Meningitis

Effect Factors of Meningeal Lymphatics (MLVs)

The regulatory mechanism for meningeal lymphatics is not fully understood yet, but research is ongoing to uncover its functions and regulation. Several factors play a role in regulating these vessels, including:

Circadian Rhythm: There is evidence suggesting that MLVs exhibit circadian rhythms in their function. For example, studies have shown variations in the clearance of waste molecules from the brain via MLVs based on circadian rhythms.

CSF Flow: The flow of CSF is intricately connected with MLVs' function. Changes in CSF dynamics, such as pressure or flow rate, can influence the activity and permeability of MLVs.

Astrocytes: Astrocytes, a type of glial cell in the brain, have been implicated in the regulation of MLVs. They are known to play roles in maintaining brain homeostasis and responding to changes in the brain microenvironment, which can affect MLV function.

Signaling Molecules: Various signaling molecules, including cytokines, growth factors, and chemokines, are involved in the regulation of MLVs. These molecules can modulate the permeability, inflammation, and immune responses associated with MLVs.

Immune Cells: Immune cells, such as macrophages and lymphocytes, interact with MLVs and contribute to their regulation. These cells can influence the inflammatory status and immune surveillance within the meninges, affecting MLV function.

Understanding the complex interplay among these factors is crucial for unraveling the regulatory mechanisms of MLVs and their significance in brain health and disease. Ongoing research aims to elucidate these mechanisms further and explore potential therapeutic targets related to MLVs in conditions like neuroinflammation, neurodegenerative diseases, and brain injuries.Circadian rhythm, CSF, Meningeal lymphatics vessels (MLVs), Regulation, Signaling molecules.

The Role of Meningeal Lymphatic Systems

The meningeal lymphatic system is a newly identified network of lymphatic vessels located within the meninges, the protective membranes enveloping the brain and spinal cord. This system is essential for clearing waste products, supporting immune responses, and ensuring the balance of brain functions.

Biogenic Nanoparticles: A Functional Platform for Antiviral Activity – An Entrepreneurial Approach

Science-based businesses are taking a new dimension today. Biotechnological innovations and inventions are given much attention in transforming laboratory findings into business. Vaccine technology, since the pandemic 2019, has become a billion-dollar business. An integrated approach of nanotechnology and biotechnology as a single unit called Nano biotechnology opens a promising avenue for business opportunities in health care. After the SARS-CoV-2 threat emerged, intensive searches were accelerated to find remedial measures from different systems of medicine. In this search, nanoparticles of both organic and inorganic origin are prioritized, and research in nano -biotechnology gets immediate attention. Laboratory research is intensified to formulate and patent some products to fight against the coronavirus attack. Bio-inspired inorganic nanoparticles are reasonable in using nanoparticles as a workhorse for biomedical applications. The biosynthesized nanoparticles and quantum dots of gold, silver, cadmium, titanium, etc., have multiple biomedical applications. The biogenic nanometal products enhance immunity, fight against viruses, help in diagnosis, and play a role in preparing antiviral dressings, face masks, and drug carriers. This venture promotes promising business avenues.

Biopharma industries are interested in developing the nanotechnology-based therapeutic drug dexamethasone for SARS-CoV-2 drugs; nano-based vaccination to boost immune responses is also progressing. The global market for nanobiotechnology is expected to reach $68.4 billion by 2026. As nanobiotechnology-based business is becoming a promising area for start-ups and entrepreneurs, the stakeholders can utilize the opportunity as quoted “make hay while the sun shines”.

CRISPR-Cas for Genome Editing - Molecular Scissors for Combating Pathogens

Clustered Regularly Interspaced Short Palindromic Repeats, abbreviated as CRISPR, is a genome-editing technology that permits the creation of precise knock-out mutants by aiding the modification of gene sequences devoid of the steps involving the insertion of foreign DNA into pathogenic microorganisms. The microorganisms are ubiquitous in nature and harbor in the complex ecosystem of the human being. Cas (acronym for CRISPR-associated) genes are present in many microbial genomes. The variable nature of the microbial genome has been utilized as an integral typing tool in epidemiologic, diagnostic, and evolutionary analyses of the prokaryotic species. The past decade has seen an accumulating growth in the development of gene-editing tools utilizing the CRISPR-Cas system, which essentially is a part of the prokaryotic immune system. The development of these unique gene-editing techniques has empowered researchers to alter and investigate organisms with ease and efficiency as never before. This editing tool can efficiently be programmed and delivered into the bacterial populations to explicitly eliminate members of a targeted micro biome. Manipulation of the gene expression and regulation of the synthesis of metabolites and proteins can be achieved by utilizing an engineered CRISPR-Cas system. Put together, these tools present with the exhilarating opportunity to explore the complex interaction between the individual species of the microbiome and the host organism and thereby reveal novel avenues for the generation of drugs to selectively target the microbiome. CRISPR-Cas technology has been employed to cope with antibiotic resistance in intracellular and extracellular pathogens. The widespread use of antibiotics and the escalation of multidrug-resistant (MDR) bacteria boost the prospect of a post-antibiotic era, which emphasizes the need for novel strategies to target MDR pathogens. The development of permissive synthetic biology techniques offers favorable solutions to carry through safe and efficient antibacterial therapies.

Unethical Clinical Trials and the Third-World Countries

Although human experimentation has greatly increased our understanding of the human body and diseases, there are still occasions when limits of morality are crossed during clinical trials. Illiteracy, poverty, corrupt health practitioners, and lack of law enforcement in developing countries have led to an increase in the exploitation of people as guinea pigs for trial purposes. These unethical clinical trials in Third World countries have caused an inferiority complex and a general mistrust in the healthcare system. It is the duty of the physician and scientists involved in medical research to protect the life, health, and integrity of research subjects, for which strict regulations are a necessity.

Autoimmune Diseases in Animals

Autoimmune diseases, known as immune-mediated diseases, occur when the immune system targets and attacks its own cells. In the field of medicine, there is a wide range of autoimmune conditions, including insulin-dependent Type 1 Diabetes Mellitus T1DM, Type 2 Diabetes Mellitus T2DM, Rheumatoid Arthritis RA, and Thyroiditis. These diseases can either be primary, with no clearly defined cause, or secondary, triggered by factors such as medications, infections, or malignancies. Animal models have proven invaluable for gaining insights into the underlying pathologies, causes, and specific signaling pathways associated with human autoimmune diseases. This is because these animal models share physiological similarities with humans and have shorter lifespans, allowing researchers to observe the entire disease progression. To replicate the complexity of autoimmune diseases in experimental models, researchers utilize various animal species, including monkeys, rabbits, rats, and mice. These methods can be broadly categorized into three strategies: immunization with autoantigens, transfer of autoimmunity, and induction through environmental factors. Numerous studies have been conducted using animal models to investigate the immunological pathophysiology of RA and assess the effectiveness of anti-rheumatic medications. There are several mouse models designed to mimic RAlike disease, each focusing on specific aspects of the condition. While animal models come with limitations, such as incomplete disease manifestations and limited genetic similarity to humans due to human genetic diversity, they remain an essential tool for understanding the pathogenesis of autoimmune diseases. Among the various animal models used in research, mice and other rodents like rats and hamsters account for over 90% of the total number of animals employed in these studies.

