Meningoencephalitis

Chikungunya Virus and Toll like Receptors

Infected mosquitoes of Aedes species spread Chikungunya fever upon the biting of the mosquitoes. Chikungunya fever first came to the limelight upon an outbreak in southern Tanzania in 1952. These days almost all countries in the world are reporting Chikungunya fever. There is no vaccine for the Chikungunya virus. The infection causes severe joint pain, nausea, vomiting, conductivities, headache, and muscle pain, followed by fever. Clinical manifestations occur after 2-7 days of the mosquito bite. This chapter addresses key issues on Chikungunya viral infection in brain cells with reference to the triggering of events associated with toll-like receptors.

Swellings of Orofacial Structures in Children

Orofacial swelling is clinically a common problem found in pediatric dental patients. The causes of these swellings are mostly diverse, and the knowledge about specific clinical as well as imaging manifestations along with the most affected sites of these swelling is needed for the formulation of a differential diagnosis. Mid-facial nonprogressive swelling is usually suggestive of a congenital defect (like a cephalocele, nasal glioma, epidermoid cyst or nasal dermoid). Swelling that is slowly progressive, may be indicative of a neurofibroma, hemangioma, vascular malformation, lymph angioma, pseudocyst or fibrous dysplasia. In cases of facial swellings that are rapidly progressive and associated with cranial nerve deficits, rhabdomyosarcoma, Ewing sarcoma, Langerhans cell histiocytosis, metastatic neuroblastoma and osteogenic sarcoma should also be included in the differential diagnosis.

Subject Index

Neuropharmacology in Alzheimer and Huntington Disease

The Alzheimer’s disease and Huntington’s disease are the two important neurodegenerative disorders currently under research for various therapeutic approaches ranging from newer biochemical molecules, plant extracts and food supplements to highly advanced biotechnological and genetic therapies. Alzheimer’s disease (AD), one of the leading causes of disability in the elderly population is exponentially rising worldwide. The acetylcholinesterase inhibitors and memantine, the mainstay of treatment only slow down the disease progression and provide symptomatic improvement. The cholinesterase inhibitors, rivastigmine and donepezil apart from improving cognition also delay hospitalization and reduce behavioural and psychological symptoms of dementia. Other cholinesterase inhibitors and cholinomimetic targets like muscarinic and nicotinic receptor agonists are in development. Extensive research in this area in the past few decades has given insight into the cellular and molecular pathogenesis of the disease. This has led to the development of certain novel strategies to modify the disease progression and prognosis. This includes amyloid and tau-based therapeutics, various immunotherapies, vaccines and food and plant supplements. Other new promising agents under research are anti-inflammatory drugs, neurotrophic factors and antioxidants. Huntington’s disease is a rare inherited neurodegenerative disorder producing motor, cognitive and psychiatric symptoms. A greater understanding of the pathology in the recent past has led to research into the development of newer therapeutic agents mainly DNA and RNA based therapies and technologies using gene editing tools. Several of these putative drugs are in preclinical studies and many of them have failed to show positive results. In this section, we are going to discuss the approved therapies for AD and HD currently in use, the status and evidence regarding drugs in various stages of clinical trial and mention advanced biotechnological and gene therapies under investigation.

Therapeutic Targets for Emerging Zika Virus Infection and Vaccines in Clinical Trials

Zika virus is a mosquito-borne disease initially limited to sporadic cases in Africa and Asia. With the recent emergence of the Zika virus in Brazil in 2015, the virus rapidly spread throughout America. Even though most of the Zika virus infections have a mild influenza-like illness, severe manifestations were also observed, including Guillain-Barre syndrome in adults and microcephaly in babies born to infected mothers. Due to the severity of this disease, structural virologists quickly studied its different features. But, even with the elucidation of the viral genome, an effective treatment or suitable vaccine is not available for this disease so far. The viral vectors, pathogenesis, genetic diversity, and co-infection with other diseases remain unanswered. The production of an effective vaccine is hence a global health concern. This chapter discusses the emergence of the Zika virus and its detailed genome structure and replication cycle. The molecular pathogenesis and Zika viral therapeutics with detailed descriptions about the host and viral targets, investigational drugs, and vaccine candidates are explained here.

Anthelmintic Drug Discovery: Current Situation and Future Perspectives

Nematode parasites cause several neglected tropical diseases in humans such as lymphatic filariasis, onchocerciasis (river blindness), and soil-transmitted helminthiasis. Approximately 30% of the human world population is infected with at least one parasite and this prevalence could be even higher in rural areas and lowincome countries. Although nematode infections are rarely lethal, they are associated with morbidity and severe consequences, particularly in children.

There are several concerns about the management and treatment of these diseases. Currently, the repertoire of nematocidal agents is limited, and these drugs are not 100% effective against all nematode parasitosis. In addition, the extensive use of these few drugs in massive administration campaigns in humans would probably lead to the development of resistance very soon. Further worsening the situation, the interest of the pharmacological industry in developing novel anthelmintics is low since these infections are mostly endemic in poor countries that do not constitute a profitable market. Under this alarming scenario, there is an urgent need to develop new and broad-spectrum antiparasitic drugs.

Traditional preclinical drug discovery is a long, expensive, and complex process. Thus, innovative strategies and alternative models, such as the free-living nematode Caenorhabditis elegans, are required to reduce costs and accelerate times. Its genetic amenability and the feasibility of performing high-throughput screening assays, convert this nematode into an excellent platform for nematocidal drug screening.

This chapter summarizes the current situation on antiparasitic drug discovery and discusses the use of C. elegans at the initial steps of drug development to accelerate the appearance of new drugs.

Different Antiviral Drugs against COVID-19 and Future Perspective

The outbreak of coronavirus disease-19 (COVID-19) across the world has caused serious health issues in terms of physical and psychological damage to human health. The spread of this virus was rapid and shortly spread to almost every country in the world. Due to the high infection rate and occurrence of complications in the infected individuals, the research and development of anti- COVID-19 drugs became the utmost necessity of time as no specific drug is available to relieve the clinical symptoms of COVID-19. We reviewed reliable information on targeted severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) candidate drugs in the present chapter. Also, we summarized novel insight into the future development of safe, effective, and less-toxic antiviral drugs available and employed for the management of COVID-19. Similarly, we focused on antiviral medications under investigation for this purpose; several medications with different mechanisms of action were noticed for the treatment of COVID-19.

