is a rare entity grouped in non– HIV-related syndromes. ICL is characterized by a marked low CD4 T cell count of <300 cells/mm3 with ambiguous natural history and prognosis. In addition, cryptococcal and nontuberculous mycobacterial infections are reported as known opportunistic infections. Therefore, management turns around vigilant follow-up and treatment of the current clinical scenario of these patients.

Case Presentation: Here, a 55-year-old lady was referred with a history of diffuse headache and intermittent fever for two months, projectile vomiting, and altered mental status for five days. Nonpruritic maculopapular rashes and diffuse desquamation of the skin were noted. She had no significant previous medical history. Based on clinical findings and investigations, she was diagnosed with ICL having disseminated cryptococcosis. Unfortunately, the patient did not undergo specific treatment as she was recognized late, and unfortunately, she died.

Conclusion: It is of paramount importance to recognize the clinical entity as early as possible to start appropriate treatment, which may positively impact the outcome. Therefore, the clinician must be aware of disseminated cryptococcosis associated with non-HIV states.

Viral Encephalitis in Adults: A Narrative Review

Viral infections of the central nervous system cause frequent hospitalization. The pathogenesis of viral encephalitis involves both the direct action of invading pathogens and the damage generated by the inflammatory reaction they trigger. The type of signs and symptoms presented by the patient depends on the severity and location of the ongoing inflammatory process. Most of the viral encephalitides are characterized by an acute development, fever, variable alterations in consciousness (confusion, lethargy, even coma), seizures (focal and generalized) and focal neurologic signs. The specific diagnosis of encephalitis is usually based on lumbar puncture. Cerebrospinal fluid examination should be performed in all patients unless absolutely contraindicated. Also, electroencephalogram and neuroimaging play a prominent role in diagnosis. Airway protection, ventilatory support, the management of raised intracranial pressure and correction of electrolyte disorders must be immediately considered in a patient with altered mental status. The only therapy strictly recommended is acyclovir in HSV encephalitis. The use of adjunctive glucocorticoids has poor-quality evidence in HSV, EBV, or VZV encephalitis. The role of antiviral therapy in other types of viral encephalitis is not well defined.

Unravelling Micro and Nano Vesicular System in Intranasal Drug Delivery for Epilepsy

Background: Epilepsy is one of the major neurological disorders, affecting about 50 million people globally. Oral, intravenous and rectal delivery systems are available for the management of epileptic seizures. However, intranasal delivery serves as beneficial for delivering antiepileptic drugs owing to the advantages it offers.

Objective: Various approaches have been developed over the years aiming to attain either a safer or faster brain delivery; a nasal delivery system proposes significant outcomes. The noninvasiveness and high vascularity contribute to the high permeability of the nasal mucosa, allowing rapid drug absorption. This review highlights some promising novel approaches to efficiently deliver anti-epileptic drugs by employing the nasal route.

Methods: The method includes a collection of data from different search engines like PubMed, ScienceDirect and SciFinder for obtaining appropriate and relevant literature regarding epilepsy, intranasal delivery of anti-epileptic agents, and novel therapeutics.

Results: The present review underlines the majority of work related to intranasal delivery in the treatment of epilepsy, aiming to draw the attention of the researchers towards the easiest and most efficient ways of formulation for the delivery of anti-epileptics during seizures.

Conclusion: This review intends to provide an understanding of the delivery aspects of antiepileptic drugs, the benefits of intranasal delivery and the novel approaches employed for the treatment of epilepsy.

Central Nervous System Disorders Associated to Immune Checkpoint Inhibitors

New therapies and alternatives for the containment of tumor progression are being proposed for the treatment of cancer. In this context, monoclonal therapies using Immune Checkpoint Inhibitors (ICI) come as a therapeutic proposal. They are responsible for immunological control by blocking PD-1, PD-L1 and CTLA-4 molecules. However, among the effects caused by therapy, the use of medications is associated with neurological diseases reported as an adverse effect, affecting the Central Nervous System (CNS) and causing a wide range of symptoms. In this regard, the present bibliographic review presents the main CNS disorders associated with this therapy, in addition to the incidence, symptoms and treatment of these diseases.

Amyloid-beta Targeted Therapeutic Approaches for Alzheimer’s Disease: Long Road Ahead

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory impairment and cognitive decline. The obvious pathological features of AD are still amyloid plaques and neurofibrillary tangles. Development of disease-modifying treatments for AD has been challenging, with almost all drugs aborted. The amyloid cascade concept has been questioned due to the failures of various amyloid-targeting prospects. Despite this, targeting amyloid-β (Aβ) active immunotherapy provided some positive results to support this hypothesis and clinical trials of these candidates are ongoing. In this review, we describe the latest advance in therapeutic strategies based on amyloidogenic processing and evaluate the pros and cons of each treatment strategy. We also highlight the current status of the hottest immunotherapy and discuss the future development direction.

Potential Neuroprotective Effect of Cannabinoids in COVID-19 Patients

The global pandemic caused by the SARS-CoV-2 virus began in early 2020 and is still present. The respiratory symptoms caused by COVID-19 are well established. However, neurological manifestations that may result from direct or indirect neurological damage after SARS-CoV-2 infection have been reported frequently. The main proposed pathophysiological processes leading to neurological damage in COVID-19 are cerebrovascular disease and indirect inflammatory/ autoimmune origin mechanisms. A growing number of studies confirm that neuroprotective measures should be maintained in COVID-19 patients. On the other hand, cannabinoids have been the subject of various studies that propose them as potentially promising drugs in chronic neurodegenerative diseases due to their powerful neuroprotective potential. In this review, we addresses the possible mechanism of action of cannabinoids as a neuroprotective treatment in patients infected by SARS-CoV-2. The endocannabinoid system is found in multiple systems within the body, including the immune system. Its activation can lead to beneficial results, such as a decrease in viral entry, a reduction of viral replication, and a reduction of pro-inflammatory cytokines such as IL-2, IL-4, IL-6, IL-12, TNF-α, or IFN-c through CB2R expression induced during inflammation by SARS-CoV-2 infection in the central nervous system.

COVID-19, the Brain, and the Future: Is Infection by the Novel Coronavirus a Harbinger of Neurodegeneration?

The possible impact of viral infections on the development or pathogenesis of neurodegenerative disorders remains largely unknown. However, there have been reports associating the influenza virus pandemic and long-term infection with the Japanese encephalitis virus with the development of post-encephalitic Parkinsonism or von Economo’s encephalitis. In the last couple of years, there has been a worldwide pandemic caused by the novel coronavirus or severe acute respiratory syndrome coronavirus (SARS-CoV)-2, which causes a severe acute respiratory syndrome and is found to be associated with symptoms or complications of the central nervous system. Its possible involvement with the central nervous system is in line with emerging scientific evidence stating that the human respiratory coronaviruses can enter the brain, infect neural cells, persist in the brain, and cause activation of myelin-reactive T cells. Currently, there is a dearth of scientific information on the acute or possible long-term impact of infection with SARS-CoV-2 on the development of dementia and/or neurodegenerative diseases. This is related to the fact that the virus is ‘new,’ and its effects on humans are still being studied. This narrative review examines the extant literature for understanding the impact of coronavirus infections on the brain as there is a possibility that coronavirus disease 2019 (COVID-19) could increase the risk for the development of neurodegenerative diseases or hasten their progression.

Clinical Signs, Prevention and Treatment of Viral Infections in Infants

Certain infectious diseases are more common in infants than any other age groups and are associated with morbidities in childhood and adulthood, and even mortality in severe cases. Environment, epidemic and maternal immunity are the main causes of these infections. Early diagnosis using molecular methods and treatment is therefore important to prevent future complications. Vaccines are recommended during infancy and childhood to prevent these infections. This review highlights some of the most commonly reported viral infections in children, their clinical signs, prevention and treatment.

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.

SARS-CoV-2 Induced Neurological Manifestations Entangles Cytokine Storm that Implicates for Therapeutic Strategies

The new coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can present neurological symptoms and induce neurological complications. The involvement in both the central and peripheral nervous systems in COVID-19 patients has been associated with direct invasion of the virus and the induction of cytokine storm. This review discussed the pathways for the virus invasion into the nervous system and characterized the SARS-CoV-2 induced cytokine storm. In addition, the mechanisms underlying the immune responses and cytokine storm induction after SARS-CoV-2 infection were also discussed. Although some neurological symptoms are mild and disappear after recovery from infection, some severe neurological complications contribute to the mortality of COVID-19 patients. Therefore, the insight into the cause of SARS-CoV-2 induced cytokine storm in context with neurological complications will formulate the novel management of the disease and also further identify new therapeutic targets for COVID-19.

West Nile Viral Meningoencephalitis in an Immunocompetent Female: A Case Report from Western Rajasthan, India

Background: West Nile virus (WNV) is a positive-sense single-stranded RNA virus of the family Flaviviridae and genus Flavivirus. The virus is transmitted primarily by the bite of Culex species mosquito and is of global concern. The infection is associated with a wide spectrum of signs and symptoms and is more fatal in the elderly, infants, and immunocompromised individuals.

Case Presentation: We report a case of WNV meningoencephalitis in an immunocompetent female who presented with features of acute meningitis with a 5-days history. After the radiological suspicion of viral meningoencephalitis, viral serology was performed and was reactive for IgM antibody against WNV, delaying the diagnosis for at least 5 days.

Conclusion: The purpose of this case report is to prime the treating physicians on the usefulness of viral serology in such a scenario. Viral serology is a simple and relatively rapid technique to diagnose or rule out the suspected viral cause of meningoencephalitis and minimize the time gap between diagnosis and start of supporting treatment wherever appropriate antivirals are not available for clinical use.

Pharmacological Strategies for COVID-19 - A Review of the Most Promising Repurposed Antiviral Drugs

A novel coronavirus, SARS- CoV-2 (2019-nCoV), emerged in December 2019 as an immediate global challenge. Comprehensive efforts at the present time are focused simultaneously on containing the spread of this virus and extenuating the ill effects. There is an immediate need for drugs that can help before a vaccine can be developed. Researchers are endeavoring to find antiviral therapies specific to the virus. As the condition is an emerging, rapidly evolving situation and development of new drugs is a long process, and is unfeasible to face the immediate global challenge. Strategy to reposition the previously used drugs can prove to be effective to combat this difficult to treat pandemic. Several drugs such as Hydroxychloroquine, Umifenovir, Remdesivir, Lopinavir/ Ritonavir, interferon, Darunavir, Favipiravir, Nitazoxanide, etc. are currently undergoing clinical studies to test the safety and efficacy of the drug against this pandemic. The present review gives a snapshot look at the current clinical experience with repurposed antiviral drugs.

Larrea tridentata and its Biological Activities

Background: Larrea tridentata is a dominant shrub in the deserts of North America and is recognized for its various traditional uses. More than 50 traditional uses have been recorded. Regarding its chemical composition, the products of the mevalonate, shikimate, and malonate pathways are predominant. L. tridentata has nordihydroguaiaretic acid (NDGA), one of its most studied secondary metabolites that exhibited remarkable different biological activities: sequestration of reactive oxygen species, inhibition of lipoxygenases (LOX) and activation of the endogenous antioxidant response mediated by nuclear factor erythroid 2-related factor 2 (NRF2).

Objective and Methods: This review seeks to draw attention to metabolites other than NDGA and which also contribute to the various biological activities of L. tridentata. Therefore, the present review includes those reports focused on the pharmacological properties of the organic extracts of L. tridentata and its natural products with promising values.

Results and Conclusion: Among the most promising and widely reported metabolites from L. tridentata, are: 3’-demethoxy-6-O-demethylisoguaiacin, 3’-O-methyldihydroguaiaretic acid, meso-dihydroguaiaretic acid, and tetra-O-methylnordihydroguaiaretic acid. These have been reported to exhibit antibacterial, antiprotozoal, anthelmintic, antifungal, antiviral, anticancer, and antioxidant activities.

Effects of Medicinal Plants on Human Hosts and Zoonotic Helminthic Infections: A Systematic Review

Parasitic worm infections are a major health issue around the world, which cause numerous physiological damages in the patient's infected organ(s). The aim of this review was to investigate the anthelmintic properties of various medicinal plants. In this systematic review, all Randomized Controlled Trials (RCTs), quasi-experimental and experimental studies examining the anthelmintic effects were retrieved from databases, including Institute for Scientific Information (ISI) and PubMed from 1988-2019 by interesting keywords. In vitro and in vivo studies have demonstrated that many medicinal plants, including their compounds and derivatives, have anthelmintic properties through various Mechanisms Of Action (MOA). Examples of MOAs include paralysis of the helminths’ central nervous system, tegumental (outer body covering) destruction, interference with enzyme functioning, increased autophagy and apoptosis and reduction in cell viability and count. These actions lead to a reduction in the helminth ability to reproduce, decrease in egg count, inhibition of energy generation, damage to digestive tissues, lipid and ion accumulation, and change in and binding to different regulatory proteins and disruption of the helminth motor activity. These MOAs can also be used for the treatment of parasitic worms. Medicinal plants and their compounds have been the primary sources of new therapeutics, and are comparably more cost-effective than synthetic drugs and provide effective methods to combat parasitic worms that have entered into the human body. Therapists must take into account the effective dose of these compounds in treating the patients and also consider their overall health status, including comorbidities. There is an urgent need to conduct clinical trials using certain approaches, such as clinical interventional trials, to identify the effectiveness of herbal medicines in treating human host and zoonotic helminthic infections.