Promising Nano-Carriers-Based Targeted Drug Delivery Approaches for the Effective Treatment of Alzheimer’s Disease

Alzheimer’s disease (AD) is an attained disorder of cognitive and behavioral impingement with progressive symptoms over time. It is mostly witnessed in elderly people, and as per the World Health Organization (WHO), it has affected more than 35 million people worldwide, and this figure is presumed to double by the year 2050. The most commonly believed cause of AD is the accumulation of beta-amyloid, which forms extracellular plaques. Presently conventional therapy for treating cognitive impairments in AD relies on a neurotransmitter or enzyme modulation strategy. Conventional approved drugs, such as acetylcholinesterase inhibitors (memantine, tacrine), are widely available for the treatment of mild to moderate AD, but due to their lower bioavailability, poor solubility, and ineffective capability to surpass the blood brain barrier (BBB), they often fail to produce the desired effect. The potency of conventional AD drugs is highly dependent on various physiological aspects such as BBB; blood-cerebrospinal fluid barrier and drug efflux by P-glycoprotein, which all hampers the capabilities of AD drugs to grasp the central nervous system (CNS). So, in order to conquer the hurdle and these existing limitations faced by CNS drugs to cross the BBB, innovative pathways in drug development have become the need of the hour. Various nanocarriers based approaches profitably meet this demand by improving the efficacy as well as facilitating the sustained release of the entrapped AD drug via targeted drug delivery. The blood-brain barrier offers protection to the central nervous system and also limits the entry of therapeutic molecules to the CNS. On the other hand, nanotechnology offers the possibility to deliver small molecules against CNS disorders across BBB due to their enormous properties, such as small surface area, controllable physicochemical properties, higher drug payload, and better drug circulation time. Plenty of nanocarriers and nanoparticle prodrugs have been reported to have inconsequential cytotoxicity in preclinical studies, and these advancements have proclaimed a new juncture for the development of new classes of nano carriers’ based potent drug formulations for the treatment of AD. A plethora of nanotechnology-based approaches such as polymers, emulsions, lipo-carriers, solid lipid carriers, carbon nanotubes, and metal-based carriers have been redefined over time, and they have been successfully focusing on both neuroprotective and neurogenerative techniques for treating AD. Many researchers also reported that nanotechnological-based techniques can improve the early diagnosis of AD and enhance the therapeutic efficacy and bioavailability of drugs.

Neurological Examination

A neurological exam, also called a neuro exam, is an evaluation of a person's nervous system that can be done in the physcians. It may be done with instruments, such as lights and reflex hammers. It usually does not cause any pain to the patient. The nervous system consists of the brain, the spinal cord, and the nerves from these areas. There are many aspects of this exam, including an assessment of motor and sensory skills, balance and coordination, mental status (the patient's level of awareness and interaction with the environment), reflexes, and functioning of the nerves. The extent of the exam depends on many factors, including the initial problem that the patient is experiencing, the age of the patient, and the condition of the patient.

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Pharmaceutical Potential of Pyrimidines as Antiviral Agents

Antiviral drugs are a class of medicines particularly used for the treatment of viral infections. Drugs that combat viral infections are called antiviral drugs. Viruses are among the major pathogenic agents that cause a number of serious diseases in humans, animals and plants. Viruses cause many diseases in humans, from self-resolving diseases to acute fatal diseases. The strategies for the development of antiviral drugs are generally focused on two different approaches, i.e., targeting the viruses themselves or the host cell factors. Antiviral drugs that directly target viruses include the inhibitors of virus attachment, inhibitors of virus entry, uncoating inhibitors, polymerase inhibitors, protease inhibitors, nucleotide reverse transcriptase, inhibitors of nucleoside and the inhibitors of integrase. The inhibitors of protease (ritonavir, atazanavir and darunavir), viral DNA polymerase (acyclovir, tenofovir, valganciclovir and valacyclovir) and integrase (raltegravir) are listed among the top 200 drugs by sales during the2010. Still, there are no effective antiviral drugs available for many viral infections. There is a couple of drugs for herpes viruses, many for influenza and some new antiviral drugs for treating hepatitis C infection and HIV. This chapter gives an overview of the pyrimidines and hetero annulated pyrimidines that have been reported to be active against viral infections; identification of novel pyrimidine leads may be used in the designing of new potent, selective and less toxic novel therapeutic agents having promising antiviral activity. An effort has been made to compile all the possible information regarding antiviral pyrimidines and bring them together to make easy availability of the existing literature on the subject. The objective of this chapter is to provide the structural and antiviral activity information as well as methods being used for the screening of the antiviral activity and antiviral potential IC50/ED50/CC50 values of the reported active pyrimidines are briefly discussed.

Marine Natural Products as Tools for Discovering New Antimicrobial Targets

The discovery of drugs for human ailments has been greatly attributed to nature ever since the existence of mankind. Continuous isolation of metabolites from terrestrial resources leads to a bargaining effect on the synthesis of novel compounds. Remarkably, marine biotope, one of nature’s resources, accommodates approximately 75% of the global surface. To acclimatize in a marine environment characterized by unique circumstances that diverge from the individuals present in other habitation, marine organisms occasionally accumulate structurally distinctive bioactive secondary metabolites that are deficient in terrestrial organisms. Marine metabolites are currently employed as the key components in pharmacological research and drug discovery, acting as drugs and active lead molecules towards the development of novel antimicrobials. Numerous marine metabolites that are derived from macro and microorganisms have attained the level of clinical assessment. Hence, marine environments are considered tools for discovering new antimicrobial agents as they comprise a vast untapped reservoir of metabolite diversity.

Theranostics Micelles for Brain Tumor Diagnosis and Treatment

Brain cancer is considered one of the most vicious and devastating tumors owing to its poor prognosis and high mortality rate. Common strategies for treatment include surgery, radiation, and chemotherapy. Unfortunately, these are limited due to their invasive nature and the inherent difficulties of brain surgery, given there is a high possibility of tumor relapse. Further, radiation and chemotherapy have a non-selective harmful effect on normal tissues, accompanied by limited drug delivery due to the presence of various barriers, including the blood-brain barrier. For this reason, the theranostic approach was developed by incorporating one or more therapeutic and diagnostic agents in a single nanocarrier moiety which could be modulated at its surface with certain proteins, legend, surface markers, or a stimuli-responsive agent that is capable of selectively targeting the tumor site after passing through the blood-brain barrier. This new field will permit the early and precise detection of cancer tissue, facilitate the process of drug delivery and assist in monitoring treatment outcomes. Micelles are considered one of the most commonly used nanocarriers due to their high stability and loading capacity, along with efficient release controlling properties. This chapter will present brief information about brain anatomy and cancer, and will discuss the main strategies implemented in the diagnosis and treatment of brain cancers. Furthermore, it will introduce the theranostic micelle approach by highlighting micelles types and preparation techniques, as well as explain the different barriers and approaches to targeting.