Pharmacotherapy of Multiple Sclerosis and Treatment Strategies

Multiple sclerosis (MS) is a well-known chronic inflammatory and neurodegenerative disease of the central nervous system (CNS). It is considered the most common autoimmune demyelinating disease of the CNS. It affects mainly young adult females between 20-40 years of age. MS was previously considered a Tlymphocyte- disease, but now B lymphocytes appeared to have a critical role in MS's pathogenesis. Affected patients showed lower quality of life with an increased death rate than the general population. The treatment of MS is challenging, and many drugs have evolved primarily for the last 20-30 years. Since the introduction of interferons in 1993, there are more than sixteen disease-modifying therapies (DMTs) approved. These drugs have different pharmacologic forms like injections, oral forms, and intravenous infusion drugs. Each one has its benefits and drawbacks. Moreover, like any other patient, MS patient has other symptoms that are not covered by DMT and need symptomatic treatment. In this chapter, we attempt to present medications used to treat acute relapse, different DMTs, symptomatic treatment for different MS symptoms. Besides, we give attention to drugs under clinical trials.

Recent Patents on Exosome-Derived Therapeutic Agents

Exosomes are extracellular vesicles that are 30-150 nm in diameter. Exosomes have recently emerged as critical mediators of cell-cell communication by the transfer of DNA, RNA, and protein structured macromolecules between cells and tissues. With the advantage of the distant endocrine signalling, cancer cells use exosomes to suppress the immune system, next contribute to the formation of premetastatic niches and angiogenesis. On the other hand, researchers have been benefited from the immunosuppressive, natural carrier, and tissue regenerating roles of exosomes and disclosed patents that are claiming the utilities of exosomes for treating chronic inflammation, autoimmunity related diseases, targeted drug delivery vehicles, and tissue regenerating agents. Moreover, the use of exosomes as vaccine components to prevent cancer, therapeutic molecules for cancer treatment, and the host of biomarkers for the diagnosis and prognosis of cancer are among the issues that are protected by recent patents. The most inspiring one among them could be the incorporation of a therapeutic siRNA that is complementary to oncogenic KRASG12D into CD47+ exosomes for the treatment of pancreatic cancer. The other one could be the demonstration of the utility of exosomes secreted from dendritic as a cancer vaccine component in phase II clinical trial. It is clear that we have started to understand the fundamentals of exosomes. However, more studies are needed to develop exosomebased cancer vaccines, drug delivery vehicles, immune-stimulating agents that evoke immune cells to kill the cancer cells, and diagnostic and prognostic markers for monitoring cancer in the next years.

Emerging Viral Diseases and Potential Therapeutic Agents for Their Control

The emerging infectious human viral diseases have been a prime concern for public health since the last decade. Various new viruses or virulent strains of old viruses have emerged during this period. Appropriate knowledge of the viral pathogenesis is required to understand their emergence and possible therapies. Various factors are involved in the emergence of viruses and new human diseases. Some of these human diseases are zoonosis. Zoonosis can be defined as human diseases caused by animal pathogens, which that are transmitted to humans. The WHO has been continuously updating the prioritizing list for various infectious, and emerging viruses. In this chapter, we discussed some important emergent viral pathogens, such as Ebola virus, Crimean-Congo Haemorrhagic Fever virus, and Marburg virus, Hanta, Hendra, and SARS. Detailed understanding of the emergence, the modes of transmission and pathogenesis, and possible treatment plans are necessary to check the invasion and outbreak caused by these viruses.

Amyloid Hypothesis in Alzheimer´s Disease

Alzheimer’s disease (AD) is a neurodegenerative condition which is highly prevalent. According to the World Health Organization (WHO) estimates, the overall projected prevalence in worldwide will reach 132 million patients by 2050. Amyloid hypothesis described in 90´s by Hardy et al, is the main therapeutic target. Since acetylcholinesterase inhibitors as symptomatic treatment, drug development for AD has been disappointing. All drugs in completed phase 2 and phase 3 trials have failed.

So, the question is, what´s wrong about this hypothesis and the immunotherapy approach? These compounds aimed at reducing Aβ formation and plaques do not restore cognition although removes amyloid plaques in PET amyloid scans.

This paper tries to discuss all the aspects and describe the current situation and the future goals.

Amyloidogenic Peptide Structure, Aggregation, And Membrane Interaction

It is estimated that 44 millions of people have Alzheimer’s disease (AD) or related dementia around the world. The AD is an irreversible progressive brain disorder that destroys the memory and thinking and causes the loss of cognitive functions. The development of AD is strongly correlated with the development of plaques and tangles in the brain. Beta-amyloid (Aβ) peptides are the main compound in the brain plaques however, their neurotoxic effects remain unclear. These peptides are generated from Amyloid Precursor Protein (APP) and the APP processing may be modulated by many factors, such as lipid rafts. Aβ coexists in different forms in the brain and the exact neurotoxic effect of each one is not understood. The majority of the studies about Aβ neurotoxicity suggests that the fibrillar form is the most neurotoxic and for this reason, much effort has been employed to understand mechanisms that modulate or inhibit the fibrillation process. Other studies suggest that the main neurotoxic form is the oligomer, which forms channels in the lipid membrane and induces cell death. In this chapter, we explore the mechanism of Aβ’s production and fibrillation, and the factors that can modulate it.

Sexually Transmitted Co-infections in Persons Living with HIV

Sexually transmitted co-infections increase HIV infectiousness through local inflammatory processes. The risk factors in acquiring genital co-infections associated with HIV infection still present many questions. There is some evidence that there is an association between certain sexually transmitted infections and HIV, but for others, there is only a marginal correlation, as will be discussed in this chapter. The most prevalent co-infections found in HIV carriers and their epidemiology, clinical features and evidence-based treatments will also be analyzed.