Astrocytes and Inflammasome: A Possible Crosstalk in Neurological Diseases

Inflammasome research has primarily focused on neurological tissue, particularly on damaged tissue. Most current neurological literature involves in vivo and in vitro studies utilizing astroglia, as astroglia express the cytoskeletal glial fibrillary acidic protein (GFAP), which is used as a hallmark of neuropathological disorders. Research suggests that astrocytes respond to all forms of neurological damage or disease through reactive astrogliosis. Additionally, there is a consensus among scientists that inflammasomes play an important role in neuroinflammation. This review focuses on the latest developments in inflammasome biology, describing the current understanding of how inflammasomes can be triggered in the brain and summarizing the literature on the relevance of inflammasome NLR in prevalent neurological diseases.

An Inducible Expression System for Recombinant Sca Proteins with an Autotransporter Domain from Orientia Tsutsugamushi in Escherichia coli

Background: Orientia tsutsugamushi (Ot) is an obligate, intracellular, gram-negative bacterium causing scrub typhus. Some of its encoded proteins play key roles in the adhesion and internalization of the Ot strain into host cells and are suitable resources for vaccine development and tools for scrub typhus diagnosis. Surface cell antigen (Sca) proteins, classified as autotransporter (AT) proteins, are one of the largest protein families involved in bacterial pathogenesis and can be promising candidates for vaccine development. These proteins are typically large and contain inhibitory domains; therefore, recombinant proteins without such domains have been evaluated for this purpose. However, the expression for recombinant Sca proteins containing the AT domain, which might largely affect their protective role against scrub typhus, has not been analyzed and optimized.

Objective: In this study, we optimized expression and purification conditions for individual Ot Sca protein fragments [ScaA (27–1461), ScaC (257–526), ScaD (26–998), and ScaE (35–760)] harboring the AT domain.

Methods: To this end, we subcloned sequences of codon-optimized DNA encoding Sca protein fragments into the Escherichia coli expression vector. In addition, the expression condition for individual Sca fragments was optimized, and the proteins were purified using one-step Ni-NTA column method. The purified fractions were re-folded by serial dilution method, followed by BCA quantification and densitometric analysis to estimate the yield and purity of proteins.

Results: We prepared platforms for expression of recombinant Sca protein fragments [ScaA (27–1461), ScaC (257–526), ScaD (26–998), and ScaE (35–760)] containing an AT domain without the signal peptide and transmembrane (TM) domain. The protein yield per liter of culture with >70% of purity was ScaC (257–576), ScaE (35–760), ScaD (26-998), and ScaA (27-1461) in order.

Conclusion: Our results could be used to develop Sca AT-domain based vaccines and tools for scrub typhus diagnosis with rapid and cost-effective ways.

Management of Idiopathic Intracranial Hypertension During the COVID-19 Pandemic

Background: In the current coronavirus disease 2019 (COVID-19) pandemic, health systems are struggling to prioritize care for affected patients; however, physicians globally are also attempting to maintain care for other less-threatening medical conditions that may lead to permanent disabilities if untreated. Idiopathic intracranial hypertension (IIH) is a relatively common condition affecting young females that could lead to permanent blindness if not properly treated. In this article, we provide some insight and recommendations regarding the management of IIH during the pandemic.

Methods: The diagnosis, follow-up, and treatment methods of IIH during the COVID-19 pandemic period are reviewed. COVID-19, as a mimic of IIH, is also discussed.

Results: Diagnosis and follow-up of papilledema due to IIH during the COVID-19 pandemic can be facilitated by nonmydriatic fundus photography and optical coherence tomography. COVID-19 may mimic IIH by presenting as cerebral venous sinus thrombosis, papillophlebitis, or meningoencephalitis, so a high index of suspicion is required in these cases. When surgical treatment is indicated, optic nerve sheath fenestration may be the primary procedure of choice during the pandemic period.

Conclusion: IIH is a serious vision-threatening condition that could lead to permanent blindness and disability at a relatively young age if left untreated. It could be the first presentation of a COVID-19 infection. Certain precautions during the diagnosis and management of this condition could be taken that may allow appropriate care to be delivered to these patients while minimizing the risk of coronavirus infection.

Neurobrucellosis: A Case Report with an Unusual Presentation

Background: Brucellosis is a highly infectious multi-systemic zoonosis, and it is caused by Gram-negative bacteria, Brucella. Despite the low incidence of neurobrucellosis, it is the most dangerous consequence of brucellosis.

Case Presentation: A 30-year-old Sudanese male patient presented to our hospital with a complaint of fever associated with confusion for three days. He had signs of meningeal irritation in the form of neck stiffness, positive Kernig’s, and Lesage’s sign. The computerized tomography of the brain was normal. The CSF analysis showed a clear colorless sample with normal tension, decreased glucose, and slightly increased CSF protein level. We reviewed his occupational history; the patient was a farmer with regular contact with cattle and camels. The patient had positive Brucella antibodies for both B. Abortus and B. melitensis with a high titer (1/640). As described in various patents, we administered triple therapy for brucellosis for two weeks. A marked improvement in the conscious level was observed, and the patient was back to normal within a few days post-treatment.

Conclusion: We encouraged physicians to consider the diagnosis of neurobrucellosis with any neurologic sign without a known cause. Our case highlights the importance of occupational history in clinical medicine.

Childhood Infectious Encephalitis: An Overview of Clinical Features, Investigations, Treatment, and Recent Patents

Background: Infectious encephalitis is a serious and challenging condition to manage. This overview summarizes the current literature regarding the etiology, clinical manifestations, diagnosis, management, and recent patents of acute childhood infectious encephalitis.

Methods: We used PubMed Clinical Queries as a search engine and used keywords of “encephalitis” AND “childhood” Patents were searched using the key term “encephalitis” in google.patents.- com and patentsonline.com.

Results: Viral encephalitis is the most common cause of acute infectious encephalitis in children. In young children, the clinical manifestations can be non-specific. Provision of empiric antimicrobial therapy until a specific infectious organism has been identified, which in most cases includes acyclovir, is the cornerstone of therapy. Advanced investigation tools, including nucleic acid-based test panel and metagenomic next-generation sequencing, improve the diagnostic yield of identifying an infectious organism. Supportive therapy includes adequate airway and oxygenation, fluid and electrolyte balance, cerebral perfusion pressure support, and seizure control. Recent patents are related to the diagnosis, treatment, and prevention of acute infectious encephalitis.

Conclusion: Viral encephalitis is the most common cause of acute infectious encephalitis in children and is associated with significant morbidity. Recent advances in understanding the genetic basis and immunological correlation of infectious encephalitis may improve treatment. Third-tier diagnostic tests may be incorporated into clinical practice. Treatment is targeted at the infectious process but remains mostly supportive. However, specific antimicrobial agents and vaccines development is ongoing.

Current Landscape of Natural Products against Coronaviruses: Perspectives in COVID-19 Treatment and Anti-viral Mechanism

Background: SARS-CoV-2 is a coronavirus, and the infection by SARS-CoV-2, termed as COVID-19, was first reported in Wuhan, China, at the end of 2019, and this outbreak became a pandemic in February of 2020. Till now, there is no effective drug or vaccine against this virus that can make a complete cure; however, a number of drugs are in trials.

Objectives: In this review, we have focused on an alternative therapeutic approach using natural products utilizing the host anti-viral responses for resolving COVID-19 pathogenesis.

Methods: We have searched databases like PubMed, Scopus, Web of Science, and Google Scholar for articles related to natural products and viral diseases, with a specific focus on coronaviruses, as well as other RNA viruses and recent updates on the COVID-19 pandemic, and collected articles and reviewed them comprehensively.

Results: Scientific studies clarified the viral pathogenesis that involved viral entrance into host cells and anti-viral response inside the cells, which can be effectively targeted by numerous natural compounds from different sources. Many of these compounds can potentially target viral genomic material or protein machinery. Natural products that were found effective against other coronaviruses, especially SARS-CoV or MERS-CoV (which emerged in 2002 and 2012, respectively), might be effective against SARS-CoV-2 due to their structural similarities.

Conclusion: COVID-19 pandemic is a global emergency thus, urgent drug development is necessary. Natural products can be the biggest source of drugs, as they have been found to be effective in other coronaviruses previously; however, time is required to establish the clinical success of these drugs for clinical applications.

Effective Antiviral Medicinal Plants and Biological Compounds Against Central Nervous System Infections: A Mechanistic Review

Background and Objective: Infectious diseases are amongst the leading causes of death in the world and central nervous system infections produced by viruses may either be fatal or generate a wide range of symptoms that affect global human health. Most antiviral plants contain active phytoconstituents such as alkaloids, flavonoids, and polyphenols, some of which play an important antiviral role. Herein, we present a background to viral central nervous system (CNS) infections, followed by a review of medicinal plants and bioactive compounds that are effective against viral pathogens in CNS infections.

Methods: A comprehensive literature search was conducted on scientific databases including: PubMed, Scopus, Google Scholar, and Web of Science. The relevant keywords used as search terms were: “myelitis”, “encephalitis”, “meningitis”, “meningoencephalitis”, “encephalomyelitis”, “central nervous system”, “brain”, “spinal cord”, “infection”, “virus”, “medicinal plants”, and “biological compounds”.

Results: The most significant viruses involved in central nervous system infections are: Herpes Simplex Virus (HSV), Varicella Zoster Virus (VZV), West Nile Virus (WNV), Enterovirus 71 (EV71), Japanese Encephalitis Virus (JEV), and Dengue Virus (DENV). The inhibitory activity of medicinal plants against CNS viruses is mostly active through prevention of viral binding to cell membranes, blocking viral genome replication, prevention of viral protein expression, scavenging reactive Oxygen Species (ROS), and reduction of plaque formation.

Conclusion: Due to the increased resistance of microorganisms (bacteria, viruses, and parasites) to antimicrobial therapies, alternative treatments, especially using plant sources and their bioactive constituents, appear to be more fruitful.

Mitochondrial Calcium Signaling as a Therapeutic Target for Alzheimer’s Disease

Mitochondria absorb calcium (Ca2+) at the expense of the electrochemical gradient generated during respiration. The influx of Ca2+ into the mitochondrial matrix helps maintain metabolic function and results in increased cytosolic Ca2+ during intracellular Ca2+ signaling. Mitochondrial Ca2+ homeostasis is tightly regulated by proteins located in the inner and outer mitochondrial membranes and by the cross-talk with endoplasmic reticulum Ca2+ signals. Increasing evidence indicates that mitochondrial Ca2+ overload is a pathological phenotype associated with Alzheimer’s Disease (AD). As intracellular Ca2+ dysregulation can be observed before the appearance of typical pathological hallmarks of AD, it is believed that mitochondrial Ca2+ overload may also play an important role in AD etiology. The high mitochondrial Ca2+ uptake can easily compromise neuronal functions and exacerbate AD progression by impairing mitochondrial respiration, increasing reactive oxygen species formation and inducing apoptosis. Additionally, mitochondrial Ca2+ overload can damage mitochondrial recycling via mitophagy. This review will discuss the molecular players involved in mitochondrial Ca2+ dysregulation and the pharmacotherapies that target this dysregulation. As most of the current AD therapeutics are based on amyloidopathy, tauopathy, and the cholinergic hypothesis, they achieve only symptomatic relief. Thus, determining how to reestablish mitochondrial Ca2+ homeostasis may aid in the development of novel AD therapeutic interventions.

Preclinical Study of the Pharmacokinetics of p75ECD-Fc, a Novel Human Recombinant Protein for Treatment of Alzheimer’s Disease, in Sprague Dawley Rats

Background: p75ECD-Fc is a recombinant human protein that has recently been developed as a novel therapy for Alzheimer’s disease. Current studies showed that it is able to alleviate Alzheimer’s disease pathologies in animal models of dementia. Thus, knowledge about the pharmacokinetic behavior and tissue distribution of this novel protein is crucial in order to better understand its pharmacodynamics and more importantly for its clinical development.

Methods: The aim of this study is to characterize the pharmacokinetics of p75ECD-Fc after single intravenous and subcutaneous injection of 3mg/kg in Sprague Dawley rats. We calculated the bioavailability of the SC route and studied the distribution of that protein in different tissues, cerebrospinal fluid and urine using ELISA and immunofluorescence techniques. In-vitro stability of the drug was also assessed. Data obtained were analyzed with Non-compartmental pharmacokinetic method using R.