Anatomy and Physiology of the Brain: Pathophysiology of Brain Tumor

The brain is an efficient processor of information. It is the most complex and sensitive organ in the body and is responsible for all functions of the body, including serving as the coordinating center for all sensations, mobility, emotions, and intellect. The magnitude of its myriad function is often realized usually when there is a disruption of the nervous system due to injury, disease, or inherited predispositions. Neuroscience is the field of study that endeavors to make sense of such diverse questions; at the same time, it points the way toward the effective treatment of dysfunctions. The two-way channel of information: findings from the laboratory leading towards stricter criteria for diagnosing brain disorders and more effective methods for treating them and in turn, the clinician's increasingly acute skills of diagnosis and observation that supply the research scientist with more precise data for study in the lab diligently expands the field of neuroscience. Tumors of the brain produce neurological manifestations through several mechanisms. Stronger hypotheses about the mechanism of a disease can point the way toward more effective treatments and new possibilities for a cure. In highly complex disorders of the brain, in which many factors genetic, environmental, epidemiological, even social and psychological—play a part, broadly based hypotheses are exceedingly useful. With the advancements in technology and a better understanding of brain anatomy and physiology, the quest to discover an efficient cure for life-threatening tumors of the brain is underway.

Nano-cosmetics and Nano-medicines

In today’s fast-moving scenario, nanotechnology has already spread its wings to nanocosmetics and nanomedicines due to the wide range of physical and chemical properties associated with nanoparticles. Different types of nanoparticles, like nanoliposomes, fullerenes, solid lipid nanoparticles etc., have made their entrance into the nanocosmetic industry. However, the safety concern of nanoparticles has forced the cosmetic industry to limit their applications. The pharmaceutical industry has explored the benefits of nanotechnology; it has developed dendrimers, micelles, drug conjugates, metallic nanoparticles etc. The brief explanation of these nanoparticles provides a salient glimpse of why they are used in nano pharmaceutical and medicinal chemistry. • Metallic nanoparticles: Used for drug delivery, cancer treatment, and also in biosensors. • Nano-liposomes: Bio-compatible and possess entrapment efficiency. • Nano-emulsions: Used for controlled delivery of bioactive materials.

Antibody Therapy as Alternative to Antibiotics

In the 1890s, Behring and Kitasato established the principle of serum therapy, which proved useful in treating infectious diseases. However, by the 1940s, serum therapy was abandoned mainly due to complications associated with the toxicity of heterologous sera and the introduction of more effective antibiotics. Although the availability of antibiotics had a tremendous impact on saving lives from infectious diseases, there was a rapid emergence of antibiotic resistance. As a result, an alternative therapy is being given due consideration. With the advent of antibody production technology, antibody therapy has gained interest as a promising treatment for emerging infectious diseases. Some monoclonal antibodies (mAbs) had already been approved for the treatment of certain infectious diseases. Many mAb candidates are currently in different phases of clinical testing for a variety of infectious pathogens. There is hope that antibody therapy may appear as a promising treatment option against infectious diseases in the near future.

Abnormalities of the Central Nervous System

Natural Sources of Immunomodulators

Nature is replete with an arsenal of compounds that can be investigated for their therapeutic potential. The immune system involvement in severe chronic illnesses or emerging infectious diseases has provided clinical evidence. The prevention and treatment of these diseases targeted at the immune system with natural immunomodulators are gaining momentum, owing to their diverse array of activities. Treating acute illnesses with modern medicines has been successful; however, treating chronic illness treatment remains elusive and disappointing. Notably, this chapter reviews the natural resources of immunomodulators. Natural immunomodulators from plants, marine, and animals are of prime importance, and they possess many pharmacological activities. Similarly, microbiota modifiers - prebiotics, probiotics, and micronutrients- are imperative in restoring immune homeostasis. This chapter summarizes these natural immunomodulators and their power to boost immunity and human well-being.

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West Nile Virus and Toll-like Receptors

West Nile Fever is transmitted by West Nile Virus (WNV), which is a single-stranded RNS flavivirus. This disease is transmitted by the bite of mosquitoes. This disease is endemic in various countries in Africa, Asia, Europe and North America [1, 2]. There is no vaccine yet for this disease which is displayed by various symptoms in humans varying from neurological squealae (encephalitis) and meningitis. Apart from this, patients report fever, headache, and myalgia as well.

Deploying Deep Learning Model on the Google Cloud Platform For Disease Prediction

A brain tumor is defined by the proliferation of aberrant brain cells, some of which may progress to malignancy. A brain tumor is usually diagnosed via a magnetic resonance imaging (MRI) examination. These images demonstrate the recently observed aberrant brain tissue proliferation. Several academics have examined the use of machine learning and Deep Learning (DL) algorithms to diagnose brain tumors accurately A radiologist may also profit from these forecasts, which allow them to make more timely decisions. The VGG-16 pre-trained model is employed to detect the brain tumor in this study. Using the outcomes of training and validation, the model is completed by employing two critical metrics: accuracy and loss. Normal people confront numerous challenges in scheduling a doctor's appointment (financial support, work pressure, lack of time). There are various possibilities for bringing doctors to patients' homes, including teleconferencing and other technologies. This research creates a website that allows people to upload a medical image and have the website predict the ailment. The Google Cloud Platform (GCP) will be utilized to install the DL model due to its flexibility and compatibility. The customized brain tumor detection website is then constructed utilizing HTML code.

Tinospora cordifolia in Neurodegeneration: A Strong Antioxidant and Anti-inflammatory Phytotherapeutic Drug Candidate

Tinospora cordifolia is a Rasayana herb of Ayurveda, commonly known as “Heavenly Elixir” or “Amrita”, and one of the most exploited herbs in herbal medicines. T. cordifolia is well reported for its various pharmacological properties, such as anti-diabetic, anti-inflammatory, antipyretic, immunomodulatory, anti-cancer, cardioprotective, neuroprotective, and hepatoprotective activities. The prevalence of neurodegenerative diseases and other neurologic disorders is increasing worldwide. Oxidative stress and neuroinflammation are among the major pathologic mechanisms underlying neurodegenerative diseases. This chapter discusses the pieces of scientific evidence of the beneficial effects of T. cordifolia in various brain-related ailments. Various research groups have demonstrated the ability of T. cordifolia and its extracts to normalize oxidative stress and suppress the inflammatory response against various causative agents, and thus suggested that T. cordifolia has the potential to be a neurotherapeutic drug candidate in the future.