TUBERCULOSIS: Epidemiological, Molecular, Immunological and Clinical Characteristics

Tuberculosis is a major public health problem in many regions of the world, accounting for up to 2 million deaths per year. The main causative agent of tuberculosis is Mycobacterium tuberculosis, which usually infects the lungs, causing symptoms such as fever, cough and chest pain. After infection, the bacilli can be cleared by a healthy immune system or, on the other hand, the infection may lead to latent tuberculosis or progress to active pulmonary tuberculosis. Moreover, in certain situations, such as cases of immunocompromised patients, these bacilli can spread through the lymphatic or hematogenous route to more distant organs, leading to extrapulmonary tuberculosis. Approximately 30% of the population worldwide has latent tuberculosis and 5 to 10% of individuals infected with M. tuberculosis progress to active tuberculosis disease. Although tuberculosis is a curable disease, some factors have been associated with the morbidity and mortality of global tuberculosis, including inadequate detection, increased abandonment rate of anti-TB treatment, co-infection with human immunodeficiency virus, increased drug resistance and inefficiency of the BCG vaccine in preventing the disease in adolescents and adults. New tools are therefore urgently needed to control tuberculosis. Knowledge of the molecular characteristics, immune response and pathogenesis of M. tuberculosis are essential for the development of new approaches to diagnosis, drugs and vaccines to assist in the clinical management and control of the disease. This first chapter on tuberculosis describes the epidemiological, immunological and clinical aspects of the disease, as well as the microbiologic and molecular characteristics of M. tuberculosis.

Systemic Fungal Infection

Fungi are responsible for approximately 10% of nosocomial infections, with Candida spp. being the most prevalent etiological agent. Immunocompromised individuals are more susceptible to fungal infections. An early determination of the etiology of the infection is extremely important for these patients because it provides valuable information for choosing the best therapeutic scheme and may increase the chances of recovery. Due to the low sensitivity of direct examination, the determination of the etiology of a fungal infection often requires culture of biological specimens for isolation and identification of the disease causative agent. Blood culture is not effective for diagnosis of invasive fungal infections, even when serial specimens are analyzed. Serological identification of fungal cell wall proteins (galactomannan, mannan, β-glucan) are considered the first line diagnosis of invasive fungal infections; however, it has low sensitivity because the antigens are rapidly removed from the bloodstream. Molecular biology diagnostic methods have been developed as an alternative for the - detection of fungal infections that are difficult or impossible to detect by conventional microbiological and serological methods. In this chapter, we provide an up-to-date review of nosocomial fungal infections, focusing on the occurrence, etiology, risk factors, clinics, as well as the conventional and molecular methods of diagnosis. We also discuss the use of molecular markers for the detection of fungal infection.

Neurodegenerative and Neuropsychiatric Disorders: Present Clinical Drug Research and Future Perspectives

Neurodegenerative disorders are elucidated as genetic and intermittent diseases which are described by progressive nervous system dysfunctions. These disorders have often being correlated with the degeneration of nerve cells. Most prevalent diseases are Alzheimer’s disease (AD) and related dementias, Encephalitis, Epilepsy, Parkinson’s disease (PD), Multiple sclerosis, Amyotrophic lateral sclerosis, Huntington’s disease, Schizophrenia and Prion diseases. All neurodegenerative diseases are disastrous and impact social as well as economic wellbeing. However, the majority of neuropatients are affected by AD, PD and together they cost the health care system almost billions of dollars per year. Besides, Schizophrenia is a severe mystery with no effective medical treatment. Therefore, AD, PD and Schizophrenia have been discussed at length in the present chapter. The AD is characterized by two neuropathological lesions, senile plaques composed of Aβ peptide and neurofibrillary tangles (NFTs) containing aggregated hyperphosphorylated Tau protein. The importance of Tau dysfunction in neurodegeneration is further supported by the enrichment of Tau genetic variants in cohorts of patients suffering from frontotemporal lobar degeneration disorder (FTLD). Memory loss, trouble sleeping, language problems, thinking and reasoning skills are the most common symptoms of AD. The PD is the second most common neurodegenerative disease which involves the breakdown and death of neurons in the brain. The core symptoms of PD are tremor, rigidity, bradykinesia and balance difficulties. Schizophrenia is a genetic brain disorder. Delusions, hallucinations, social withdrawal and disturbed thinking are some of its key symptoms. The genes causing these neurodegenerative disorders have been identified for more than two decades. Key researchers in this field have revealed numerous events at molecular and cellular levels, thus playing an important role in these fatal disorders. Many associated pathological events and therapeutic correlations are not clearly understood and therefore, there is no known cure for these chronic and progressive neurological disorders. This chapter aims to address AD, PD and Schizophrenia researches that may divulge novel mechanisms and targets for therapeutic intervention. It collates the significant findings of various experts in studying these degenerative diseases and stimulates novel perception to the campaign against devastating neurodegenerative diseases.

Prevention and Eradication of Biofilm in Medical Indwelling Devices

The use of medical indwelling devices (MID) became a hallmark in medicine during the last few decades. While it represents a considerable progress in terms of chances of patient survival, several associated drawbacks demand continuous research in terms of optimization of such devices or of its use in order to cope with complications, which could be life threatening. Notably infection remains one of the most inherent complications associated with MIDs, constituting the most feared threat. Very frequently, it demands MID replacement, often leading to its lost, to prolonged patient hospitalization and, ultimately, to patient death. In any case, it represents a serious burden to healthcare systems in terms of allocated resources and financial costs. The formation of biofilm became the paradigm of MID infection. Independently of the nature of such devices, following its placement or implantation infection remains hard or impossible to control with common antibiotics. In fact, antibiotic drugs hardly penetrate the polymeric matrix of biofilm, which allows organisms to evade its activity. Moreover, organisms in biofilm display increased antibiotic resistance, in comparison to its planktonic counterparts. While diverse preventive strategies have been attempted, with variable success, fewer options remain available once overt infection develops, apart from device removal. Nevertheless novel alternatives have been proposed and recent research efforts with specific devices have provided encouraging results. Our research team has been addressing this problematic from a clinical perspective and, in particular, from a laboratorial point of view, conducting both in vitro and in vivo studies in biofilm infection models. The authors propose to conduct an extensive review and discussion of the literature available concerning biofilm involvement in MID infection, having as main focus the eradication of biofilm at the surface of MID, apart from prevention of the initial steps of its formation. While a large variety of devices will be discussed, like central venous catheters, prosthetic or cardiovascular implants, special consideration will be dedicated to high value devices such as heart pace-makers and cerebral stimulators, attending to the direct high costs associated to its lost following infection.