Results: Results showed that the bioavailability of SC route was 66.15%. Half-life time was 7.5 ± 1.7 and 6.2 ± 2.4 days for IV and SC injection, respectively. Tissue distribution of p75ECD-Fc was modest with the ability to penetrate the blood brain barrier. It showed high in vitro stability in human plasma.

Conclusion: These acceptable pharmacokinetic properties of p75ECD-Fc present it as a potential candidate for clinical development for the treatment of Alzheimer’s disease.

Emerging Promise of Immunotherapy for Alzheimer’s Disease: A New Hope for the Development of Alzheimer’s Vaccine

Background: Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the characteristics of this devastating disorder include the progressive and disabling deficits in the cognitive functions including reasoning, attention, judgment, comprehension, memory, and language.

Objective: In this article, we have focused on the recent progress that has been achieved in the development of an effective AD vaccine.

Summary: Currently, available treatment options of AD are limited to deliver short-term symptomatic relief only. A number of strategies targeting amyloid-beta (Aβ) have been developed in order to treat or prevent AD. In order to exert an effective immune response, an AD vaccine should contain adjuvants that can induce an effective anti-inflammatory T helper 2 (Th2) immune response. AD vaccines should also possess the immunogens which have the capacity to stimulate a protective immune response against various cytotoxic Aβ conformers. The induction of an effective vaccine’s immune response would necessitate the parallel delivery of immunogen to dendritic cells (DCs) and their priming to stimulate a Th2-polarized response. The aforesaid immune response is likely to mediate the generation of neutralizing antibodies against the neurotoxic Aβ oligomers (AβOs) and also anti-inflammatory cytokines, thus preventing the AD-related inflammation.

Conclusion: Since there is an age-related decline in the immune functions, therefore vaccines are more likely to prevent AD instead of providing treatment. AD vaccines might be an effective and convenient approach to avoid the treatment-related huge expense.

An Insight into Nanomedicinal Approaches to Combat Viral Zoonoses

Background: Emerging viral zoonotic diseases are one of the major obstacles to secure the “One Health” concept under the current scenario. Current prophylactic, diagnostic and therapeutic approaches often associated with certain limitations and thus proved to be insufficient for customizing rapid and efficient combating strategy against the highly transmissible pathogenic infectious agents leading to the disastrous socio-economic outcome. Moreover, most of the viral zoonoses originate from the wildlife and poor knowledge about the global virome database renders it difficult to predict future outbreaks. Thus, alternative management strategy in terms of improved prophylactic vaccines and their delivery systems; rapid and efficient diagnostics and effective targeted therapeutics are the need of the hour.

Methods: Structured literature search has been performed with specific keywords in bibliographic databases for the accumulation of information regarding current nanomedicine interventions along with standard books for basic virology inputs.

Results: Multi-arrayed applications of nanomedicine have proved to be an effective alternative in all the aspects regarding the prevention, diagnosis, and control of zoonotic viral diseases. The current review is focused to outline the applications of nanomaterials as anti-viral vaccines or vaccine/drug delivery systems, diagnostics and directly acting therapeutic agents in combating the important zoonotic viral diseases in the recent scenario along with their potential benefits, challenges and prospects to design successful control strategies.

Conclusion: This review provides significant introspection towards the multi-arrayed applications of nanomedicine to combat several important zoonotic viral diseases.

“Proposals for Amendments in the Diagnosis and Treatment of Encephalitis caused by Free-living Amoebae”

Encephalitis caused by Free-living amoebae (FLA) has a mortality rate of around 95- 98%, a fraction that has not changed in the past decades. Pathogenic FLA include Acanthamoeba, Balamuthia mandrillaris, and Naegleria fowleri that are known to target the brain after an extra cerebral infection in the case of Acanthamoeba and Balamuthia mandrillaris, or directly the brain, as in the case of the Naegleria fowleri. The Acanthamoeba spp. and Balamuthia mandrillaris cause granulomatous amoebic encephalitis (GAE) while Naegleria fowleri, the so termed “brain eating amoeba” causes primary amoebic meningoencephalitis (PAM). The attempts to obtain a speedy diagnosis and an aggressive treatment protocol are the areas where advances can make a difference and reduce the mortality rates. At first, we highlight the reasons behind the diagnostic delays and treatment failures and provide proposals to establish a quick diagnosis in both PAM and GAE. Secondly, we emphasize the use of a transcribrial device, and a prompt, but vigilant surgical reduction of the intracranial pressure in these patients which could be life-saving. We also debate that an exudate obtained from the olfactory region by irrigation via a modified transcribrial device or by conventional methods, instead of a cerebrospinal fluid sample, could serve as a source of obtaining amoeba in PAM for a real-time polymerase chain reaction-based definitive diagnosis of PAM. Also, introduced is the rationale that has the potential to deliver the drugs to the brain in patients with PAM and the GAE localized to the frontal lobe of the brain, by bypassing the blood brain barrier. We put forward these proposals for debate and deliberation to our fellow colleagues in order to spot the potential of their application to reduce the mortality rates caused by the rare but fatal encephalitis caused by these FLA.

Virulence Factors in Sporothrix schenckii, One of the Causative Agents of Sporotrichosis

Sporothrix schenckii is one of the etiological agents of sporotrichosis, a fungal infection distributed worldwide. Both, the causative organism and the disease have currently received limited attention by the medical mycology community, most likely because of the low mortality rates associated with it. Nonetheless, morbidity is high in endemic regions and the versatility of S. schenckii to cause zoonosis and sapronosis has attracted attention. Thus far, virulence factors associated with this organism are poorly described. Here, comparing the S. schenckii genome sequence with other medically relevant fungi, genes involved in morphological change, cell wall synthesis, immune evasion, thermotolerance, adhesion, biofilm formation, melanin production, nutrient uptake, response to stress, extracellular vesicle formation, and toxin production are predicted and discussed as putative virulence factors in S. schenckii.

The Functional Significance of Endocrine-immune Interactions in Health and Disease

Hormones are known to influence various body systems that include skeletal, cardiac, digestive, excretory, and immune systems. Emerging investigations suggest the key role played by secretions of endocrine glands in immune cell differentiation, proliferation, activation, and memory attributes of the immune system. The link between steroid hormones such as glucocorticoids and inflammation is widely known. However, the role of peptide hormones and amino acid derivatives such as growth and thyroid hormones, prolactin, dopamine, and thymopoietin in regulating the functioning of the immune system remains unclear. Here, we reviewed the findings pertinent to the functional role of hormone-immune interactions in health and disease and proposed perspective directions for translational research in the field.

Nanoparticle-Mediated Drug Delivery: Blood-Brain Barrier as the Main Obstacle to Treating Infectious Diseases in CNS

Background: Parasitic infections affecting the central nervous system (CNS) present high morbidity and mortality rates and affect millions of people worldwide. The most important parasites affecting the CNS are protozoans (Plasmodium sp., Toxoplasma gondii, Trypanosoma brucei), cestodes (Taenia solium) and free-living amoebae (Acantamoeba spp., Balamuthia mandrillaris and Naegleria fowleri). Current therapeutic regimens include the use of traditional chemicals or natural compounds that have very limited access to the CNS, despite their elevated toxicity to the host. Improvements are needed in drug administration and formulations to treat these infections and to allow the drug to cross the blood-brain barrier (BBB).

Methods: This work aims to elucidate the recent advancements in the use of nanoparticles as nanoscaled drug delivery systems (NDDS) for treating and controlling the parasitic infections that affect the CNS, addressing not only the nature and composition of the polymer chosen, but also the mechanisms by which these nanoparticles may cross the BBB and reach the infected tissue.

Results: There is a strong evidence in the literature demonstrating the potential usefulness of polymeric nanoparticles as functional carriers of drugs to the CNS. Some of them demonstrated the mechanisms by which drugloaded nanoparticles access the CNS and control the infection by using in vivo models, while others only describe the pharmacological ability of these particles to be utilized in in vitro environments.

Conclusion: The scarcity of the studies trying to elucidate the compatibility as well as the exact mechanisms by which NDDS might be entering the CNS infected by parasites reveals new possibilities for further exploratory projects. There is an urgent need for new investments and motivations for applying nanotechnology to control parasitic infectious diseases worldwide.

Repositioning of HIV Aspartyl Peptidase Inhibitors for Combating the Neglected Human Pathogen Trypanosoma cruzi

Chagas disease, caused by the flagellate parasite Trypanosoma cruzi, is a wellknown neglected tropical disease. This parasitic illness affects 6-7 million people and can lead to severe myocarditis and/or complications of the digestive tract. The changes in its epidemiology facilitate co-infection with the Human Immunodeficiency Virus (HIV), making even more difficult the diagnosis and prognosis. The parasitic infection is reactivated in T. cruzi/HIV co-infection, with the appearance of unusual manifestations in the chronic phase and the exacerbation of classical clinical signs. The therapeutic arsenal to treat Chagas disease, in all its clinical forms, is restricted basically to two drugs, benznidazole and nifurtimox. Both drugs are extremely toxic and the therapeutic efficacy is still unclear, making the clinical treatment a huge issue to be solved. Therefore, it seems obvious the necessity of new tangible approaches to combat this illness. In this sense, the repositioning of approved drugs appears as an interesting and viable strategy. The discovery of Human Immunodeficiency Virus Aspartyl Peptidase Inhibitors (HIV-PIs) represented a milestone in the treatment of Acquired Immune Deficiency Syndrome (AIDS) and, concomitantly, a marked reduction in both the incidence and prevalence of important bacterial, fungal and parasitic co-infections was clearly observed. Taking all these findings into consideration, the present review summarizes the promising and beneficial data concerning the effects of HIV-PIs on all the evolutionary forms of T. cruzi and in important steps of the parasite’s life cycle, which highlight their possible application as alternative drugs to treat Chagas disease.

Dynamics of T Cells Repertoire During Trypanosoma cruzi Infection and its Post-Treatment Modulation

Chagas disease courses with different clinical phases and has a variable clinical presentation and progression. The acute infection phase mostly exhibits a non-specific symptomatology. In the absence of treatment, the acute phase is followed by a chronic phase, which is initially asymptomatic. This chronic asymptomatic phase of the disease is characterized by a fragile balance between the host’s immune response and the parasite replication. The loss of this balance is crucial for the progression of the sickness. The virulence and tropism of the T. cruzi infecting strain together to the inflammation processes in the cardiac tissue are the main factors for the establishment and severity of the cardiomyopathy. The efficacy of treatment in chronic Chagas disease patients is controversial. However, several studies carried out in chronic patients demonstrated that antiparasitic treatment reduces parasite load in the bloodstream and leads to an improvement in the immune response against the Trypanosoma cruzi parasite. The present review is mainly focused on the cellular patterns associated to the clinical status and the evolution of the disease in chronic patients, as well as the effectiveness of the treatment related to T. cruzi infection control. Therefore, an emphasis is placed on the dynamics of specific-antigens T cell subpopulations, their memory and activation phenotypes, their functionality and their contribution to pathogenesis or disease control, as well as their association with risk of congenital transmission of the parasite.

Active Amyloid-β Vaccination Results in Epigenetic Changes in the Hippocampus of an Alzheimer’s Disease-Like Mouse Model

Background: While evidence accumulates for a role of epigenetic modifications in the pathophysiological cascade of Alzheimer’s disease (AD), amyloid-β (Aβ)-targeted active immunotherapy approaches are under investigation to prevent or slow the progression of AD. The impact of Aβ active vaccines on epigenetic markers has not been studied thus far.

Objective: The current study aims to establish the relationship between active immunotherapy with a MER5101-based vaccine (consisting of Aβ1-15 copies conjugated with a 7 aa spacer to the diphtheria toxoid carrier protein, formulated in a Th2-biased adjuvant) and epigenetic DNA modifications in the hippocampus of APPswe/PS1dE9 mice.

Methods: As we previously reported, immunotherapy started when the mice were 10 months of age and behavioral testing occurred at 14 months of age, after which the mice were sacrificed for further analysis of their brains. In this add-on study, global levels of DNA methylation and hydroxymethylation, and DNA methyltransferase 3A (DNMT3A) were determined using quantitative immunohistochemistry, and compared to our previously analyzed immunization-induced changes in AD-related neuropathology and cognition.

Results: Active immunization did not affect global DNA methylation levels but instead, resulted in decreased DNA hydroxymethylation and DNMT3A levels. Independent of immunization, inverse correlations with behavioral performance were observed for levels of DNA methylation and hydroxymethylation, as well as DNMT3A, while Aβ pathology and synaptic markers did not correlate with DNA methylation levels but did positively correlate with DNA hydroxymethylation and levels of DNMT3A.

Conclusion: Our results indicate that active Aβ vaccination has significant effects on the epigenome in the hippocampus of APPswe/PS1dE9 mice, and suggest that DNA methylation and hydroxymethylation may be involved in cognitive functioning.