Current Antifungal Drugs

Fungal infections are one of the major causes of fatalities worldwide, causing an estimated 1.5 million deaths annually. Over the past few decades, the incidences of fungal infection have risen with the increase in the cases of immunocompromised patients. However, the impact of fungal diseases on public health is often underestimated. These infections are predominantly caused by the Aspergillus, Candida, and Cryptococcus species. Current therapeutic approaches to treat such fungal infections are limited to five distinct classes of antifungal drugs, viz. polyenes, echinocandins, azoles, pyrimidine analogs, and allylamines. Moreover, a few synthetic molecules are also used as fungicidal agents. Despite the current antifungal armamentarium, the burden of fungal infection is exacerbated by the emergence of drug resistance, host toxicity, and negative interactions with other drugs. The paucity of new antifungal drugs has further complicated the treatment of fungal infections. These limitations provide a rationale for developing novel antifungals preferably with new mechanisms and molecular targets. This chapter thus summarizes the currently used antifungal drugs, their effective combinations, and the challenges inherent to the development of new antifungal drugs. The chapter also addresses strategies to bolster the antifungal pipeline involving emerging new targets for better management of fungal infections.

Emergence of Multidrug Resistance Microbes: Bacteria, Fungi, and Viruses

Increased incidences of multidrug-resistant (MDR) microorganisms has become a global health concern for humans, animals, and agriculture. The advent of newer resistance mechanisms evolving in microorganisms at a high rate compared to the treatments available urges the need to understand its origin and reservoirs. The expanded use of antimicrobial drugs, inefficient diagnosis as well as broad use in agriculture and veterinary contributes to the emergence of resistance in microorganisms. Presently, almost all infectious agents (bacteria, fungi, and viruses) have developed MDR. About 7 lac people die of bacterial resistance to antibiotics every year, with an estimated ~10 million deaths by 2050. Similarly, MDR arising in pathogenic fungi like Candida, Aspergillus, or Fusarium to the limited therapeutic options is highly challenging. Bacteria and fungi develop resistance mainly due to biofilm formation, increased efflux pump activity, drug target mutations, drug binding alterations, chromosome abnormalities, and the ability to escape host immune defenses. The co-existence of MDR bacteria and fungi forming biofilms is even much of an alarm in medicinal applications. Apart from these, drug resistance to current antiviral therapeutics has imposed significant risk amidst life-threatening diseases caused due to viruses like HIV and influenza A. Owing to its severity and complexity, we aim to illustrate the detailed mechanism and evolution of MDR in bacteria, fungi, and viruses. We also review different approaches to deal with MDR, emphasizing alternatives, vaccine development, global surveillance programs and stewardship measures to combat resistance.

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Postoperative Management of Postnatal Complications

The postpartum period is the time after delivery when physiological changes by the pregnancy return to the previous state. Primary postpartum haemorrhage takes place during the first 24 hours, and secondary postpartum haemorrhage occurs between 24 hours and 6 weeks after delivery. Many disorders can occur in the immediate postpartum period, there is a considerable source of morbidity and mortality in women of reproductive age, which can be mild to severe and life-threatening. Protocols aimed at the multidisciplinary management of postpartum haemorrhage, and together with the use of coadjuvant hemostatic agents, the activation of massive transfusion protocols in a responsible manner, and surgical management have improved the prognosis of these patients.

Anesthetic Management of Pregnant Patients with Infectious Disease

Fever is often the result of an infection. The most common sites for infection during pregnancy are fetal membranes, urinary and respiratory tracts, and the postpartum uterine cavity. The most frequent etiologies of intrapartum fever are chorioamnionitis and neuraxial anesthesia. Maternal and fetal exposure to hyperthermia and inflammation is associated with adverse consequences for the mother and the neonate. In pregnant women with fever, anesthesiologists are not only involved in providing analgesia, but also in the correct anesthetic management for the surgical treatment of the infectious region. Thus, as pyrexia may change both obstetric and anesthetic management, preventing maternal fever is imperative. Emerging and challenging infectious diseases, as COVID-19, remind us of the susceptible nature of pregnant and early postpartum women to severe respiratory infections, reinforcing the importance of vaccines and therapeutic measures during pregnancy.

Subject Index

Teething in Children – Fact and Fiction

Teething is a natural process of eruption of the first deciduous teeth. Over the years, teething has been blamed for a wide array of childhood illnesses. Hippocrates (fourth century B.C) and others observed that teething was associated with fever, convulsions, diarrhea, and inflammation of the gums. The association of teething with infant mortality was popular in medieval times. By the twentieth century, the controversy surrounding teething subsided and the morbid conditions initially associated with teeth in infants were found to have other causes. It is assumed that the inflammatory mediators present in the dental follicle are responsible for the local symptoms of teething. The most frequent signs and symptoms associated with teething are irritability, drooling, decreased appetite, sleeping problems, rhinorrhea, fever, diarrhea, rash, and vomiting.

Bioactive Compounds as Therapeutic Intervention in Mucocutaneous Cancers

There are several beneficial effects of plant bioactive compounds in the evidence-based prevention and treatment of mucocutaneous cancers. For instance, several bioactive compounds via various antioxidant and immunomodulatory mechanisms have been shown to positively improve different diseases, including cancer. Considering the complex, multifactorial processes that regulate genetic and cellular function in cancer development, the use of small phytochemical molecules capable of targeting multiple carcinogenetic genes and pathways is plausible. Furthermore, the identification of molecular targets and cognate dietary bioactive molecules in mucocutaneous cancer, using applied combinatorial chemistry approaches, potentially presents a key complementary ancillary tool for developing robust, physiologically bioavailable, diversity-oriented, and cost-effective therapies. These systems biology and omics-based theragnostic tools are crucial for the management of cancers that affect the oral mucous membranes and skin in a resourcelimited setting. Natural products and nutraceuticals are poised to ameliorate the burden of mucocutaneous cancers and improve the drug discovery pipelines if state-of-the-art research techniques are used to elucidate their therapeutic values in the era of precision medicine. Hence, this review focuses on the currently available and potential therapeutic benefits of plant bioactive compounds in the prevention and management of mucocutaneous cancers.