Nanomedicine and Neurodegenerative Diseases: An Introduction to Pathology and Drug Targets

Neurodegenerative diseases are debilitating conditions that result in progressive degeneration and death of neuronal cells. One of the hallmarks of neurodegenerative diseases is the formation of protein aggregates. Progressive accumulation of similar protein aggregates is recognized as a characteristic feature of many neurodegenerative diseases. Particularly in Parkinson’s Disease (PD), aggregated forms of the protein α-synuclein (α-syn); and in Alzheimer's Disease (AD) and cerebral amyloid angiopathy (CAA), aggregated Aβ amyloid fibrils form the basis of parenchymal plaques and of perivascular amyloid deposits, respectively. In Amyotrophic Lateral Sclerosis (ALS), the RNA-binding protein TDP-43 is prone to aggregation. The focal aggregates at early disease stages later on result in the spreading of deposits into other brain areas and many neurodegenerative diseases display a characteristic spreading pattern. Here, we will summarize the anatomy and pathology of the predominant neurodegenerative diseases focusing on AD and PD and review their clinical manifestation to highlight the urge of novel therapeutic strategies. Additionally, given that development of treatments requires suitable animal models, the most commonly used model systems are introduced and their pathology compared to the human situation is mentioned briefly. Finally, possible drug targets in neurodegenerative diseases are discussed.

Iatrogenic Lesions in Neurology

Iatrogenic neurological disorders can be induced by several factors, such as pharmacological agents prescribed for treatment or prevention (drug-induced neurological disorders [DIND]), complications of diagnostic and treatment procedures, like cerebral angiography or lumbar puncture, organ transplantation (related to the surgical procedure of transplantation, post-transplant immunosuppression, opportunistic infection or the inherent disorders that lead to transplantation), radiation therapy, etc. Iatrogenic neurological effects may be devastating due to the higher potential irreversibility of central nervous system, peripheral nervous system, neuromuscular junction (NMJ) and/or muscular system involvement. DIND represent the majority of iatrogenic neurological disorders. Drugs may directly induce neurological damage (through primary neurotoxicity, such as damage to the bloodbrain barrier [BBB], disturbances of brain energy metabolism, ion channels/neurotransmitters disturbances, mitochondrial dysfunction, metabolitemediated toxins, drug-induced selective cell death) or do so indirectly (cardiovascular, hematological or renal effects). Identification of DIND is important because early recognition and drug withdrawal can prevent irreversible damage. The numerous intrinsic risk factors for DIND should be well known by medical practitioners.

Subject Index

Free-living Amoebae

Acanthamoeba Species is the most common free living amoeba present in environment. It is isolated from soil, water, contact lens solutions, transplant units and various other hospital environment. There are many species of Acanthamoeba such as A.astronyxis, A.castellani, A.culbertsoni, A.hatchetti, A.keratitis etc. which are known to cause opportunistic infection in both immunocompetent as well as immunocompromised host. Transmission mainly occurs through direct contact. There are two described morphological forms; a trophozoite form and a cyst form. The trophozoites have characteristics pointed thorn like acanthapodias, containing one nucleus with central dense large nucleolus. The cytoplasm measures between 15-50μm, granular and contains various organelles. Clinically patients usually presents with granulomatous amoebic encephalitis (GAE) which is characterized by focal neurological deficit, headache, visual disturbances, seizures and behavioral abnormalities which develops over months to years. Laboratory diagnosis of Acanthamoeba spp. is done by examining CSF which generally shows predominant lymphocytes, elevated proteins and low glucose levels. Histopathological samples of the brain generally reveals cerebral edema, multiple necrotic and hemorrhage lesions. Acanthamoeba can easily be cultivated on non-nutrient agar with overlay of Escherichia coli or Entrobacter spp. Amoeba feeds on bacteria’s and confluent growth is seen in 4-5 days of culturing. The combination therapy is advisable in proven cases of Acanthamoeba infection. Combining Amphotericin B plus Trimethoprim- Sulphamethoxazole plus rifampicin has successfully used in few cases.

Naegleria Fowleri: The organism was first reported in Australia in 1965. It is an environmental ameboflagellate parasite found in variety of water bodies such as ponds, swimming pools; aquarium etc. prefers temperature of 30-45ºC. There are three stages seen in Naegleria life cycle: the infective trophozoites, transient flagellated and the resistant cystic stage. The portal of entity of trophozoites is via olfactory neuroepithelial cell lining covering the cribriform plate to reach olfactory bulb. Demyelination and myelinoclasis are observed in gray matter due to vascular blockage. These pathological changes are attributed to release of phospholipolytic enzymes which causes breaks in the lipid membrane of neuronal cells. Clinically, patients of primary amoebic meningoencephalitis (PAM) usually presented with high grade fever,headache, photophobia and features of raised intracranial pressure. Laboratory diagnosis is done using peripheral smear, CSF examination, culture, histopathological examination and imaging modalities. Hematological findings are leukocytosis with predominant neutrophils. The CSF shows low glucose and high protein levels. Centrifugation of fresh CSF sample up to 500 RPM may reveal motile trophozoites. Morphologically, the size of trophozoites ranges between 12-25μm, with a single nucleus and centrally placed nucleolus in the absence of peripheral chromatin. Liquid culture media such as such as Nelson’s medium containing ox liver digest and glucose are used with serum for growing amoebae. Mammalian cell lines can be employed to demonstrate cytopathic effect. Multiplex PCR detects free living amoeba within 6 hours but routine use in diagnostic laboratory is limited due to rarity of finding these organisms and having high cost of PCR. Brain imaging is easy to perform but restricted by nonspecific findings such as cerebral edema. Specifically, infraction involving frontal, orbital and cerebellum area can be observed in few cases of PAM. There is no optimal treatment regime for Naegleria fowleri. Literature suggests combination therapy works best with amphotericin, rifampicin and azithromycin.

Balamuthia Mandrillaris: Over 200 cases were reported from South America and United States. The true prevalence of disease is unknown in south East Asia. Organism is commonly isolated from soil contact with activities related to soil such as gardening, agriculture pose risk of acquiring the organism. It was first isolated in 1986 from baboon brain that died of meningoencephalitis. The portal of entry of the organism is via cutaneous lesions, nasal mucosa and then subsequent spread to brain. CNS lesions mimic acanthamoeba encephalitis and have chronic slowly progressive course over many years. The life cycle of Balamuthia involves two stages: trophozoites and the cyst. The morphologically variable trophozoites are 12- 60 microns in size containing single nucleus with large centrally placed nucleolus. Cysts are spherical in shape measuring 12-30μm and contain a single nucleus with double wall having outer ectocyst, middle fibrillar layer and inner amorphous endocyst.The trophozoites, cysts and inflammatory cells are observed in perivascular regions of the infected tissue. In CSF, elevated protiens, reduced glucose are common findings. Balamuthia spp. can be grown in tissue cultures such as Monkey Kidney cell lines, Human Lung fibroblast and Human Brain Microvascular Endothelial cell lines. ELISA test is very specific to detect high antibodies titers. The antibodies do not cross react with other free living amoebae. PCR is also highly specific and sensitive test in which primers are developed against mitochondrial rRNA genes. Recently, real time PCR are developed targeting RNAase P gene of B.mandrillaris.