Peripheral Immunity, Immunoaging and Neuroinflammation in Parkinson’s Disease

Parkinson’s disease (PD) is the second most common neurodegenerative disorder among elderly population, characterized by the progressive degeneration of dopaminergic neurons in the midbrain. To date, exact cause remains unknown and the mechanism of neurons death uncertain. It is typically considered as a disease of central nervous system (CNS). Nevertheless, numerous evidence has been accumulated in several past years testifying undoubtedly about the principal role of neuroinflammation in progression of PD. Neuroinflammation is mainly associated with presence of activated microglia in brain and elevated levels of cytokine levels in CNS. Nevertheless, active participation of immune system as well has been noted, such as, elevated levels of cytokine levels in blood, the presence of auto antibodies, and the infiltration of T cell in CNS. Moreover, infiltration and reactivation of those T cells could exacerbate neuroinflammation to greater neurotoxic levels. Hence, peripheral inflammation is able to prime microglia into pro-inflammatory phenotype, which can trigger stronger response in CNS further perpetuating the on-going neurodegenerative process.

In the present review, the interplay between neuroinflammation and the peripheral immune response in the pathobiology of PD will be discussed. First of all, an overview of regulation of microglial activation and neuroinflammation is summarized and discussed. Afterwards, we try to collectively analyze changes that occurs in peripheral immune system of PD patients, suggesting that these peripheral immune challenges can exacerbate the process of neuroinflammation and hence the symptoms of the disease. In the end, we summarize some of proposed immunotherapies for treatment of PD.

Heterogeneity in Cost-Effectiveness Analysis of Vaccination for Mild and Moderate Alzheimer’s Disease

Background: Immunotherapy for Alzheimer’s disease(AD) has gained momentum in recent years. One of the concerns over its application pertains to Cost-Effectiveness Analysis (CEA) from population average and specific subgroup differences, as such a therapy is imperative for health decisionmakers to allocate limited resources. However, this sort of CEA model considering heterogeneous population with risk factors adjustment has been rarely addressed.

Methods: We aimed to show the heterogeneity of CEA in immunotherapy for AD in comparison with the comparator without intervention. Economic evaluation was performed via incremental Cost- Effectiveness Ratio (ICER) and Cost-Effectiveness Acceptability Curve (CEAC) in terms of the Quality- Adjusted Life Years (QALY). First, population-average CEA was performed with and without adjustment for age and gender. Secondly, sub-group CEA was performed with the stratification of gender and age based on Markov process.

Results: Given the threshold of $20,000 of willingness to pay, the results of ICER without and with adjustment for age and gender revealed similar results ($14,691/QALY and $17,604/QALY). The subgroup ICER results by different age groups and gender showed substantial differences. The CEAC showed that the probability of being cost-effective was only 48.8%-53.3% in terms of QALY at population level but varied from 83.5% in women aged 50-64 years, following women aged 65-74 years and decreased to 0.2% in men≥ 75 years.

Conclusion: There were considerable heterogeneities observed in the CEA of vaccination for AD. As with the development of personalized medicine, the CEA results assessed by health decision-maker should not only be considered by population-average level but also specific sub-group levels.

Brain-eating Amoebae Infection: Challenges and Opportunities in Chemotherapy

Pathogenic free-living amoeba are known to cause a devastating infection of the central nervous system and are often referred to as “brain-eating amoebae”. The mortality rate of more than 90% and free-living nature of these amoebae is a cause for concern. It is distressing that the mortality rate has remained the same over the past few decades, highlighting the lack of interest by the pharmaceutical industry. With the threat of global warming and increased outdoor activities of public, there is a need for renewed interest in identifying potential anti-amoebic compounds for successful prognosis. Here, we discuss the available chemotherapeutic options and opportunities for potential strategies in the treatment and diagnosis of these life-threatening infections.

Therapeutic Strategies Targeting Amyloid-β in Alzheimer’s Disease

Alzheimer’s disease (AD) is a neurodegenerative disorder linked to protein misfolding and aggregation. AD is pathologically characterized by senile plaques formed by extracellular Amyloid-β (Aβ) peptide and Intracellular Neurofibrillary Tangles (NFT) formed by hyperphosphorylated tau protein. Extensive synaptic loss and neuronal degeneration are responsible for memory impairment, cognitive decline and behavioral dysfunctions typical of AD. Amyloidosis has been implicated in the depression of acetylcholine synthesis and release, overactivation of N-methyl-D-aspartate (NMDA) receptors and increased intracellular calcium levels that result in excitotoxic neuronal degeneration. Current drugs used in AD treatment are either cholinesterase inhibitors or NMDA receptor antagonists; however, they provide only symptomatic relief and do not alter the progression of the disease. Aβ is the product of Amyloid Precursor Protein (APP) processing after successive cleavage by β- and γ-secretases while APP proteolysis by α-secretase results in non-amyloidogenic products. According to the amyloid cascade hypothesis, Aβ dyshomeostasis results in the accumulation and aggregation of Aβ into soluble oligomers and insoluble fibrils. The former are synaptotoxic and can induce tau hyperphosphorylation while the latter deposit in senile plaques and elicit proinflammatory responses, contributing to oxidative stress, neuronal degeneration and neuroinflammation. Aβ-protein-targeted therapeutic strategies are thus a promising disease-modifying approach for the treatment and prevention of AD. This review summarizes recent findings on Aβ-protein targeted AD drugs, including β-secretase inhibitors, γ-secretase inhibitors and modulators, α-secretase activators, direct inhibitors of Aβ aggregation and immunotherapy targeting Aβ, focusing mainly on those currently under clinical trials.

Screening of Natural Lead Molecules Against Putative Molecular Targets of Drug-resistant Cryptococcus spp: An Insight from Computer-aided Molecular Design

Cryptococcosis is one of the major invasive fungal infections distributed worldwide with high mortality rate. C. neoformans and C. gattii are the major organisms that cause various types of infections. Anti-fungal resistances exhibited by the mentioned species of Cryptococcus threaten their effective prevention and treatment. There is limited information available on human to human transmission of the pathogen and virulent factors that are responsible for Cryptococcus mediated infections. Hence, there is high scope for understanding the mechanism, probable drug targets and scope of developing natural therapeutic agents that possess high relevance to pharmaceutical biotechnology and medicinal chemistry. The proposed review illustrates the role of computer-aided virtual screening for the screening of probable drug targets and identification of natural lead candidates as therapeutic remedies. The review initially focuses on the current perspectives on cryptococcosis, major metabolic pathways responsible for the pathogenesis, conventional therapies and associated drug resistance, challenges and scope of structure-based drug discovery. The review further illustrates various approaches for the prediction of unknown drug targets, molecular modeling works, screening of natural compounds by computational virtual screening with ideal drug likeliness and pharmacokinetic features, application of molecular docking studies and simulation. Thus, the present review probably provides AN insight into the role of medicinal chemistry and computational drug discovery to combat Cryptococcus infections and thereby open a new paradigm for the development of novel natural therapeutic against various drug targets for cryptococcal infections.

Nanoneuromedicines for Neurodegenerative Diseases

Introduction: Neurodegenerative disease is a collective term for a number of diseases that affect the neurons in the human brain. The location of the neuronal loss in the brain leads to the specified disease based on the progression of the clinical symptoms. No drugs are available for complete cure of these diseases. Most of the drugs only slow down the progression of neuronal damage. The combination of drugs with nanotechnology gave a new promising hope for the treatment of neurological disorders. Nanomedicines are extremely useful for safe, effective, target oriented and sustained delivery. Due to their size in nanometer, they possess distinct and improved properties in comparison to their bulk counterpart. The utility of nanomedicines in neurological disorders including neurodegenerative diseases constitutes nanoneuromedicines.

Conclusion: In this article, a comprehensive overview of the application of nanoneuromedicines in neurodegenerative diseases such as Alzheimer’s Disease (AD), Parkinson’s Disease (PD) and Amyotrophic Lateral Sclerosis (ALS) is provided.

Global Warming Favors Pathogenicity of the Brain-Eating Amoebae

Innovative Methodology in the Discovery of Novel Drug Targets in the Free-Living Amoebae

Despite advances in drug discovery and modifications in the chemotherapeutic regimens, human infections caused by free-living amoebae (FLA) have high mortality rates (~95%). The FLA that cause fatal human cerebral infections include Naegleria fowleri, Balamuthia mandrillaris and Acanthamoeba spp. Novel drug-target discovery remains the only viable option to tackle these central nervous system (CNS) infection in order to lower the mortality rates caused by the FLA. Of these FLA, N. fowleri causes primary amoebic meningoencephalitis (PAM), while the A. castellanii and B. Mandrillaris are known to cause granulomatous amoebic encephalitis (GAE). The infections caused by the FLA have been treated with drugs like Rifampin, Fluconazole, Amphotericin-B and Miltefosine. Miltefosine is an anti-leishmanial agent and an experimental anti-cancer drug. With only rare incidences of success, these drugs have remained unsuccessful to lower the mortality rates of the cerebral infection caused by FLA. Recently, with the help of bioinformatic computational tools and the discovered genomic data of the FLA, discovery of newer drug targets has become possible. These cellular targets are proteins that are either unique to the FLA or shared between the humans and these unicellular eukaryotes. The latter group of proteins has shown to be targets of some FDA approved drugs prescribed in non-infectious diseases. This review out-lines the bioinformatics methodologies that can be used in the discovery of such novel drug-targets, their chronicle by in-vitro assays done in the past and the translational value of such target discoveries in human diseases caused by FLA.

The Role of Inflammation in Neurological Disorders

Traditionally neurological diseases have been classified, on the basis of their pathogenesis, into vascular, degenerative, inflammatory and traumatic diseases. Examples of the main inflammatory neurological diseases include multiple sclerosis, which is characterized by an immune-mediated response against myelin proteins, and meningoencephalitis, where the inflammatory response is triggered by infectious agents. However, recent evidence suggests a potential role of inflammatory mechanisms also in neurological conditions not usually categorized as inflammatory, such as Alzheimer’s disease, Parkinson’s disease, Huntington’ disease, amyotrophic lateral sclerosis, stroke and traumatic brain injuries. The activation of glial cells and of complement-mediated pathways, the synthesis of inflammation mediators, and the recruitment of leukocytes are the key elements of secondary inflammatory injury following a wide spectrum of primary brain injuries. A better understanding of the role that inflammatory processes play in the natural history of diseases is essential in order to identify potential therapeutic targets and to develop integrated pharmacological approaches acting at different levels and stages of the diseases.

Preparation and In vitro Evaluation of Efficacy and Toxicity of Polysorbate 80-coated Bovine Serum Albumin Nanoparticles containing Amphotericin B

Objective: In this study, bovine serum albumin (BSA) nanoparticles coated with polysorbate- 80 (PS-80) and containing amphotericin B (AmB) were developed using a coacervation method.

Methods: The nanoparticles were spherical, had a uniform size distribution (polydispersity < 0.25), a small mean size (185 ± 5 nm), a high zeta potential (-38.0 ± 0.7 mV), and a high AmB encapsulation efficiency (93 ± 1%). The AmB release profile was prolonged and diffusion-controlled, resulting in a low degree of AmB aggregation in solution. The physicochemical characteristics of these AmB containing nanoparticles were evaluated by X-ray diffraction, Fourier transform infrared spectroscopy, differential scanning calorimetry, and derivative thermogravimetry and showed that the nanoencapsulation process lead to AmB amorphization while maintaining its chemical integrity.

Results: In a hemolysis assay, AmB-loaded PS-80-coated BSA nanoparticles demonstrated an absence of cytotoxicity toward erythrocytes, whereas pure and commercial AmB were highly hemolytic.

Conclusion: In an assay to assess antifungal activity against Cryptococcus neoformans, AmB-charged PS-80-coated BSA nanoparticles were effective, however, due to the prolonged AmB release from the nanoparticles, the MIC was higher than for pure or commercial AmB. PS-80-coated BSA nanoparticles are potential carriers for the delivery of AmB for the treatment of Cryptococcus sp infections.

A UBI 31-38 Peptide-coumarin Conjugate: Photophysical Features, Imaging Tracking and Synergism with Amphotericin B Against Cryptococcus

Cryptococcosis is a fungal disease of global significance for which new effective treatments are needed. The conjugation of the synthetic antimicrobial peptide fragment UBI 31-38 to a coumarin derivative showed to be an effective approach for the design of a novel anticryptococcal agent. In addition to antifungal activity, the conjugate exhibited intense fluorescence, which could be valuable for mechanistic investigations of this molecule. In this work, we studied the photophysical properties of the conjugate and confocal scanning laser microscopy was used to inspect the distribution of the peptide-coumarin conjugate in Cryptococcus cell. The synergism of this compound with amphotericin B or fluconazole against C. gattii and C. neoformans strains was also investigated. The results indicated that the fluorescent conjugate alone as well as its combination with amphotericin B are promising tools against cryptococcosis.