Application of Biomarkers in the Diagnostic Distinction of Bacterial and Viral Infections

Infectious diseases, which pose a great threat worldwide, have a significant impact on public health and the world economy. It contributes to increased healthcare costs, unnecessary drug-related side effects, and increased antimicrobial resistance. It is not always easy to distinguish the etiological differentiation of diseases that can develop with bacteria and viruses. Therefore, one of the biggest challenges in medicine is how to correctly distinguish between the different causes of these infections and how to manage the patient. Because bacterial and viral infections often present similar symptoms. The real decision is whether the infection is caused by bacteria or viruses and whether to treat the patient with antibiotics. There are many different methodological approaches to diagnosing infections. Biomarkers have been used in the diagnosis of diseases and other conditions for many years. Biomarkers are molecules found in blood and body fluids in measurable amounts, which can evaluate biological and pathological processes. These key indicators can provide vital information in determining disease prognosis, predicting response to treatments, adverse events and drug interactions, and identifying key risks. An effective biomarker is extremely important for the early diagnosis of various diseases. The explosion of interest in biomarker research is driving the development of new predictive, diagnostic, and prognostic products in modern medical practice. The purpose of this review is to demonstrate the use and diagnostic potential of current and investigational biomarkers in the distinction between bacterial and viral infections.

Biomarkers and their Clinical Applications in Pediatrics

Biomarker studies are becoming increasingly interesting for many fields of medicine. The use of biomarkers in medicine is involved in detecting diseases and supporting diagnosis and treatment decisions. New research and new discoveries on the molecular basis of the disease show that there may be a number of promising new biomarkers for use in daily clinical practice. Clinical trials in children lag behind adult research both in quality and quantity. The number of biomarkers validated to optimize pediatric patient management is limited. In the pathogenesis of many diseases, it should not be extrapolated to the pediatric clinical setting, taking into account that biomarkers that are effective in adults are clearly different in children and that ontogeny directly affects disease development and therapeutic response in children. The search for ideal biomarkers or markers that can make an early and definitive diagnosis in neonatal sepsis is still ongoing. The ideal biomarker for pediatric diseases should be costeffective, noninvasive, applicable to pediatric specific diseases, and its results should correspond to age-related physiological changes. Lactate, troponin and B-type natriuretic peptide are valuable biomarkers in the evaluation and management of critically ill children with cardiac disease. Tumor markers in children are biochemical substances used in the clinical treatment of pediatric tumors and to detect the presence of cancer (regression or progression). In this chapter, current and brief information about biomarkers and their clinical applications used in the diagnosis and monitoring of pediatric diseases is presented.

COVID-19 in Children and Newborn

COVID 19 has already affected more than 191 million people worldwide and has claimed more than 4 million lives to date (22nd July 2021). Yet, we still do not completely understand this disease. Data on children are even more sparse, making it difficult to lay down a comprehensive guideline for the same.

However, thanks to a handful of studies, we now understand that children are less affected, are less infectious, have lesser mortality and risk of complications. Children with underlying chronic diseases and infants under 1 year are especially at risk and are advised selective shielding. Diagnosis is done by RT-PCR or serology, just like in adults. Most affected children are asymptomatic, and even the symptomatic children have a good outcome and usually need supportive management and monitoring only. Up to 7% of children were found to require PICU support, and mortality was less than 2%. Most deaths were attributed to underlying conditions and immunological complications, especially MIS-C. Treatment is predominantly supportive, with little consensus on specific treatments, including corticosteroids, remdesivir, and IVIg. Management is best individualized by a multidisciplinary team involving pediatricians, hematologists, immunologists, and intensivists. Prevention of COVID 19 can be achieved by proper hygiene, face masks, and social distancing. The upcoming vaccines are expected to bring down the cases and hopefully bring this pandemic to a halt.

Otolaryngological and Ocular Manifestations in COVID-19

An adult patient with COVID-19 usually presents with symptoms of flu like dry cough, myalgia, headache, fever with chills, breathing difficulty and sore throat. Unlike common flu, acute anosmia without nasal obstruction, hyposmia and dysgeusia are considered as early signs and warrant self-isolation and testing. Children usually have milder symptoms with a good prognoses. Nasopharynx and oropharynx being the reservoirs of the viral load, Otolaryngologist becomes the most vulnerable for infection transmission while screening, sampling or operating on any such patient.

Ocular involvement in COVID-19 is extremely low, and manifests mainly as conjunctivitis, in the form of conjunctival hyperaemia, chemosis, increased secretions and/or epiphora. Although it is presumed to be self-limiting, tears are potential source of SARS-CoV-2 transmission. The nature and proximity of ophthalmic examination makes the eye care personnel highly prone to COVID-19 infection. There are reports of ophthalmologists getting infected with COVID-19, and succumbing to this disease. Besides the recommended practice guidelines, surgical interventions in ENT and ophthalmology practice should be limited to urgent and semi-urgent indications.

Controlled Ovarian Stimulation

For conception to occur, whether naturally or via assisted reproductive technology (ART), three things are required; a healthy sperm for fertilization, an ovum released from both ovaries (in the fallopian tubes for natural pregnancy or in the laboratory in IVF/ICSI), and a healthy place for the embryo to implant (a healthy receptive endometrial cavity), so any defect in any of the aforementioned pregnancy requirements will affect the achievement of pregnancy in both types; the natural one or that resulting from ART [1]. Ovarian stimulation is used to overcome any ovulatory disorder or in ART to collect as many eggs as possible (10-15 eggs at least) [2] to maximize the chances of pregnancy. Assessment of ovarian reserve is the first and most important step in ovarian stimulation, as this will indicate the proper method and dose needed for ovulation induction. We test for ovarian reserve using Biomarkers (FSH and AMH) and physical markers (antral follicles count(AFC)) by transvaginal ultrasound(TVS). Both AMH and AFC have similar accuracy in assessing ovarian reserve and are both superior to FSH as they have no cyclic variations [3]. This chapter will discuss all aspects of the physiology of the ovulation process and ovarian stimulation.

Brief Description of Public Health and Burden of Neurodegenerative Diseases

Physical and mental well-being is treasure for mankind in a competitive and progressive global scenario. For a country, result oriented tasks can be accomplished only with its healthy population. Along with many diseases of global concern, neurological disorders have drawn concern globally as these are sharing an increasing proportion in global burden of diseases. Further cases of neurodegenerative disorders, majorly affecting aged population, have been recently reported to record a considerable increase which has complicated the health and care-giving (old age homes) services as part of public health. Many public health policies have been laid down by many developed and developing countries in accordance of WHO guidelines which in turn based on GBD studies, made till date. Major share of neurodegenerative disorders is contributed by Alzheimer’s Disease, Parkinson’s Disease, Amyotrophic Lateral Sclerosis & Multiple Sclerosis. The recent past has witnessed growing number of deaths and disability adjusted life years, DALY, caused by neurodegenerative diseases. Public health services and related government policies are not enough, according to WHO, to properly address the current situation. Lack of public awareness towards neurological disorders of all kind, is one of the major challenges to Figure out actual data; for prevalence of neuro-disorders.