Sappinia Species: Two species of Sappinia are well-known cause of CNS infections in humans, Sappinia diplodea and Sappinia pedata. S.diploidea was first isolated from lizard faeces. As this parasite is found in animal faeces, persons handing livestock are at higher risk. Only one known case of Sappinia encephalitis infection reported in literature. The diagnosis was confirmed on histopathological sample, which showed necrotizing haemorrhagic inflammation of infected tissue, containing trophozoites. The trophozoite of Sappinia is characterized by two opposing nucleus with central flattening. Diagnosis can also be done by amplifying rDNA of both Sappinia diploidea and Sappinia pedata using SSU primers. The real time PCR can also be used based on 18rRNA gene sequences. Sappinia spp. is cultivated on non- nutrient agar with overlay of Enterobacter or Escherichia coli. Vahlkamphia spp. and Paravahlkamfia francinae are other emerging free living amoebas that were first isolated from CSF of young patient who presented with typical symptoms of primary amoebic meningoencephalitis.

Acute Posterior Multifocal Placoid Pigment Epitheliopathy

Uncommon Cause of Stroke: Diagnosis and Treatment (Part II)

This chapter contains detailed, up-to-date information about the nature, diagnosis, and treatment of those relatively uncommon types of cerebrovascular disease that cause strokes. Although many of the conditions discussed are rare, the chapter covers the causes of up to 10% to 15% of all strokes and of up to 40% of strokes in young adults. This chapter may be an essential resource to help physicians diagnose and treat stroke patients who do not fit well into the usual clinical categories.

Discussed in this chapter are the various form of inherited small vessel disease such as CADASIL but even the less known Col 4A1/2 related syndromes, CARASIL, TREX1- gene mutations disorders and the cerebroretinal microangiopathy with calcifications and cysts. Three form of metabolic disorders causing stroke such as Fabry disease, Homocystinuria and MELAS as well as the most relevant form of hematological disorders (antifospholipid syndrome and sickle cell disease) are discussed. Finally intriguing disorders such as migrainous infarction and drugs related stroke disorders are detailed as well as some other rare disease such as Kohlmeier–Degos disease and acute posterior multifocal placoid pigment epiteliopathy.

Crude Extracts and Isolated Compounds with Trypanocidal Activity

Chagas’ disease, or American trypanosomiasis, is a potentially mortal disease caused by the protozoan Trypanosoma cruzi. It is included in the list of neglected diseases or poverty-linked diseases. An estimate of 5.7 million people in the endemic areas are infected, resulting in 7000 yearly deaths. The disease is distributed in Central and South America, Mexico, and the southern United States. Due to rural-urban migration, the parasite is transmitted by blood transfusion, by vertical transmission from mother to child, or by organ transplantation; on the other side, some cases have been detected in non-endemic zones both in America and in Europe. Chagas’ disease is among the 17 neglected diseases; it is a complex zoonosis, involving interaction of vectors species with wild, peridomestic, and domestic mammals, showing several clinical pictures and transmission modes. It poses the highest economic burden among parasitic diseases in Latin America due to its long chronicity. The clinical manifestations and epidemiologic traits of the disease vary from region to region. The current medication against T. cruzi, nifurtimox and benznidazole, has adverse effects. Aiming to make new treatment alternatives known, the activity of plant-isolated compounds from Central America, South America, and Mexico is herein discussed, along with their action against different stages of Trypanosoma cruzi.

Recent Perspective About the Amyloid Cascade Hypothesis and Stem Cell-Based Therapy in the Treatment of Alzheimer's Disease

Alzheimer's disease (AD) is a complex neurodegenerative condition that is clinically characterized by impaired cognitive functions. The major morphologically observed lesion of AD encompasses the accumulation of extracellular amyloid aggregates (plaques) formed of amyloid-β (Aβ) protein and of intracellular neurofibrillary tangles (NFT) of hyperphosphorylated Tau protein. According to the currently accepted amyloid cascade hypothesis, the major induction factor underlying the loss of cholinergic neurons in the cortex and hippocampus is the pathological accumulation of a smaller protein fragments known as amyloid-β which in turn is derived from a larger membrane protein called amyloid precursor protein (APP). Based on this hypothesis, several diagnostic and drug-based therapeutic interventions were suggested, mostly targeting amyloid-β and hyperphosphorylated Tau proteins. Several data have emerged that might indicate the inconsistency of the amyloid cascade hypothesis. Moreover, due to the purely palliative nature of AD drugs used so far, new stem cell-based therapy has been suggested as a promising potential therapeutic approach. Several cell sources have been used, such as embryonic stem cells, neural stem cells, mesenchymal stem cells, and induced pluripotent stem cells. While this suite of cell-based trials has shown promising results in preclinical paradigms, stumbling blocks still exist in the current treatment regimens. The present review highlights the recent perspective that argues against the long standing amyloid cascade hypothesis as well as the major efforts in the experimental application of stem cellbased therapies used as treatment options for AD, and discusses the major impediments against their successful translation into clinical.

Recent Clinical Developments in Alzheimer’s Disease

Alzheimer’s disease is the most common neurodegenerative disease. Despite intensive research, promising therapies have failed to translate to the clinic. This chapter will review the prevailing mechanistic hypotheses to explain AD pathogenesis, including the cholinergic, amyloid-cascade, inflammatory and metal dyshomeostasis theories, present an update on the clinical developments in therapies targeting each of the hypotheses, and highlight promising areas requiring further research.

Microbial and Parasitic Diseases of Fish

Diseases of fish, caused by biological agents (bacteria, fungi, virus or parasites), are better known in farmed or ornamental fish, since the access to the affected fish coming from the natural environment is less probable. In fact, the fish that are infected by a specific pathogenic agent, natural inhabitants of the marine, estuarine or freshwater ecosystems, are rapidly eliminated from its biotopes by other predatory animals, due to its higher vulnerability and susceptibility to the social interactions.

Diffusion of pathogenic bacteria, fungi, virus or parasites in the aquatic environments is more efficient than in the terrestrial ones. Diagnosis and therapeutics of fish disease have specific difficulties and the application of preventive measures is a very complex issue. Some of those diseases have the same epidemiological problems of the infectious diseases of the terrestrial animals: High spread of diffusion, very significant economic losses, restrictions to fish travel or commerce and some (few) have zoonotic impacts.