The Neonatal Immune System: General Concepts and Clinical Correlations

Background: The neonatal immune system is biased toward tolerance, which is necessary to prevent attacks on commensal organisms and benign antigens. However, this tolerogenic bias also leads to overwhelming infection in many neonates each year.

Methods: We review the differences between various components of the neonatal versus adult immune system and discuss how these changes affect the immune response to pathogens and vaccines.

Results: B cell activity is impaired in neonates, which is partially compensated by acquisition of maternal antibodies. Regulatory T cells are abundant, and CD4 T cell differentiation is skewed away from Th1 and toward Th2 and Th17 responses. Effector functions of CD8 T cells and natural killer cells are less effective, and antigen presenting cells make fewer inflammatory cytokines.

Conclusion: Nearly every component of the neonatal immune system shows differences from adults. As research progresses, a clearer understanding of the mechanisms of neonatal immune suppression will allow for the development of therapeutic interventions to help neonates overcome serious infections.

Research Progress of Mechanisms of Ceftriaxone Associated Nephrolithiasis

Background: Urinary calculi can be caused by a variety of reasons, such as metabolic abnormalities, urinary tract infection and obstruction. Certain medications can induce urinary stone disease. Ceftriaxone, a third generation cephalosporin with broad spectrum antibiotic activity, primarily eliminated by the kidneys, has now been widely used for treatment of infection. It has been long considered safe, especially in children. However, more and more cases about ceftriaxone induced nephrolithiasis as a rare side effect have been reported.

Conclusion: This complication generally resolves spontaneously with cessation of the drug. Severe nephrolithiasis can cause post renal acute renal failure (PARF). There is limited information about how this complication develops, though high doses and extended treatment periods are generally considered to be responsible. Understanding the mechanisms would help the doctors to be aware of this rare complication and respond with proper treatment. The primary goal of this review is to discuss the possible mechanisms based on the most recent literatures.

Genetic Modifications of Icosahedral Plant Virus-based Nanoparticles for Vaccine and Immunotherapy Applications

Vaccine development is one of the greatest achievements of modern medicine. Vaccines made of live-attenuated pathogens can revert to virulent live strains, which causes safety concerns. On the other hand, the use of purified antigenic components as subunit vaccines is safer, but less effective, as these components induce lower levels of protective immunity. Multiple copy presentation of an antigenic determinant in a well-ordered and well-defined orientation on a nanosized particle can mimic the natural host-pathogen surface interaction to provide antigen stability and immunogenicity similar to that of conventional vaccines with improved safety. The icosahedral symmetry of plant viral capsid based nanoparticles is highly ordered and their multivalent structured protein nanostructures facilitate genetic modifications that result in the display of heterologous epitopes or antigens attached to coat proteins. These recombinant plant virus-based nanoparticles (PVNs) provide platforms for the induction of humoral and cellular immune responses to genetically fused antigens from pathogenic viruses, bacteria, tumors, and toxins in man and animals. Here, we comprehensively review the developments of several recombinant PVNs as prophylactic and/or therapeutic vaccines for the prevention or treatment of several microbial diseases, pathologies, and toxin poisoning.

Safety of Systemic Biologic Agents in the Treatment of Non-malignant Skin Disorders

Introduction: The recent significant breakthroughs in the understanding of the pathogenetic mechanisms of psoriasis and other immune-mediated inflammatory disorders, have led to the emergence of a wide array of biologic agents or biologics, which are especially designed to target selective intracellular or extracellular components and pathways of the dysregulated immune response.

Method: These targeted biologic agents have altered the landscape in dermatotherapy aiming to offer higher therapeutic efficacy and an alternative in patients who either failed on conventional systemic regimens or have no other therapeutic options. In the last two decades, the number of the commercially available biologic agents and the extent of their use have dramatically increased; today, these compounds represent a substantial part of modern dermatologic armamentarium.

Results: Due to the immunosuppressive potential of biologics, serious concerns were raised about their safety profile, already during the pre-approval period. These concerns did not subside after the incorporation of the postmarketing experience, particularly after the withdrawal of a biologic agent (efalizumab) due to its serious and even fatal side effects.

Conclusion: The purpose of the present article is to review the cutaneous and systemic side effects of all systemic biologic agents used so far in modern treatment of non-malignant skin disorders and to contribute to a better and updated awareness of their safety risks among clinicians, which will enable the latter to make the best informed and personalized drug selection and therapeutic decisions. This review was mainly based on data derived from Medline and Scopus databases and from manufacturing companies, as well.

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.

Challenges with Mosquito-borne Viral Diseases: Outbreak of the Monsters

Background: The viruses responsible for mosquito-borne diseases are on an exploring mode, expanding their horizon, adapting to the situation and comfortably making their presence felt globally, from South Africa to Asia, Europe and United States. The current global scenario and recent documentations indicate towards the real monsters, outbreak of Zika, dengue and chikungunya viruses. Zika, dengue and chikungunya viruses are positive sense single-stranded RNA arbovirus and so their initial symptoms are almost 80% similar and all three are spread by mosquitos which bite during the day. Zika virus may damage brain by targeting the neuron cells in babies, and thereby it is very perilous to pregnant women.

Dangerous Type: A less common but highly dangerous type of dengue is one which causes haemorrhagic fever and shock syndrome which are lethal. Chikungunya is not as lethal as Zika and dengue are, but it triggers joints pain which could last for months and even for years.

Conclusion: The vaccines against Zika, dengue and chikungunya viruses are at different stages of development. The challenges associated with the epidemic wave of Zika, dengue and chikungunya viruses have been explained and the current status of drug/ vaccine development against these viruses has been reviewed.

Recombinant Antibody Fragments for Neurodegenerative Diseases

Background: Recombinant antibody fragments are promising alternatives to full-length immunoglobulins and offer important advantages compared with conventional monoclonal antibodies: extreme specificity, higher affinity, superior stability and solubility, reduced immunogenicity as well as easy and inexpensive large-scale production.

Objective: In this article we will review and discuss recombinant antibodies that are being evaluated for neurodegenerative diseases in pre-clinical models and in clinical studies and will summarize new strategies that are being developed to optimize their stability, specificity and potency for advancing their use.

Methods: Articles describing recombinant antibody fragments used for neurological diseases were selected (PubMed) and evaluated for their significance.

Results: Different antibody formats such as single-chain fragment variable (scFv), single-domain antibody fragments (VHHs or sdAbs), bispecific antibodies (bsAbs), intrabodies and nanobodies, are currently being studied in pre-clinical models of cancer as well as infectious and autoimmune diseases and many of them are being tested as therapeutics in clinical trials. Immunotherapy approaches have shown therapeutic efficacy in several animal models of Alzheimer´s disease (AD), Parkinson disease (PD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), Huntington disease (HD), transmissible spongiform encephalopathies (TSEs) and multiple sclerosis (MS). It has been demonstrated that recombinant antibody fragments may neutralize toxic extra- and intracellular misfolded proteins involved in the pathogenesis of AD, PD, DLB, FTD, HD or TSEs and may target toxic immune cells participating in the pathogenesis of MS.

Conclusion: Recombinant antibody fragments represent a promising tool for the development of antibody-based immunotherapeutics for neurodegenerative diseases.

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.

The Widespread Anti-Protozoal Action of HIV Aspartic Peptidase Inhibitors: Focus on Plasmodium spp., Leishmania spp. and Trypanosoma cruzi

The introduction of the HIV aspartic peptidase inhibitors (HIV-PIs) has revolutionized the medical arena, since they have drastically reduced the number and the severity of opportunistic infections, including the protozoal diseases that afflict the HIV-infected individuals worldwide. HIV-PIs rapidly and profoundly diminish the viral load, which is paralleled by increase in the CD4+ T lymphocyte counts and stimulation of the survival and activation of neutrophil, monocyte and endothelial cells, culminating in a vigorous reduction in the number of deaths due to the AIDS, in the number of new cases of AIDS and in the number of hospitalization days. Many research groups around the globe are trying to decipher both the in vitro and in vivo antiprotozoal mechanisms behind the use of HIVPIs. These studies have been supported by the urgent need to discover novel active compounds able to treat incurable parasitoses, including three major neglected diseases: malaria, leishmaniasis and Chagas’ disease. The present review summarizes the recent advances on the effects of HIV-PIs against Plasmodium spp., Leishmania spp. and Trypanosoma cruzi.

Clear Shot at Primary Aim: Susceptibility of Trypanosoma cruzi Organelles, Structures and Molecular Targets to Drug Treatment

Chagas disease, caused by Trypanosoma cruzi, stands out due to its socio-economic effects on low-income tropical populations. This disease affects millions of people worldwide. The current chemotherapy for it is based on benznidazole (Bz) and nifurtimox (Nif) and is unsatisfactory. In this review, we will focus on the search for potential target organelles and molecules for the chemotherapy of Chagas disease. We consider as potential target organelles those that are absent or significantly different in host cells and present in the clinically relevant forms of the parasite (trypomastigotes and amastigotes), which are the mitochondrion, cytoskeletal-related structures, the acidocalcisomes/ contractile vacuole complex and glycosomes. Most molecular targets are key enzymes involved in processes that are essential to parasite survival, such as sterol biosynthesis, antioxidant defences and bioenergetic pathways. Among the molecular targets, enzymes of the sterol pathway, particularly C14α-sterol demethylase, are still the most promising target, even if clinical trials with posaconazole and E1224 have failed to sustain efficacy. We believe that in the near future, the Chagas community will have a “clear shot” at new drug candidates for Chagas disease based on the accumulated knowledge about trypanosomatid biochemistry, preclinical studies, advances in screening technologies, the efforts of medicinal chemists in the synthesis of both azolic and non-azolic inhibitors, and the interest of pharmaceutical companies in the development of new antifungal agents, which form a critical mass of information.

The Medical Potential of Antimicrobial Peptides from Insects

Antimicrobial peptides (AMPs) are peptide-based effector molecules produced by the innate immune system to combat microbes. Insects produce the broadest repertoire of AMPs, and their potent antimicrobial activity in vitro and in vivo has promoted their development as alternatives to conventional antibiotics, in an attempt to address the threat of multidrug-resistant pathogens. Here we discuss current obstacles that hinder the therapeutic development of novel insect-derived AMPs, including potential cytotoxic, immunogenic and allergenic side effects, and the high costs of large-scale production. These challenges may be overcome by the falling costs of synthetic peptide analogs and the heterologous production of recombinant peptides in insect cells or plants (molecular pharming). Insect AMPs offer a promising alternative for the treatment of skin, eye and lung infections, and could also restore the susceptibility of multidrug-resistant pathogens to conventional antibiotics when used as combinatorial treatments. Insect AMPs can also be used as templates for the rational design of peptide mimetics to overcome the drawbacks of natural therapeutic peptides.

Editorial (Thematic Issue: From Current Diagnostic Tools and Therapeutics for Alzheimer's Disease Towards Earlier Diagnostic Markers and Treatment Targets)

Challenges in Chagas Disease Drug Discovery: A Review

Chagas disease or American trypanosomiasis is a neglected tropical disease caused by the parasite Trypanosoma cruzi. Although the number of infected individuals has decreased, about 6-7 million people are infected worldwide. The chemotherapy drugs currently used are limited to benznidazole and nifurtimox. They are effective in acute phase, congenital transmission and children with chronic infection; however, recent clinical trials have shown limitations in adults with chronic infection, presenting drawbacks during the treatment. Thus, there is an urgent need for new effective, safe and affordable drugs to fight against this complex disease. There were high expectations for azole derivatives as they appeared to be the most promising drugs for the treatment of Chagas disease during the last decade; however, the disappointing results obtained so far in clinical trials evidenced the lack of correlation between preclinical and clinical development. Therefore, the feedback obtained from these studies should define the starting point for addressing a roadmap for the drug discovery process in the fight against this disease. To tackle this challenge, it is important to keep in mind the drug target profile, already defined by panels of experts, and the coordinated work involving multi-disciplinary networks focusing not only on the discovery of new drugs but also on the standardization of the protocols that would allow acceleration in the Chagas disease drug discovery process.

Traumatic Brain Injury and Blood-Brain Barrier Cross-Talk

Traumatic brain injury, often referred to as the “silent epidemic,” is a nondegenerative, non-congenital insult to the brain due to a blow or penetrating object that disrupts the function of the brain leading to permanent or temporary impairment of cognition, physical and psychosocial functions. Traumatic brain injury usually has poor prognosis for long-term treatment and is a major cause of mortality and morbidity worldwide; approximately 10 million deaths and/or hospitalizations annually are directly related to traumatic brain injury. Traumatic brain injury involves primary and secondary insults. Primary injury occurs during the initial insult, and results from direct or indirect force applied to the physical structures of the brain. Secondary injury is characterized by longer-term degeneration of neurons, glial cells, and vascular tissues due to activation of several proteases, glutamate and pro-inflammatory cytokine secretion. In addition, there is growing evidence that the blood-brain barrier is involved in the course of traumatic brain injury pathophysiology and has detrimental effects on the overall pathology of brain trauma, as will be discussed in this work.