Emerging Therapeutic Approaches for Neurodegenerative Diseases

The most common neurodegenerative diseases (ND) include Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD), as well as frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Protein misfolding and aggregation are the key hallmarks of these neurodegenerative diseases, which may lead to cell death, axonal regeneration failure, demyelination, and overall neuronal structural and functional deficits. Usually, ND is diagnosed at a very advanced stage and conventional therapies are directed at treating neurological symptoms but have no effect on disease progression. In general, several pathological processes contributes to misfolding proteins/protein aggregates and their postconsequences, including impairment of autophagy, microtubule destabilization, neuroinflammation, proteostasis, mitochondrial dysfunction, oxidative stress, endoplasmic reticulum stress, calcium homeostasis, and neurogenesis impairment. Indeed, several signaling pathways critically linked with these pathological processes are now becoming attractive targets and investigated for their beneficial effects by restricting the progression of ND. In particular, certain signaling mechanisms and proteins found to show an integral involvement in the pathogenesis of ND and had shown promising results in preclinical and/or clinical contexts. For ex; novel autophagy stimulators, drugs acting on mTOR, NRF2, TLR, purinergic signaling; drugs acting on neuroinflammatory signaling pathways, Heat Shock Proteins (HSP), sestrins, sirtuins, some PDE-inhibitors, miRNA’s have gained a lot of attention in the therapy of ND and are included in the following discussion.

Subject Index

Mitochondrial DNA and Streptococcus pneumoniae Infection – Induction of Immuno-inflammatory Response

Streptococcus pneumoniae, or pneumococcus, is one of the leading causes of morbidity and mortality associated with lower respiratory infections. Usually, it colonizes asymptomatically the human upper respiratory tract, but it can eventually migrate to other body sites to cause invasive and non-invasive diseases. The polysaccharide capsule (CPS) is the main pneumococcal virulence factor and it is used in the currently available vaccines against this pathogen. However, novel therapeutic and prevention approaches are urgently needed to target emergent non-vaccine serotypes, especially those associated with antimicrobial resistance. Besides CPS, pneumococcus has several other virulence factors that contribute to its pathogenesis, including surface proteins (e.g., CbpA), the pore-forming toxin pneumolysin (PLY), as well as enzymes that produce hydrogen peroxide (H2O2). Here, we describe the pathogenesis of pneumococcal infections as well as host cell molecular signaling, focusing on major molecules responsible for host cell invasion and translocation, and disturbance of mitochondrial function, resulting in mitochondrial DNA (mtDNA) leakage, inflammation and tissue damage. Understanding molecular and immunoinflammatory mechanisms underlying pathogenesis and pathogen-host cell interactions is crucial to developing novel approaches to prevent and treat pneumococcal diseases.

Early Detection of Crop Fungal Pathogens for Disease Management using DNA and Nanotechnology Based Diagnostics

Virulent fungal plant pathogens are a serious threat to crop productivity and are considered a major limitation to food security worldwide. To meet these challenges, pathogen detection is crucial for taking appropriate measures to curb yield losses. Disease diagnosis at an early stage is one of the best strategies for crop protection. Earlier, traditional methods were used to diagnose and manage fungal diseases, which included visual scouting of the disease symptoms and spray of fungicides. The utility of immunoassays for early detection and precise identity has been appreciably stepped forward following the improvement of enzyme-connected immunosorbent assay (ELISA) and monoclonal antibodies. Nucleic acid-based diagnostic techniques have turnout to be the preferred type because of their greater speed, specificity, sensitivity, reliability, and reproducibility. The biosensor eliminates the need of sample preparation and can be used for on-site detection of fungal pathogens at latent infection stages so that preventive measures can be taken. Currently, multiple human and animal diseases have been detected with the help of biosensors. However, reports on plant pathogen detection using biosensors are still in infancy. Despite many applications of antibodies, there are also multiple drawbacks, including high cost, low physical and chemical stability, and the ethical issues associated with their use. Now, DNA based biosensors are gaining popularity because of their sensitive and precise detection of DNA target sequences. Immunological and DNA-based techniques combined with nanotechnology offer highly sensitive and selective gel-free detection methods, and the lab-on-chip (LOC) feature of biosensors makes them a very reliable tool in crop protection.

Principles of Respiratory Diseases - Tuberculosis a Brief Study

Tuberculosis (TB) is one of the worst lung infections caused by bacteria

called Mycobacterium tuberculosis. It is a disease that can be controlled in cases where

it is quickly identified and treated. As sputum microscopy is a simple and low-cost

approach, most countries use this technique as an initial step in the diagnosis of TB.

For this, the patients' morning sputum is collected and submitted to the Ziehl Neelsen

staining procedure before the examination. Then a digital microscope is used, where

the images of the sputum slides can be recorded for analysis. In this context, numerous

research projects have been developed in the field of computer-aided detection of

mycobacteria for pulmonary tuberculosis. The survey of these works was discussed

here in this work, as well as their limitations.

Neuropathological Features of Covid-19

In December 2019, the world witnessed the spread of a new pandemic from the Wuhan city, China, which was later known as Coronavirus disease (COVID-19) caused by SARS-CoV-2. The main effects of Coronavirus disease (COVID-19) have been reported on human respiratory and cardiovascular systems, but neurological impacts have also been witnessed in most of the patients. Some common symptoms of COVID-19, such as stroke, anosmia, and dysregulation of breathing, are somehow related to the neuropathological processes. The detailed studies dealing with the neurological impacts of COVID-19 have revealed that the central nervous system is affected by SARS-CoV-2. Still, this disease also impacts the peripheral nervous system (PNS) and the muscles as well. T Guillain-Barré syndrome, Miller Fisher syndrome, polyneuritis cranialis, and viral myopathy with rhabdomyolysis are some of the diseasesthat affect muscles and the peripheral nervous system (PNS), but these diseases are usually less frequent. Usually, the symptoms of Coronavirus disease (COVID-19) impacting the neurological system are reported in cases of severe illness. Thus care must be taken during the treatment of Coronavirus (COVID-19) patients. A careful diagnosis is key before starting the treatment. This chapter aims to discuss the neuropathological impacts of the infection caused by SARS-CoV-2.

Conclusion, Outlook, and Prospects: Bionanomaterials in Clinical Utilization

Nanomaterials have contributed to significant advancements in the realms of biotechnology and medicine. A holistic examination of the different biocompatible nanocomposites is discussed in this chapter. Their compatibility with state-of-the-art engineering techniques, such as additive manufacturing to design practical surgical implants, is also discussed. The importance and potential of nanocomposites and manufacturing processes in implantable medical device industries are also thoroughly considered. Nanomaterials' unique characteristics contrast with their large counterparts, such as high surfaces, reactivity, and reproducibility. Their incorporation in matrices has shown that the resultant composites' mechanical, chemical, and physical properties can be improved.Consequently, a wide variety of technical technologies, such as energy products, biomedical applications, micro-electrical equipment etc., have been intensively researched. Furthermore, the foundation for many new medicines and surgical instruments, including nanorobots, has been built on nanobiotechnology. It has been utilized in almost every medical sector, and its usage in the treatment of different diseases, such as cancer, neurobiology, cardiovascular disorders, joint and bone disorders, eye diseases, and infectious diseases, has been evident through different studies. Nanobiotechnology can promote diagnostics and the advancement of customized medicine, i.e., prescribing unique therapeutics that are tailored to an individual's needs. Many advances have already begun, and a definite effect on medicine practice will be felt in a decade.