At the Crossroad between Neuronal Hyperexcitability and Neuroinflammation: New Therapeutic Opportunities for Alzheimer’s Disease?

Alzheimer’s disease (AD) is a multi-faceted neurodegenerative disease. Clinically available treatments, such as cholinesterase inhibitors, are based mainly on the cholinergic hypothesis of AD. These treatments, as well as those targeting the NMDA type of glutamate receptors all provide only a limited therapeutic benefit. The field of AD research has also shifted focus to develop intervention strategies that prevent overt symptoms, such as amyloid plaque deposition and memory loss, in agreement with the more recent amyloid hypothesis of AD. However, to date, all amyloid-directed therapeutics for the treatment of AD have failed, suggesting that additional factors may be involved in the etiology of the disease and mobilizing the search for additional drug targets. By studying the early stages of AD, candidate drug targets (e.g. cytokines or neuronal network activity) have been identified and are now at advanced stages of preclinical development. Throughout this chapter we will focus on two aspects of AD that have garnered widespread attention with respect to future therapeutic intervention strategies. First, a common feature of both mouse models of AD and patients with the disease is hyperexcitability at the level of the synapse as well as neuronal networks. New research is starting to uncover the causes of this hyperexcitability and which cell types are vulnerable, thus, providing attractive therapeutic targets. Second, AD brains are affected by neuroinflammation-like alterations at early stages, which turn into overt neuroinflammation at the late stages. Reducing this activity by targeting the proinflammatory cytokine, tumor necrosis factor-α (TNFα), is thought to be a promising strategy to treat AD. Furthermore, given the cross-talk between the nervous system and the immune system, we hypothesize that the hyperexcitability and progressive induction of neuroinflammation may be related. Here, we summarize studies in both animal models of AD and AD patients related to hyperexcitability and neuroinflammation in the early stages of the disease. Finally, we propose that a combination treatment targeting these factors in addition to the amyloid burden would be a possible way to target more facets of AD.

Halting the Decline in Cognition: New Insights into Alzheimer’s Disease

Alzheimer’s disease is a major public health concern globally and has been identified as a research priority. Although this disease has been recognized for more than a century, there is an urgent need to improve our understanding of its pathogenesis in order to advance development of disease-modifying treatments. Clinical diagnosis of Alzheimer’s disease remains the main method of identifying the disease but neuroimaging and biomarkers are emerging as adjunct tests in selective cases. Only a few pharmacological treatments are available for Alzheimer’s disease and modest benefits are only observed in the mild-to-moderate disease. Without effective treatment, non-pharmacological approaches and prevention remain important. Nonpharmacological approaches such as exercise, cognitive stimulation therapy and computerized mind games are potentially beneficial in slowing the progression of Alzheimer’s disease. Behavioural and psychological symptoms in Alzheimer’s disease are still challenging to manage and require a combination of non-pharmacological and pharmacological approaches. Several novel therapies are currently under investigation and clinical trials of these agents will reveal if they are beneficial in the treatment of Alzheimer’s disease.

Immunotherapy

The relationship between a host and a pathogen is dynamic, and its outcome depends on the virulence of the invader and the relative degree of resistance or susceptibility of the host at that particular occasion. Fortunately, only an infinitesimal minority of microorganisms are able to avoid the host defenses and eventually cause disease. The host has evolved multifaceted strategies for defending itself against invasion, and pathogens have evolved their own strategies of counter-attack for host defenses pointing us to the co-evolution of “defense” and “attack” mechanisms. Many factors determine the outcome of the bacterium-host relationship. In this battle, the development of antibiotics was a game-changing turn. Unfortunately, more and more strains of pathogenic bacteria have become antibiotic resistant. One of this century’s greatest medical challenges is the rapid emergence of multidrug-resistant pathogens. Discovery of new antimicrobial classes and alternative therapeutic options would be especially welcomed in this era. The fact that some bacterial infections might no longer be successfully treated with antibiotics, combined with an increasing population density and mobility, justifies the urgent demands for the development of novel treatments, of which immunotherapies are considered most promising. Immuno modulatory regimens offer an attractive approach as they often have fewer side effects than existing drugs, including less potential for creating resistance in microbial diseases. Nowadays, treating emerging chronic and multidrug-resistant infectious, autoimmune and oncological diseases through reinforcement of the immune system became a major priority.

Current and Investigational Drugs for Treatment of Alzheimer's Disease

Alzheimer’s disease is characterized pathologically by the presence of neuritic plaques containing β-amyloid and neurofibrillary tangles containing tau. These have become two targets of investigational drugs aimed at preventing or slowing the disease. Early findings of extensive cholinergic degeneration inspired the development of drugs targeting cholinergic function. Cholinesterase inhibitors were the first drugs to be approved for treatment, followed by the NMDA receptor antagonist memantine. This chapter will focus on the development, mechanism of action, and results of clinical trials for drugs currently used or in development for treatment of Alzheimer’s disease. Examples of these include drugs targeting cholinergic neurons, such as cholinesterase inhibitors, muscarinic receptor agonists and nicotinic receptor agonists, as well as memantine. Several drugs aimed at reducing levels of β-amyloid or tau are in development and will be addressed. Finally, drugs directed at other targets that may be useful in treatment of Alzheimer’s disease will be discussed.

Clinical Aspects and The Infectious Process of Anthrax

Systemic infections usually result in the patient reaching “the point of no return”. Among the three forms of anthrax: cutaneous, gastrointestinal, and inhalation, the cutaneous form constitutes 95% of all reported human cases. The clinical aspects of all three forms are presented in notable detail with illustrations. Meningeal anthrax infections resulting in the “red Cardinal's cap” are nearly always fatal. The major known virulence factors in anthrax include the cell-surface-associated antiphagocytic poly-Dglutamic acid capsule, the protective antigen (PA), and the edema (ET) and lethal (LT) toxins. Penicillin G, doxycycline, and the fluoroquinolone ciprofloxacin are considered the drugs of choice for the treatment of anthrax.