The use of Immunoglobulin Therapy in Primary Immunodeficiency Diseases

Immunoglobulin therapy represents a lifesaving intervention for many patients with primary immunodeficiency (PID). Antibody defects represent approximately half of the well-known PIDs requiring immunoglobulin replacement therapy. Following immunoglobulin therapy in PID patients, protection against serious upper and lower respiratory tract infections and pulmonary function improves which leads to an increase in the quality of life of these patients. Successful treatment of PID patients depends on the type of immunodeficiency, regular monitoring of the patient, comorbidities of the patient, and the availability of the products.

Applied Proteomics in Companion Animal Medicine

Background: Proteomics in companion animal medicine has been used chiefly, in order to identify proteins, which may be used as biomarkers for early diagnosis of a variety of pathological conditions, as well as to elucidate pathogenesis of various diseases by describing, at molecular level, signal transductions in diseased organs.

Objective: The review of some of currently available knowledge in proteomics, as can be applied in companion animal medicine and can be of use to veterinarians active in the field, in order to solve scientific or clinical questions regarding signal transduction.

Method: Specific clinical applications of the methodologies are reviewed.

Results: Proteomics may be employed in supporting early and accurate diagnosis of leishmaniosis, as well as for the identification of proteins of the causative protozoon, and can also be helpful in cases of neoplastic diseases; proteins identified in blood serum or tears of dogs or cats may be used to support diagnosis of various neoplastic conditions and to monitor treatment and predict future metastases. Proteomics have helped to identify proteins with diagnostic significance in the blood serum of Cavalier King Charles Spaniels with myxomatous mitral valve degeneration and in the bronchoalveolar lavage fluid of West Highland White Terriers with idiopathic pulmonary fibrosis and have also been used for studying the musculoskeletal system of horses, specifically in laminitis, osteoarthritis and osteochondrosis and exertional rhabdomyolysis. The technology has also been applied in various other diseases of dogs and cats (e.g., Leptospira infections, Babesia infections, Golden Retriever muscular dystrophy, degenerative myelopathy, degenerative changes in the brain, azotaemia, periodontitis), as well as in uveitis and endometritis in horses and in staphylococcal infections and tularaemia in rabbits.

Conclusion: In the long term, proteomics will contribute to improvements in all facets of companion animal medicine. Mining deeper into the various proteomes and application of new methodological strategies in clinical studies will provide information about disease processes, which will be of benefit to practising veterinarians. Improvement of diagnostic techniques, establishment of prognostic tools and development of vaccines against diseases are key-areas for targeted research.

Therapeutic Approaches Targeting Pathological Tau Aggregates

Neurodegenerative diseases characterized by the accumulation of tau aggregates are increasing in prevalence to epidemic-like levels and there is currently no effective treatment. For many years, the focus of tau-based research was on the fibrillar, neurofibrillary tangles. However, the compilation of evidence obtained from numerous laboratories in the past few years suggests that soluble intermediate aggregates—tau oligomers—are actually the most toxic protein species in disease. Thus, therapeutic agents that target oligomeric tau specifically may be the most effective routes for treatment. A great deal of progress has been made in the pre-clinical evaluation of a number of different anti-tau therapeutics. Upstream modulators of tau modifications have been evaluated and may provide some benefits, but likely will not be capable of eliminating toxic tau entirely. Protein chaperones capable of modulating the structure of tau and targeting it for degradation are another field of study, however, the broad effects of chaperones make side effects a concern. Thus, more specific agents capable of eliminating the most toxic species in disease are promising. Small molecules designed to inhibit aggregation, as well as immunotherapy with antibodies specific for toxic tau aggregates present the most advancement as potential treatments. The concerted effort across a number of groups to investigate potential mechanisms to inhibit tau toxicity represents great progress in the field and provides hope that effective treatments will be discovered.

Management and Treatment of Dengue and Chikungunya - Natural Products to the Rescue

Neglected tropical diseases (NTDs) flourish mostly in impoverished developing nations of the world. It is estimated that NTDs plague up to 1 billion people every year thereby inducing a massive economic and health burden worldwide. Following explosive outbreaks mostly in Asia, Latin America, Europe and the Indian Ocean, two common NTDs namely, Chikungunya and Dengue both transmitted by an infected mosquito vector principally Aedes aegypti have emerged as a major public health threat. Given the limitations of conventional medicine in specifically targeting the Chikungunya and Dengue virus (CHIKV and DENV), natural products present an interesting avenue to explore in the quest of developing novel anti; mosquito, CHIKV and DENV agents. In this endeavor, a number of plant extracts, isolated phytochemicals, essential oils and seaweeds have shown promising larvicidal and insecticidal activity against some mosquito vectors as well as anti CHIKV and DENV activity invitro. Other natural products that have depicted good potential against these diseases include; the symbiotic bacterial genus Wolbachia which can largely reduce the life span and infectivity of mosquito vectors and the marine Cyanobacterium Trichodesmium erythraeum which has shown anti- CHIKV activity at minimal cytotoxic level. The impetus of modern drug discovery approaches such as high throughput screening, drug repositioning, synthesis and computer-aided drug design will undeniably enhance the process of developing more stable lead molecules from natural products which have shown promising antiviral activity in-vitro.

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

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

Vaccination to Alzheimer Disease. Is it a Promising Tool or a Blind Way?

Alzheimer disease (AD) is an irreversible neurodegenerative disorder associated with cognitive dysfunction. The disease incidence has growing tendency worldwide with strong impact on healthcare funds. The fact that there is no effective therapy makes the disorder more serious. Currently, AD manifestation can be suppressed by having impact on enzyme acetylcholinesterase: donepezil, rivastigmine, and galantamine or ionotropic glutamate NMDA receptor ( memanitine). Contrary to the drugs effecting symptomatically, vaccination against amyloid plaques or neurofibrillary tangles and their precursors amyloid beta and hyperphosphorylated tau are expected to be more suitable. Huge numbers of works have been done on the issue. Unfortunately, the promising vaccines like the AN 1792 were halted during clinical trials because of adverse effects like meningoencephalitis. Monoclonal antibody specific to amyloid plaques, Bapineuzumab, was closest to the practical performance but the clinical trials were also stopped. The review summarizes facts about AD, opportunities in AD vaccination, and obstacles that limit the vaccination including reasons why the recent trials have fallen.

Peripheral Immune Signatures in Alzheimer Disease

According to the current paradigm, the main cause of AD is the accumulation of neurotoxic amyloid beta (Aβ) peptide aggregates resulting from the cleavage of the amyloid precursor protein into peptides of different length, with the 42 amino acid long Aβ42 being the most toxic form. Aβ can aggregate and form plaques in the brain. It further promotes the hyperphosphorylation of the tau protein which forms characteristic neurofibrillary tangles and thereby loses its important role in axonal transport and contributes to neurodegeneration. Therefore, treatments have targeted Aβ, but clinical trials of immunotherapies caused severe side effects and showed that Aβ clearance alone did not result in any cognitive improvement. This leads to the question: what else promotes AD pathology? Here, we review data on systemic inflammation and the possible roles that the immune system might play in AD. Microglia and astrocytes are activated and secrete inflammatory cytokines and chemokines. Via a disturbed blood-brain barrier, peripheral immune cells are activated and recruited towards inflamed brain lesions and amyloid plaques, but due to the chronic nature of the amyloid burden and their reduced function, these cells are not able to control inflammation and the associated detrimental immune responses. In addition, age-related inflammation and chronic infection with herpes viruses might contribute to the systemic inflammation and exacerbate attempts to restore the balance of inflammation.

Probabilistic Cost-Effectiveness Analysis of Vaccination for Mild or Moderate Alzheimer’s Disease

Background: Studies on the immunotherapy for Alzheimer’s disease (AD) have increasingly gained attention since 1990s. However, there are pros (preventing of AD) and cons (incurred cost and side effects) regarding the administration of immunotherapy. Up to date, there has been lacking of economic evaluation for immunotherapy of AD. We aimed to assess the cost-effectiveness analysis of the vaccination for AD. Methods: A meta-analysis of randomized control trials after systemic review was conducted to evaluate the efficacy of the vaccine. A Markov decision model was constructed and applied to a 120,000-Taiwanese cohort aged ≥65 years. Person years and quality-adjusted life years (QALY) were computed between the vaccinated group and the the unvaccinated group. Economic evaluation was performed to calculate the incremental cost-effectiveness ratio (ICER) and cost-effectiveness acceptability curve (CEAC). Results: Vaccinated group gained an additional 0.84 life years and 0.56 QALYs over 10-years and an additional 0.35 life years and 0.282 QALYs over 5-years of follow-up. The vaccinated group dominated the unvaccinated group by ICER over 5-years of follow-up. The ICERs of 10-year follow-up for the vaccinated group against the unvaccinated group were $13,850 per QALY and $9,038 per life year gained. Given the threshold of $20,000 of willingness to pay (WTP), the CEAC showed the probability of being cost-effective for vaccination with QALY was 70.7% and 92% for life years gained after 10-years of follow-up. The corresponding figures were 87.3% for QALY and 93.5% for life years gained over 5-years follow-up. Conclusion: The vaccination for AD was cost-effective in gaining QALY and life years compared with no vaccination, under the condition of a reasonable threshold of WTP.

Severe Adenovirus Pneumonia Followed by Bacterial Septicaemia: Relevance of Co-Infections in Allogeneic Hematopoietic Stem Cell Transplantation

Infections are one of the major complications after allogeneic stem cell transplantation (allo-SCT). Disseminated infections with human adenoviruses species A, B or C are associated with a lethality of 24 to 36 %. Fatal outcome is usually observed with high viral loads in blood (median peak HAdV DNAemia 10⁸ copies/mL). Here we report two adult patients with disseminated infection with human adenovirus C2 after allo-SCT. Interestingly, both patients developed bacterial septicaemia following the disseminated HAdV infection. Despite lower peak adenoviral loads in blood (<106 copies/mL) than usually reported for fatal cases of HAdV infection and broad spectrum antimicrobial therapy both patients experienced a rapidly fatal outcome. These cases shared the following similarities: disseminated adenovirus infection, adenovirus pneumonia, neurological symptoms and bacterial septicaemia. This suggests that in patients undergoing allo-SCT, viral bacterial co-infections worsen the clinical outcomes.

Incidence of Profound Hypogammaglobulinemia and Infection Rate in Lymphoma Patients Following the Combination of Chemotherapy and Rituximab

Background: The Anti-CD20 monoclonal antibody Rituximab suppresses B-lymphocytes and may induce hypogammaglobulinemia in treated patients. The incidence and clinical significance of rituximab induced hypogammaglobulinemia in lymphoma patients is underestimated.

Methods: We retrospectively analyzed the rates of hypogammaglobulinemia, infection and infectionrelated mortality in 136 lymphoma patients who were treated with a combination of chemotherapy and rituximab.

Results: Rituximab given in more than 8 doses (OR 6.05, 95% CI: 1.24-29.5), relative hypogammaglobulinemia at time of lymphoma diagnosis (OR 4.2, 95% CI: 1.26-14.1) and the combination of fludarabine with rituximab (OR 3.4, 95% CI: 1.24-9.47) were factors significantly associated with prolonged (more than 6 months) hypogammaglobulinemia. The combination of fludarabine and rituximab (OR 6.4, 95% CI: 1.49-27.0) and secondarily prolonged hypogammaglobulinemia (OR 4.5, 95% CI: 1.19-18.5) were found to be predictive factors for severe infections and infection-related mortality.

Conclusion: These data suggest the importance of following serum immunoglobulin levels before and after combination immuno-chemotherapy, particularly in patients with recurrent infections or relapsed/refractory disease.

Novel Therapeutic Strategies for Dementia

Dementia represents a major problem of health and disability, with a relevant economic impact on our society. Despite important advances in pathogenesis, diagnosis and treatment, its primary causes still remain elusive, accurate biomarkers are not well characterized, and the available pharmacological treatments are not cost-effective. Alzheimer disease (AD), the most prevalent form of dementia, is a polygenic/multifactorial/complex disorder in which hundreds of defective genes distributed across the human genome may contribute to its pathogenesis. Diverse environmental factors, cerebrovascular dysfunction, and epigenetic phenomena, together with structural and functional genomic dysfunctions lead to amyloid deposition, neurofibrillary tangle formation and premature neuronal death, the major neuropathological hallmarks of AD.