Infectious Diseases: Pharmaceutical Nanoscience Targeted Drug Delivery

Infectious diseases are one of the greatest challenges of our new era. Due to their high incidence and outbreak rate, they can affect human health. Furthermore, the use of conventional drugs to treat infectious diseases is gradually being exhausted due to increasing rates of resistance. Herbal medicines and natural ingredients may also be a good resource for drug production. Several innovations, including the development of nano-drug delivery systems, have new mechanisms of action and various loadings for herbal and non-herbal treatments; this helps decrease the pathogenicity of infectious diseases. In addition, these nano-drug delivery systems provide a good opportunity to improve the efficacy of herbal and non-herbal treatments. They have also been used to deliver target medicinal agents, increase solubility, improve bioavailability, extend half-life for herbal and non-herbal treatments, increase stability, minimize adverse effects, and tissue engineering. Nanocarriers are advanced engineering tailors that control the physicochemical properties of nanoparticles for infectious diseases, leading to targeting by passive or active mechanisms. In this chapter, we highlight the advances in nanocarriers loaded with herbal and nonlherbal agents for treating infectious diseases.

Introduction to Nanotechnology and Herbal-Based Nanoparticulate Systems

This introductory chapter reviews the history of nanotechnology and its benefits and challenges in the pharmaceutical field. In general, the chapter summarizes the types of nanoparticles and the techniques used to formulate nanoparticles. In detail, it discusses the principle of nanotechnology in improving solubility and dissolution rate. It discusses and describes different types of nanoparticles, including polymeric, metallic nanoparticles, and other types, such as solid lipid nanoparticles (SLN) and liposomes. Nanosization can be performed by various techniques, including top-down, bottom-up, and combination techniques. The method of these techniques has been discussed in this chapter. One of the disadvantages of nanoparticles is their stability. Nanoparticles suffer from various types of instability problems, including aggregation, sedimentation, and crystal growth. Therefore, in this chapter, the authors discuss the problem of stabilization of nanoparticles and describe the different pathways of physical instability and the mechanism of stabilizers to stabilize the colloidal system. Finally, the importance of herbs and natural products in the medical field and how the use of nanotechnology addresses various drawbacks of herbal products are also discussed.

Antimalarial, Antibiotics, Antibacterial and Antifungal Drugs

This chapter deals with the class of aminoquinolines or quinolone

antimalarial, antibiotic, antibacterial and antifungal drugs. Brand names of the

antimalarial agent (e.g. Chloroquin, Primaquine), antifungal agent (e.g. Fluconazole),

antibiotic agent (Nalidixic acid, Norfloxacin, Chloramphenicol), antibacterial and

antifungal agents (Sulphonamides, Sulfamethoxazole, Sulphacetamide, Trimethoprim)

along with the uses, mode of action and side effects have been discussed in this

chapter. Various synthetic methods have shown for these drug molecules. Different

types of name reactions have included as the key for their synthesis.

Updates on Pediatric Demyelinating Disorders

Myelin is a protective layer that enwraps the axonal terminals and is an essential component of the central nervous system white matter. Loss of myelin leads to conduction block in the axon leading to demyelinating disorders. Inherited poor formation of myelin is known as hypomyelination, and abnormally formed myelin is called dysmyelination. Demyelinating disorders exclude diseases where degeneration of the axon is the initial event and myelin is degraded secondarily. Most neurologists use the term demyelination only for acquired forms of loss of myelin with relative preservations of axons due to inflammation such as multiple sclerosis. Demyelinating disease in children may be monophasic (e.g., acute disseminated encephalomyelitis, optic neuritis, and transverse myelitis) or chronic (multiple sclerosis and neuromyelitis optica). Pediatric multiple sclerosis is the most common demyelinating disorder in children. Recent genetic and clinical researches have significantly improved our understanding of the diverse spectrum of pediatric demyelinating disorders. In this chapter, an updated summary of the current knowledge on the categories, diagnosis, as well as management of pediatric demyelinating disorders has been presented.

Updates on Pediatric Epilepsy Syndromes

This chapter examines the basics of pediatric epilepsy syndromes and the new factors in the field that lead to and result from the disturbed function. Some disorders such as febrile seizures and idiopathic seizure disorders are fairly common in children, and pediatricians should be familiar with the approaches used to investigate such disorders. However, others, such as rare genetic diseases, are increasing in incidence due to the recent advances in genetic testing and personalized medicine. Nevertheless, epilepsy syndromes carry significant morbidity and even mortality in children. The advent of new genetic discoveries has also brought forth new lines of management for previously refractory diseases. The truly intractable epilepsy syndromes might be managed with surgery as a final resort.

Updates on Common Oral Diseases in Children

Oral and dental diseases are among the most common problems in children worldwide. If these problems remain untreated, they can have long-term effects on the orofacial system, chewing and speaking abilities, oral health-related quality of life, and overall health status. Dental caries, periodontitis and gingivitis, dental malocclusion, dental trauma, and some oral soft tissue lesions are among the most common oral disorders in children. Early diagnosis and management of these conditions by pediatric dentists and pediatricians necessitate being aware of the clinical manifestations of each disease at every age. Implementing preventive intervention, accurate diagnosis, proper treatment, and performing regular follow-ups are among the key factors for eliminating harmful long-life consequences of poor oral and dental health status in children and adolescents.

Introduction of Common Pediatric Diseases

Pediatric health has improved over the past decades and there is a decline in deaths caused by infectious diseases. Yet, the top three causes of disease in children younger than 10 years in 2019 include neonatal disorders, lower respiratory tract infections, and diarrheal diseases. While in the adolescence age group, the major causes are road injuries, headache disorders, and self-harm. Preterm birth complications, pneumonia, and birth asphyxia are the most leading cause of death in children under five years. While in the five to nine years of age group, injuries, including road traffic injuries, drowning, burns, and falls, are the leading causes of death.

Modulation of Mesenchymal Stem Cells, Glial Cells and the Immune System by Oligodeoxynucleotides as a Novel Multi-target Therapeutic Approach Against Chronic Pain

Despite our growing understanding of chronic pain mechanisms, an

alarming proportion of patients worldwide remains refractory to treatment. Chronic

pain is complex, involving the interaction of both neuronal and non-neuronal systems.