Therapeutics Targeting Intracellular Amyloid β-Protein in Alzheimer’s Disease: A Novel Effect of Apomorphine

The amyloid cascade hypothesis is a well known hypothesis describing the pathogenesis of Alzheimer’s disease (AD). Based on this hypothesis, many dugs, which contribute to the inhibition of amyloid β-protein (Aβ) generation and aggregation, or to the enhancement of extracellular Aβ removal, are currently under clinical trials. Intracellular Aβ may be even more important than extracellular Aβ, since intraneuronal Aβ accumulation commonly precedes extracellular Aβ deposition in several familial AD-related mutant presenilin 1-transgenic mice. Various pathogenic mechanisms involving intracellular Aβ such as mitochondrial toxicity, proteasome impairment and synaptic damage have been suggested. In addition, we have reported that intracellular Aβ42 accumulation may enhance p53-related apoptosis. Thus, we searched for a novel drug that promotes degradation of intracellular Aβ, and have recently found apomorphine (APO). In addition, APO treatment improved memory function and AD pathology in an AD mouse model, 3xTg-AD, proving to become a promising cure for AD. In this article, the pathogenicity of intracellular Aβ and potential of APO for the therapeutics in AD are reviewed.

Pharmacotherapies for Alzheimer’s Disease: From Natural Compounds to Target Synthetic Drugs

Alzheimer’s disease (AD) is a most prevalent neurodegenerative disorder and most common cause of dementia, which affects approximately 36 million people worldwide as of 2011 and threatens to be the scourge of the 21st century. AD is characterized by progressive cognitive decline that usually starts with memory deficit and progresses to cause a more generalized cognitive dysfunction, behavioral dysregulation, and neuropsychiatric symptoms, which result in complete loss of life skills and death. The high morbidity and mortality are always the case attributed to lack of effective therapies and prevention strategies because many aspects of its pathogenesis remain unclear. This review discusses the effectiveness and problems with current pharmaceutical treatment. It exemplifies natural compounds and target synthetic drugs as appropriate therapies and formulates rational guidelines for prevention of AD.

Different Approaches in the Treatment of Alzheimer's Disease: Comprehensive Insight

Alzheimer's disease (AD) is a progressive and most common form of dementia. Pathogenesis of AD is multifactorial and yet fully unknown. Proper and on-time diagnosis of this disease is pivotal but however not easy to achieve. Studies indicate that early diagnosis of AD provides best treatment outcomes. Risks for AD include age, genetic, environmental, vascular, life-style factors and low educational income. Novel findings suggest that inflammation, oxidative stress as well as disturbance of immune system may also play significant role in the development of AD. This disease is neuropathologically characterized by presence of neurofibrillary tangles and senile neuritic plaques, amyloid-β peptid deposits and widespread neuronal loss. Main symptoms of AD are cognitive decline, memory loss, altered behavior and language deficit. As they progress in time, these symptoms lead to severe impairment in daily functioning and in later stages AD patients require total care. The aim of this review is to provide a comprehensive insight into the different, currently available, approaches in the treatment of AD. Furthermore, review presents findings of ongoing clinical trials and drug research studies in advanced stages of development and their application in the prevention and treatment of AD.

Based on currently available FDA guidelines, treatment options for AD include acetycholine esterase inhibitors for mild to moderate cases and memantine, an N-methyl-D-aspartate receptor antagonist, for moderate to severe forms of AD. Alongside with symptomatic drugs, novel disease modifying approaches are currently tested such as amyloid-based therapies, inhibitor and/or modulators of secretases, statins, inhibitors of receptors for advanced glycation end products, aggregation inhibitors, erythropoetin derivatives, peroxisome proliferator-activated receptor-gamma agonists and immunotherapy. Furthermore, therapeutic targets in the treatment of AD include approaches directed against tau protein such as tau protein aggregation inhibitors and inhibitors of tau kinases. Anti-inflammatory drugs and antioxidants are also used as neuroprotective advancements in AD therapy. Finally, alteration of ion homeostasis and neuronal regeneration approaches are currently implemented in the attempt to modify AD progression, stop neurodegeneration or enhance neurogenesis.

Even though AD treatment options as stated above are numerous,in majority of cases these drugs produce only modest improvements of AD symptoms and none of the available treatment options can cure or stop disease progression. Only full and complete knowledge of its etiology will provide favorable results in AD prevention and therapy.

Next Generation Drugs in Alzheimer's Disease Treatment: From Benchtop to Bedside

Alzheimer’s disease (AD), the most common cause of dementia in the elderly, is a neurodegenerative disorder characterized by severe and progressive cognitive impairment, including impaired decision making and orientation, inability to perform activities of daily living, language impairment and psycho-behavioural disturbances.

Molecular studies based on interdisciplinary approaches, including biochemical investigations, immunohistochemistry, molecular and cell biology, genetic approaches and animal models, have revealed that AD is a multifactorial disease with many different etiopathogenic mechanisms. The two major AD hallmarks are extracellular amyloid beta (A) plaques and intracellular neurofibrillary tangles (NFTs), but additional pathogenic mechanisms have been described, including inflammation, oxidative damage, iron dysregulation, cholesterol metabolism and other amyloid-independent hypotheses.

There are still no effective treatments to prevent, stop or revert AD: the existing treatments only provide symptomatic relief, but poorly affect the progression of the disease.

Current approved therapy is based on the cholinesterase inhibitors and NMDA receptor antagonists. These treatments are symptomatic and drug discovery has been directed, in recent years, to develop “disease modifying drugs” able to counteract the progression of AD by modifying the evolution of disease. Recent advances on diagnostic criteria for the disease based on biological markers, even in a preclinical phase, can facilitate the identification of new effective therapies, impacting on drug development and monitoring disease progression during therapeutic trials.

The aim of this work is to provide an overview on the main therapeutic approaches, summarizing current treatments and new molecules still under clinical development and also discussing new perspectives on therapeutic intervention.

Immunotherapy with Anti-Aβ Monoclonal Antibodies in Alzheimer’s Disease: A Critical Review on the Molecules in the Pipelines with Regulatory Considerations

Alzheimer’s disease (AD) is the most common dementia in the industrialized world with prevalence rates far over 30% in the over 80 years old population. The dementia causes enormous cost to the social health care systems besides the personal tragedies for the patients, families and caregivers.