For the past 20 years, over 1,000 different compounds have been studied as potential candidate drugs for the treatment of AD. About 50% of these substances are novel molecules obtained from natural sources. The candidate compounds can be classified according to their pharmacological properties and/or the AD-related pathogenic cascade to which they are addressed to halt disease progression. In addition to the Food and Drug Administration (FDA)-approved drugs since 1993 (tacrine, donepezil, rivastigmine, galantamine, memantine), most candidate strategies fall into 6 major categories: (i) novel cholinesterase inhibitors and neurotransmitter regulators, (ii) anti-amyloid beta (Aβ) treatments (amyloid-β protein precursor (APP) regulators, Aβ breakers, active and passive immunotherapy with vaccines and antibodies, β - and γ - secretase inhibitors or modulators), (iii) anti-tau treatments, (iv) pleiotropic products (most of them of natural origin), (v) epigenetic intervention, and (vi) combination therapies. The implementation of pharmacogenomic strategies will contribute to optimize drug development and therapeutics in AD and related disorders.

Exposure to Perinatal Infections and Bipolar Disorder: A Systematic Review

Bipolar disorder (BD) is a debilitating psychiatric disorder and a growing global public health issue. Notwithstanding BD has been conceptualized as a neuroprogressive illness, there are some evidences to suggest a role for neurodevelopmental pathways in the patho-etiology of this disorder. Evidences on the associations between perinatal infections and risk for bipolar disorder have been inconsistent across studies. Here, we performed a systematic review of observational studies on the relationship between exposure to perinatal pathogens and bipolar disorder. A computerized literature search of the PubMed, Embase, and PsyINFO databases till January 31^st, 2015 was performed. Twenty-three studies ultimately met inclusion criteria. Studies investigated exposure to several pathogens namely Cytomegalovirus (CMV), Epstein–Barr Virus (EBV), Herpes simplex virus-1 (HSV-1), Herpes simplex virus-2 (HSV-2), Human herpesvirus 6 (HHV-6), Toxoplasma gondii, Influenza, and Varicella zoster virus (VZV). Overall, studies provided mixed evidences. Thus, contrary to schizophrenia, the role of perinatal infections as risk factors for BD remain inconclusive. Larger studies with a prospective design would be necessary to elucidate the role of previous exposure to infectious agents as a potential risk factor for BD.

Validating Immunotherapy in Alzheimer’s Disease: The EB101 Vaccine

Vaccination has become one of the most promising immunotherapeutic approaches in the prevention and treatment of Alzheimer’s disease (AD) and related neuropathological hallmarks. Numerous immunotherapeutic interventions have attempted to achieve adaptive immunity against A with a range of different antigenic designs and immunomodulatory strategies, most of them with great success in AD mouse model studies. Most of these studies have shown that both active and passive immunization can drastically reduce amyloid deposition and prevent the decline in cognitive performance. New approved clinical trials are under investigation to test the effectiveness of those different vaccination approaches, although previous data showed modest clinical success with some adverse inflammatory events in immunized elderly patients. The search for new approaches to overcome these severe side effects has led to novel technical methods such as live vector or DNA vaccines, although the use of innovative adjuvants combined with selected amyloid peptides is among the most auspicious. In this review, we compare and discuss the past and contemporary vaccines and the future strategies that may lead to a viable improvement in AD prevention and treatment.

Super aggregated form of Amphotericin B: a novel way to increase its therapeutic index

Amphotericin B (AmB)-deoxycholate micellar formulation, Fungizone®, is the drug of choice for the treatment of unidentified mycotic infections. However, it usage has been marred by long therapeutic regimes and severe side effects. The less toxic lipid associated AmB formulations have been limited by their high expense, with some loss in activity. The quest for decreasing AmB cytotoxicity as well as production cost has resulted in the development of AmB super-aggregate as an alternative to its existing lipid formulations. AmB super-aggregate is spectroscopically distinct from the aggregate present in Fungizone, displaying enhanced thermodynamic stability. The poly-aggregated form of AmB exhibits reduced toxicity in mammalian cells in vitro and to mice in vivo, while maintaining its ‘gold standard’ antifungal activity. Poly-aggregated AmB interacts predominantly with serum albumin and also attenuates its ability to induce potentially harmful cytokines. Bio-distribution studies have demonstrated that the selfassociated AmB shows greater accumulation in reticulo-endothelial organs while sparing kidney, one of the principal organs where its toxic effects are seen. The super-aggregated AmB can thus be used to improve the therapeutic index of AmB against a plethora of fungal infections including candidiasis and cryptococcosis, thus providing a fitting solution to growing demand of an active, less toxic substitute of AmB.

Potential Relevance of Melatonin Against Some Infectious Agents: A Review and Assessment of Recent Research

Melatonin, a tryptophan-derived neurohormone found in animals, plants, and microbes, participates in various biological and physiological functions. Among other properties, numerous in vitro or in vivo studies have reported its therapeutic potential against many parasites, bacteria and viruses. In this concern, melatonin was found to be effective against many parasites such as Plasmodium, Toxoplasma gondii, and Trypansoma cruzi, via various mechanisms such as modulation of calcium level and/or host immune system. Likewise, a recent investigation has reported in vitro activity of melatonin against Leishmania infantum promastigotes which is the causative agent of fascinating visceral Leishmaniasis. This review was initially undertaken to summarize some facts about certain physiological and therapeutic effects of melatonin. It also reviews the effects and action mechanisms of melatonin in bacterial and viral infection besides biology of different parasites which may provide a promising strategy for control of many diseases of public health importance.

Anti-Alzheimer Therapeutic Drugs Targeting γ-Secretase

γ-secretase is a membrane-embedded aspartyl protease carrying out cleavage of more than 100 single transmembrane-spanning proteins, including APP, Notch, N-cadherin, etc. Its subunit, presenilin (PS) is the catalytic component, of which mutations are a major cause of early onset familial Alzheimer disease (FAD). These mutations lead to an increase in the production of the highly amyloidogenic Aβ42 isoform. Drugs aimed at γ-secretase are now considered to be promising therapeutic targets for AD. γ-secretase inhibitors (GSIs) were first introduced into clinical trials due to their efficacy in lowering Aβ production, but later were found to cause severe adverse events due to their blockage of the Notch signaling process. γ-secretase modulators (GSMs) were developed to modulate γ-secretase activity by selectively targeting Aβ42 reduction over the Notch pathway, which have been shown to have less side effects. Although clinical studies show that none of the GSIs or GSMs have been proven to be fully effective, they shed light on the physiological role of γ-secretase and PS in AD development. At the same time, natural products, due to their structural diversity and pleiotropic profile, can modulate γ-secretase activity in a dose-dependent manner, broadening our vision of drug development. With the structural information of γ-secretase released recently, we speculate there will be an explosion of γ-secretase modulators targeting not only the proteolysic center but also the interaction of its different components.

Anti-Viral Agents in Neurodegenerative Disorders: New Paradigm for Targeting Alzheimer’s Disease

Alzheimer’s disease (AD) is a neurodegenerative disease affecting geriatric populations for which several causes have been proposed. These include a relationship with known pathogens although the exact nature of such a relationship remains uncertain. Herpes simplex virus-1 has been proposed as potential cause of AD because of its ability to form ß amyloid(Aß) and neurofibrillary tangles due to tau hyperphosphorylation and action of beta & gamma secretase on amyloid precursor protein(APP) together with genetic association with apolipoprotein-E₄(ApoE-Ɛ4), which points out to latent Herpes Simplex virus-1 as an agent causing AD. There are numerous studies that linked HSV-1 with AD like anti-HSV-1 IgM antibodies, nectin-2, heme oxygenase-1, phosphorylated eukaryotic initiation factor-2A, caspase-8 and nucleus-specific alteration of raphe neurons. Various possible mechanisms by which HSV-1 might lead to development of AD such as ApoE, ß-amyloid, tau phosphorylation, inflammation and oxidative stress are also discussed. Thus, this review discusses patent information and a strong relationship between latent HSV-1 and AD and also proposes antiviral therapy for AD.

Oral Administration of Thioflavin T Prevents Beta Amyloid Plaque Formation in Double Transgenic AD Mice

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the fourth leading cause of death in the United States and most common cause of adult-onset dementia. The major hallmarks of AD are the formation of senile amyloid plaques made of beta amyloid and neurofibrillary tangles (NFT) which are primarily composed of phosphorylated tau protein. Although numerous agents have been considered as providing protection against AD, identification of potential agents with neuroprotective ability is limited. Thioflavin T has been used in the past to stain amyloid beta plaques in brain. In this study, Thioflavin T (ThT) and vehicle (infant formula) were administered orally by gavage to transgenic (B6C3 APP PS1; AD-Tg) mice beginning at 4 months age and continuing until sacrifice at 9 months of age at 40mg/kg dose. The number of amyloid plaques was reduced dramatically by ThT treatment in both male and female transgenic mice compared to those in control mice. Additionally, GFAP and Amylo-Glo labeling suggest that astrocytic hypertrophy is minimized in ThT-treated animals. Similarly, CD68 labeling, which detects activated microglia, along with Amylo-Glo labeling, suggests that microglial activation is significantly less in ThT-treated mice. Both Aβ-40 and Aβ-42 concentrations in blood rose significantly in the ThT-treated animals suggesting that ThT may inhibit the deposition, degradation, and/or clearance of Aβ plaques in brain.

Novel Synthetic Compounds as Potential Anticryptococcal Agents

Cryptococcosis, an invasive fungal infection that affects both immunocompromised and immunocompetent individuals, has emerged as an important public health problem in Africa, Asia, and America. The limited number of antimycotic drugs available to treat this disease, their side effects and toxicity, and the emergence of resistant strains support the search for more effective and less toxic compounds. This review compiles examples of novel synthetic compounds, which could be used as templates for developing novel drugs for the treatment of Cryptococcus infections.

Human Anthrax as a Re-Emerging Disease

Anthrax is primarily a disease of herbivores and the etiological agent is B. anthracis which is a gram-positive, aerobic, spore-forming, and rod shaped bacterium. Bacillus anthracis spores are highly resistant to heat, pressure, ultraviolet and ionizing radiation, chemical agents and disinfectants. For these reasons, B. anthracis spores are an attractive choice as biological agents for the use of bioweapon and/or bioterrorism. Soil is the main reservoir for the infectious agent. The disease most commonly affects wild and domestic mammals. Human are secondarily infected by contact with infected animals and contaminated animal products or directly expose to B. anthracis spores. Anthrax occurs worldwide. This infection is still endemic or hyperendemic in both animals and humans in some part of areas of the world; particularly in Middle East, West Africa, Central Asia, some part of India, South America. However, some countries are claiming free of anthrax, and anthrax has become a re-emerging disease in western countries with the intentional outbreak. Currently, anthrax is classified according to its setting as (1) naturally occurring anthrax, (2) bioterrorism-related anthrax. Vast majority of human anthrax are occurring as naturally occurring anthrax in the world. It is also a threaten disease for western countries. The aim of this paper is to review the relevant patents, short historical perspective, microbiological and epidemiological features, clinical presentations and treatment.

Currently Used Biologic Agents in the Management of Behcet’s Syndrome

Behcet’s s yndrome (BS) is a multisystem vasculitis with frequent mucocutaneous, joint, eye and visceral organ involvement. From early 2000s, biologic drugs have been increasingly used in the management of BS, enabling rapid and complete remission in most cases with critical organ involvement. Despite the current experience with steroids and traditional immunosuppressives, biologics are exceptionally promising for treatment of resistant cases. Among the biologics used in BS, TNF-alpha antagonists are the oldest and their efficacy has been proven in recalcitrant ocular, vascular, gastrointestinal and neurologic involvements. These drugs have significantly reduced morbidity and mortality in BS and they have an acceptable safety profile. Tocilizumab, an IL6 receptor antibody, has been shown to be effective in BS patients with neurologic involvement and amyloidosis, and IL1β antagonists such as anakinra, canakinumab, gevokizumab were effective in the management of ocular involvement. Studies investigating the efficacy of daclizumab, IL2 receptor antibody, and secukinumab, IL17 monoclonal antibody, in the management of BS with eye involvement failed to demonstrate significant clinical improvement and both studies were halted. A monoclonal vascular endothelial growth factor antagonist, bevacizumab, was shown to be effective in BS-related macular edema. Alemtuzumab and ustekinumab are among other biologics which were effective in controlling disease symptoms. In this review, we discuss the efficacy and safety of various recently developed biologic agents targeting different pathways involved in the pathogenesis of BS.

Current Developments in Therapeutic and Diagnostic Strategies for Q Fever: Glimpses of Patent Analysis

Coxiella burnetii is an infectious and etiological agent responsible for causing Q fever. There are mainly two forms of the Q fever that are chronic and acute. Though the acute type is usually linked with symptoms like pneumonia and hepatitis, the chronic form is shown to have mortality rate of 5%. Percentage of mortality rate might increases from 5% to 25% if left untreated. The present treatments of disease include the recommended dose of drugs and vaccine. Presently, extensive attempt is in progress to find novel therapies to combat the disease. This review is projected to provide a brief introduction of C. burnetii and Q fever while emphasizing therapeutics, prophylactic measures and diagnostic applications based on recent patents prospects.