One of the pathological protein aggregations that occur in AD is the Amyloid-beta (Aβ) aggregation in extracellular plaques, accompanied by Tau hyperphosphorylation, chronic neuroinflammation and oxidative stress, leading to severe neurodegeneration of brain areas involved in learning and memory. Plaques, thus Aβ, appeared to be the more druggable and promising target for disease-modifying therapeutic strategies like passive immunotherapy with monoclonal antibodies (mAbs) against Aβ, though today it is clear that Aβ is a dreadful target. Meanwhile, the first-in-class mAb Bapineuzumab and the fast-follower mAb Solanezumab failed in Phase III whereas several other candidates – some of them modified 2^nd generation mAbs – now entered Phase I (PF-05236812, BAN2401, SAR228810 and BIIB037) and Phase II (Gantenerumab and Crenezumab) respectively. Others are known to be in preclinical stages. On the first view, the above-cited mAbs cleared or improved amyloid burden and validated the proposed Aβ read-out biomarkers, but have yet not shown relevant improvement in the major aim in AD therapy: cognition. Also, currently under Phase III investigation, are human IgG from healthy donors. The latest, so-called IVIG, are nowadays interestingly reported to stabilize cognition in AD patients.

In this review we discuss the immunological basis for the mechanism of action of passive Aβ immunotherapy, anti-Aβ mAbs and scaffolds in the pipelines and patents, their preclinical and clinical outcome and strategies for 2^nd generation biobetters.

Stem Cell Therapy in Alzheimer’s Disease Models: Neurogenesis Versus Trophic Support

With an ageing population, Alzheimer’s disease (AD) represents a serious social and economic threat to most societies. While AD’s key histopathological features, the amyloid- plaques and the tau tangles, have been described more than a century and the first disease-causing mutations in familial cases of AD already two decades ago, there is still no cure for this debilitating disease. Current treatment is limited to various acetylcholine esterase (AChE) inhibitors and the NMDA receptor antagonist, memantine, yet neither of these strategies halts the degenerative process that characterizes AD [1]. More recently, strategies have been developed that target both amyloid- and tau, but none of these has reached the patient [1]. Here we review what we have learned from animal models about the pathogenesis of AD and treatment options. We further review current attempts to use stem cells to restore the function of degenerating neurons or to replace them.

Meningitis & Encephalitis

Infections of the meninges (meningitis) and the brain (encephalitis) needs to be identified and managed promptly in order to prevent associated morbidity and mortality. Symptoms and signs of raised intracranial pressure are frequently the initial features of meningitis caused by bacterial or viral infections. Encephalitis is more frequently caused by viral infections with features that include seizures, personality change, decreased consciousness, and focal neurological manifestations. As the infection progress, mixed features are frequently encountered (meningoencephalitis). In this chapter, an updated overview of meningitis and encephalitis in infants and children is presented.

Drug Effects on Drug Targets: Inhibition of Enzymes by Neuroleptics, Antimycotics, Antibiotics and Other Drugs on Human Pathogen

This paper reviews the inhibition of various enzymes by neuroleptics, anti-mycotics, antibiotics and other drugs on three species of human pathogenic amoebas, mainly Entamoeba histolytica, Acanthamoeba polyphaga and Naegleria fowleri, and their antiproliferative effects. A recent patent registered by Philip relates to the combination of an antibacterial formulation and antifungal agent for producing a therapeutically effective quantity of an antimicrobial that is suitable for suppressing or treating fungal growth. The rationale behind this patent focused on essential and valid targets with a description of the main pathogenic characteristics of these amoebas. The study of new targets, such as trypanothione and trypanothione reductase, and the drug effects of selected agents were arranged into six main groups: A) Inhibition of disulfide reducing enzymes by neuroleptics, antimycotics and antibiotics; B) Comparative evaluation of the efficacies of several drugs with antiproliferative activities; C) Inhibition of the enzymes for the synthesis of trypanothione, such as ornithine decarboxylase, spermidine synthase and trypanothione synthetase; D) Inhibition of the glycolytic enzyme PPidependent phosphofructokinase (PFK) from Entamoeba and Naegleria by pyrophosphate analogues, different from the host enzyme; E) Inhibition of enzymes secreted by these parasites to invade the human host, for example cysteine proteinases; and F) Inhibition of encystment pathways and cyst-wall assembly proteins.

Legionella and Free Living Amoeba Contamination in Natural Hot Spring Pools in Thailand: Overview

Legionella is important human pathogen.The surveillance for legionella in water reservoir is suggested. Contamination by legionella in natural hot springs may pose a significant health risk to people who use such water for recreation activities.The aim of this work is to summarize the pattern on legionella contamination in hot spring pools in Thailand. According to the search, there are 13 on radon in 83 hot spring pools in Thailand (December 2007). The number of hot springs with legionella contamination is equal to 48 (57.8 %). In addition to legionella, situation on free living amoeba in hot spring pools in Thailand is also presented in this article.

Parasitic Contamination in Water and Soil: A Brief Review

An important problem at present is the contamination of drinking water. In this paper, the author will focus on the parasitic contamination in water and further implication on human health. The important parasites that are usually mentioned as major contaminants will be briefly reviewed. In addition to water contamination, soil contamination is another important problem. Basically, soil contamination with pathogenic parasite is a big public health problem in tropical developing countries. Diseases transmitted by soil are common in many tropical areas, including Thailand. In this article, the author summarized the prevalence of soil contamination with pathogenic parasite in Thailand. According to analysis, overall prevalence of contamination is equal to 7.8 %. There is no significant correlation between setting and prevalence.

Index

The Treatment of Chagas Disease

Presently, the treatment of the infection by Trypanosoma cruzi has been considered unsatisfactory. The eradication of the infection and the interruption of the chronic disease evolution have not been reached by treatment in several clinic and experimental trials. To be unanimous, the indication of determined treatment it should be deposed of undesirable side effects and, even if it did not produce the cure (elimination) of the infection, it should at least stop its evolution. However, the treatment with anti-trypanosome nitro derivatives did not show a clear advantage, when cost and effectiveness were analyzed. Although millions of people with the acute T. cruzi infection do not present a clinic disease, the treatment is clearly indicated in several situations in which the patient’s life is in danger. The controversy on the efficacy of the treatment of T. cruzi infection with the available drugs shows that this is one of the aspects of the investigation on Chagas disease that deserve research incentives. The suggestion that the pathogenesis of the disease is associated to the introduction of kDNA mutations from the parasite’s genome to the host’s defines the need of one or more drugs that are truly effective against the infection. The persistence of the infection, throughout the life of the patient may represent a source of kDNA which introduces cumulative mutations. The effect of these mutations on the evolution of the disease could be avoided with the infection elimination. Maybe, this is an aspect of scientific research with possibilities of generating real benefits to the 18 million people infected by T. cruzi, reminding that one third of them will present clinic manifestations of Chagas disease.