The Intracellular Domain of Amyloid Precursor Protein is a Potential Therapeutic Target in Alzheimer’s Disease

Amyloid-β (Aβ) is widely believed to cause Alzheimer’s disease (AD), as it is the major constituent of the amyloid plaques observed in the brains of people with AD (the so-called amyloid hypothesis). Based on this hypothesis, therapies utilizing immune responses against Aβ have been performed and have succeeded in effectively removing amyloid plaques, but have shown no evidence of improvements in survival and/or cognitive function. Thus, it may be necessary to think about this problem from a different viewpoint. γ-Secretase was initially identified as an enzyme that cleaves amyloid precursor protein (APP) and produces Aβ. Although the primary function of -secretase has not been fully clarified, this enzyme is well known to play a central regulatory role in Notch signaling. After the shedding of the Notch ectodomain by metalloproteases, γ-secretase releases the intracellular domain (ICD) of Notch, which immediately translocates to the nucleus to modify the expression of certain genes. Recently, many type 1 transmembrane proteins have also been reported as substrates for γ-secretase. Interestingly, several of these substrates may share a γ-secretase-regulated signaling mechanism similar to that of Notch. Indeed, we have demonstrated that the ICD of APP (AICD) induces dynamic changes in gene expression and neuron-specific apoptosis, suggesting that APP also has a signaling mechanism that is closely linked with AD. In this review, we first summarize the evidence that γ-secretase–regulated mechanisms similar to Notch signaling may play wide-ranging roles in signaling events involving type 1 transmembrane proteins, including APP. We also focus on the possibility that APP signaling is involved in the onset and progression of AD. Based on these ideas, we hypothesize that APP signaling, especially AICD, may be an attractive therapeutic target in AD.

4Aβ1-15-Derived Monoclonal Antibody Reduces More Aβ Burdens and Neuroinflammation than Homologous Vaccine in APP/PS1 Mice

The common pathological hallmark of Alzheimer’s disease (AD) is β-amyloid plaque deposition. The ideal therapy would reduce the Aβ burden with a low inflammatory immune response. Passive immunotherapy is an advanced treatment that dramatically reduces brain Aβ pathologies in AD animal models. The objective of our study was to observe the effects of 5C8H5, a novel monoclonal antibody derived from 4Aβ1-15, on brain Aβ pathology in an APP/PS1 mouse model of AD. Six-month-old transgenic mice were administered 5C8H5, 4Aβ1-15 or IgG, and same-aged wild-type untreated C57Bl/6J mice were employed as controls. Inflammatory factors and Aβ40/42 levels were detected by ELISA, while Aβ plaques, microglial cell activation, microhemorrhages and neurogenesis were evaluated by immunohistochemical staining. Compared with 4Aβ1-15-treated mice, the mice in the 5C8H5 group induced more Aβ clearance with less microglial cell activation in a niche of Th2-polarized immune response. The levels of proinflammatory factors, including IL-1β, IL-6, TNF-α and IFN-γ, were significantly decreased in the CNS, while the level of antiinflammatory IL-4 was increased. Moreover, the mice in the 5C8H5 group induced more neurogenesis without microhemorrhage exacerbation and thereby performed better in behavioral assays than did the 4Aβ1-15 group. In conclusion, the novel monoclonal antibody induces more Aβ clearance and less microglial cell activation in the absence of inflammation, accompanied by an increased Th2-polarized immune response, which makes it a more promising therapeutic strategy. These data provide evidence that passive immunity could alleviate pathologic Aβ alterations by modulating inflammation and should be pursued further for the treatment of AD.

New Developments of Clinical Trial in Immunotherapy for Alzheimer's Disease

Active or passive immunotherapy is expected to slow or stop the pathological process of Alzheimer’s disease (AD). Immunotherapy for AD has demonstrated that targeting beta-amyloid (Aβ) or tau protein with vaccines or antibodies can reduce AD pathologies. Active anti-Aβ immunization for AD includes using AN1792 and second generation vaccines such as ACC-001, CAD106 and AFFITOPE vaccines, while antibodies for passive immunization include monoclonal antibodies and intravenous immunoglobulin (IVIG). Preclinical trials have shown powerful evidence of significant advances for more than a decade; however, there are still issues that need to be addressed in clinical trials. In the phase IIa AN1792 trial, 6% of patients who received the vaccination were diagnosed with meningoencephalitis as an adverse effect. There was a high incidence of amyloid-related imaging abnormalities (ARIA) in patients treated with some monoclonal antibodies. Moreover, several phase 3 clinical trial findings of immunization targeting Aβ were negative. These issues require attention in order to improve the safety and efficacy of immunization strategies in AD. Prevention studies and other novel immunization strategies have the potential to dramatically impact AD care. Herein we review the recent advances in clinical trials involving immunotherapy for AD.

Vanutide Cridificar and the QS-21 Adjuvant in Japanese Subjects with Mild to Moderate Alzheimer’ s Disease: Results from Two Phase 2 Studies

Objective: Multiple lines of evidence indicate that pathological accumulation of amyloid beta (Aβ) peptide in the brain is linked to the pathophysiology of Alzheimer’s disease (AD). Removal of Aβ from the brain by binding to anti-Aβ specific antibodies is under active investigation. Vaccination with a full-length Aβ₄₂ peptide (AN1792) successfully elicited anti-Aβ antibodies in human subjects with AD, but was associated with meningoencephalitis. To avoid this safety issue, an aminoterminal Aβ1-7 peptide conjugate, vanutide cridificar (ACC-001), was designed and is currently in clinical development. This report describes two phase 2 multiple ascending-dose studies in Japanese subjects with mild to moderate AD. Safety and immunogenicity evaluation were the primary and secondary objectives, respectively. Methods: ACC-001 was administered to three cohorts of subjects at doses of 3, 10, or 30 μg, with or without a QS-21 adjuvant in Study 1, and with a QS-21 adjuvant in Study 2; control groups consisted of QS-21 alone (both studies) and phosphate-buffered saline (Study 1 only). Results: A variety of treatment-emergent adverse events (TEAEs) were reported from most subjects during the studies; most of these were mild or moderate in intensity. Three subjects withdrew from the study because of an adverse event (in Study 2). The most common treatment-associated TEAE was injection site reactions. No deaths were observed in either study. All doses of ACC-001 + QS-21 elicited high, sustained anti-Aβ antibody titers; QS-21 was necessary for this effect. Conclusion: These data will provide valuable information on further investigation of anti-Aβ vaccine therapy for AD.

Non-Classical Therapeutic Approach in the Treatment of Alzheimer's Disease: A Mini Review

Alzheimer's disease (AD) is a multi factorial disease, related to the loss of neurons and synapses in cerebral cortex and subcortical structures, leading to degenerative changes and atrophy. Despite abundance of facts related to AD and its pathology, the only drugs used in the prevention and treatment are those from the cholinesterase inhibitors group. However, there is growing evidence that a non-classical therapeutic approach in the treatment of AD has beneficial effects. In this review we summarized recent literature data related to the non-classical drugs for the treatment of AD predominantly used in clinical testing, such as amyloid aggregation inhibitors, beta-sheet breakers, antioxidants, estrogens and immunotherapeutics.

Intravenous Immunoglobulins for Alzheimer's Disease

Alzheimer’s disease (AD) is a chronic neurodegenerative disease associated with intracerebral accumulation of aggregated amyloid-beta (Aβ) and tau proteins, as well as neuroinflammation. Human intravenous immunoglobulin (IVIG) is a mixture of polyclonal IgG antibodies isolated and pooled from thousands of healthy human donors. The scientific rationale for testing IVIG as a potential AD treatment include its natural anti-Aβ antibody activity, its favorable safety profile and inherent anti-inflammatory/immunomodulatory properties. Over the past decade, several clinical and pre-clinical experimental findings, advanced our knowledge about biological and therapeutic properties of IVIG that are relevant to AD therapy. Anti-amyloid antibodies in IVIG show significantly higher binding avidity for amyloid oligomers and fibrils than for Aβ monomers. In a double transgenic murine model of AD, intracerebral injection of IVIG causes suppression of Aβ fibril pathology whereas long term peripheral IVIG treatments causes elevation of total brain Aβ levels with no measurable impact on Aβ deposits or tendency for inducing cerebral microhemmorhage. Furthermore, chronic IVIG treatment suppressed neuroinflammation and fostered adult hippocampal neurogenesis. In clinical studies with AD patients, IVIG showed an acceptable safety profile and has not been reported to increase the incidence of amyloid related imaging abnormalities. Preliminary studies on small number of patients reported clinical benefits in mild to moderate stage AD patients. However, double blind, placebo controlled studies later did not replicate those initial findings. Interestingly though, in APOE4 carriers and in moderate disease stage subgroups, positive cognitive signals were reported. Nevertheless, both clinical and experimental (mouse) studies show that antibodies in IVIG can accumulate in CNS and its biological activities include neutralization of Aβ oligomers, suppression of neuroinflammation and immunomodulation. Identifying mediators of IVIG’s effects at the cellular and molecular level is warranted. In light of its favourable safety profile and aforementioned biological properties, IVIG is still an enigmatic experimental candidate with enormous potential for being an AD therapeutic.

Bacteriophage - A Common Divergent Therapeutic Approach for Alzheimer's Disease and Type II Diabetes Mellitus

Alzheimer's disease, the most important neurodegenerative disorder, is an irreversible, age-dependent disease of the brain characterized by problems in progressive impairments in memory, language, reasoning, behavior and visuospatial skills. It is characterized by the deposition of amyloid beta peptide, forming compact fibrillar plaques and neurofibrillary tau tangles. Another major and much more prevalent cause of morbidity and mortality in world is diabetes especially type 2 diabetes mellitus. It is caused by a combination of resistance to insulin action and an inadequate compensatory insulin secretory response. Chronic wounds caused by antibiotic resistant bacterial infections that fail to heal are a common complication of diabetes mellitus and the most frequent reason for nontraumatic lower limb amputation. Holistically, these two diseases are linked at molecular level but the exact mechanism is a topic of debate. Bacteriophages are viruses infecting bacteria and lack ability to infect mammalian cells. They are neither causative agent for Alzheimer's disease or type 2 diabetes mellitus nor involved in their pathogenicity but promises for a novel divergent therapeutic approach. The great versatility of the phage system has led to the development of improved phage delivery vectors, as well as immunomodulation of anti-amyloid beta peptide response. Phages could also constitute valuable prophylaxis against bacterial infections, especially in immunocompromised patients like in the case of diabetes. Patients having diabetes have a high risk of developing foot ulcers which are difficult to be treated by antibiotics alone due to ever increasing antibiotic resistance strains. Combination therapy based on multiple phage and broad spectrum antibiotics holds great promise. The potential therapeutic phage therapy arises from its lack of natural tropism for mammalian cells, resulting in no adverse effects.

The Effects of Soluble Aβ Oligomers on Neurodegeneration in Alzheimer's Disease

The neurodegenerative process that defines Alzheimer’'s disease (AD) is initially characterized by synaptic alterations followed by synapse loss and ultimately cell death. Decreased synaptic density that precedes neuronal death is the strongest pathological correlate of cognitive deficits observed in AD. Substantial synapse and neuron loss occur early in disease progression in the entorhinal cortex (EC) and the CA1 region of the hippocampus, when memory deficits become clinically detectable. Mounting evidence suggests that soluble amyloid-β (Aβ) oligomers trigger synapse dysfunction both in vitro and in vivo. However, the neurodegenerative effect of Aβ species observed on neuronal culture or organotypic brain slice culture has been more challenging to mimic in animal models. While most of the transgenic mice that overexpress Aβ show abundant amyloid plaque pathology and early synaptic alterations, these models have been less successful in recapitulating the spatiotemporal pattern of cell loss observed in AD. Recently we developed a novel animal model that revealed the neurodegenerative effect of soluble low-molecular-weight Aβ oligomers in vivo. This new approach may now serve to determine the molecular and cellular mechanisms linking soluble Aβ species to neurodegeneration in animals. In light of the low efficiency of AD therapies based on the amyloid cascade hypothesis, a novel framework, the aging factor cascade hypothesis, is proposed in an attempt to integrate the new data and concepts that emerged from recent research to develop disease modifying therapies.

Detection of Cryptococcus neoformans Capsular Antigen in HIV-Infected Patients in the State of Para in the North of Brazil

Cryptococcus neoformans is an important cause of morbidity in HIV-infected patients worldwide. In the northern region of Brazil, the prevalence of this infection is poorly known due to a lack of systematic investigations. This study aimed to determine the occurrence of cryptococcosis by detecting antigenaemia in HIV-infected patients in the State of Pará, Brazil. A latex Cryptococcus antigen detection kit was used to test 418 serum samples from HIV-infected patients seen at two Infectious Disease Specialized Units in the State of Pará. The C. neoformans antigenaemia prevalence was 2.6%, and titres reached 1:8. The cases occurred mainly in asymptomatic females, and 45% presented CD4⁺ T lymphocyte counts of fewer than 200 cells/mm³. These results show the importance of early C. neoformans antigenaemia detection to prevent fungal disease.