Several studies focused on immune, glial and mesenchymal stem cells (MSCs) have

recently revealed key roles of these non-neuronal players in the initiation and

perpetuation of chronic pain. The complexity of chronic pain is reflected by the

difficulty of its therapeutic control, in particular when using mono-target drugs. A good

proportion of these drugs target neuronal pathways, and serious concerns arise when it

comes to the use of opioids and abuse liability. In contrast, novel pain drugs targeting

non-neuronal components of chronic pain are scarce. Exceptions include classical nonsteroidal

anti-inflammatory drugs, or those modulating trophic factors, although their

use remains restricted to the presence of appropriate targets. Synthetic

oligodeoxynucleotides have been used as immune system modulators for the last 15

years. One of them, IMT504, a non-CpG oligodeoxynucleotide, exhibits remarkable,

long-lasting anti-allodynic and anti-inflammatory properties upon single-dose systemic

administration in rodent models of inflammatory or neuropathic pain. Mounting

evidence suggests that the beneficial effects of IMT504 relate to actions on the immune

system, glial cells and MSCs. In this state-of-the-art chapter, we address the current

knowledge of the role of IMT504 over non-neuronal cells, its impact on chronic pain,

and its translational potential. We also propose that further analysis on its mechanisms

of action will be key to the identification of novel and effective multi-target pain drugs

without abuse liability.

Subject Index

Nanoformulations and Their Therapeutic Advantages

Cancer therapy involves nanomedicine, which can provide a plethora of

advantages unattainable via conventional medicine as the materials of nano-level

exhibit unique physicochemical and biological properties. Both cancer therapy and

cancer therapy research utilize nanoformulations based on liposomes, polymeric

nanoparticles, solid lipid nanoparticles, metal nanoparticles, dendrimers, and

nanoemulsions for facilitating high specificity negating off-target toxicity, prolongedrelease

maintaining drug concentration and reducing dosing frequency, increased

solubilization and absorption, and penetration of impermeable barriers. The entrée to

this chapter is thus made with a brief description of nanomedicine, which is followed

by a description of the designing of nanoformulations for therapeutics. Explanations on

the types and advantages of nanoformulations are also given. The second section of the

chapter describes nanoformulations as therapeutics for cancer, explaining the different

targeting strategies and novel approaches involving nanoparticles. Like numerous other

cancers, nanoformulations are researched extensively in therapy for hepatocellular

carcinoma, the second leading cause of cancer-related deaths. The final section of the

chapter deals with the therapeutic advantages of nanoformulations in hepatocellular

carcinoma. The prominent nanomaterials investigated in hepatocellular carcinoma

therapy include nanoparticles of biopolymers, nanoparticles of artificial biodegradable

polymers, metallic nanoparticles, carbon nanotubes, and mesoporous nanoparticles.

Targeting of drug-loaded nanoparticles is achieved in therapy for hepatocellular

carcinoma via passive targeting and/or active targeting. A key milestone in

hepatocellular carcinoma therapy is the approval of the drug Zinostatin stimalamer, an

emulsion-based formulation, by the Japanese Ministry of Labour, Health, and Welfare.

Subject Index

Neuropsychiatric Systemic Lupus Erythematosus (NP-SLE)

Neuropsychiatric systemic lupus erythematosus (NP-SLE) is one of the most

serious organ complications of SLE, affecting health, quality of life, and prognosis of

life in patients with SLE. Neurological symptoms are various. Among the pathological

conditions of SLE, those including neurologic syndromes of the central nervous

system, peripheral nervous system, and diffuse psychiatric and neuropsychiatric

syndrome are called NP-SLE in the American College of Rheumatology (ACR)

nomenclature. In NP-SLE, such a variety of pathophysiology should be considered

when selecting a treatment. In this article, we describe the neurological lesions of SLE

with illustrations.

Immunotherapy of Sepsis

Sepsis is a clinical condition that occurs due to dysregulated fundamental

host reaction to an infection, resulting in organ dysfunction. Proinflammatory

mediators are related to indications watched early in patients with sepsis. In spite of

decades of investigation, the morbidity and mortality of sepsis stay exceptionally very

high. Regardless of the recognition of numerous prospective targets in the complex

immune response pathways, no specific immunotherapeutic medicines are at present

accessible. Presently, immunosuppression in sepsis is a subject matter of strong

research amongst various pre-clinical and clinical studies. In fact, an improved

consideration of a patient’s immune status on a constant basis will plausibly allow

focused immunotherapy. This book chapter provides an overview of the epidemiology,

etiology, pathogenesis of sepsis and gives an outline of the challenges in

immunotherapy for patients suffering from sepsis.

From Cells to Clinic - Direct Biomolecule Quantification of Clinically Relevant Biomolecules

Translation of investigative cellular analysis into reliable clinical settings is

a challenge and surface enhanced Raman spectroscopic (SERS) technique has the

potential to move beyond laboratorial examinations. Quantitative and qualitative

measurement of cellular components and their properties is essential indicative of

healthy or disease state. Pre-emptive analysis of diseased state offers synchronization

with early diagnosis of certain medical conditions and is requisite for initiation of

therapeutic interventions. High sensitivity and capacity for multiplexing renders SERS

suitable for biochemical analysis for disease diagnosis a critical step towards

formulation of therapeutic regime. SERS assists in a deeper understanding of cellular

processes and its micro environment without disturbing and damaging the cellular

milieu in 3 dimensional (3D) set up without invading the tissues. Fabrication of novel

nanostructures with enhanced plasmonic effects has also propelled the growth of SERS

based analysis of cellular structure in normal and abnormal circumstances. Thus, SERS

is operating as diagnostic tool for in-vitro, ex-vivo and in-vivo investigations for

assessing onset of disease as well as prognosis of the therapy in hospitals and clinics.

Application of Raman Spectroscopy in Amyloid Research

Raman scattering spectroscopy was discovered in 1928 by CV Raman and

KS Krishnan. The technique has developed enormously and it is becoming useful in

many ways for studying biochemical events and structural intricacy of biological

macromolecules such as RNA, DNA, protein and their assemblies. The focus of this

review is on the recent application of Raman spectroscopy to research achievements of

protein aggregation and fibrillation of several proteins and peptides. Particularly we

analyzed the protein secondary structure of different assembly structures captured in

the fibril formation pathway with a particular focus on oligomeric intermediate which

is believed now to be most cytotoxic. This intermediate structure attains characteristic

morphological features while the constituent protein may/may not differ much in their

secondary and tertiary structure in the native physiological conditions. Conformation

states of proteins in the oligomeric state obtained by Raman spectroscopic analysis,

particularly aid in comprehending the structure of the oligomer and overall mechanisms

of fibrillation and amyloid formation. It has been established that the backbone amide

band and side-chain vibrations of amino acid residues present in protein molecules

largely affected the fibril formation pathway and it follows a concerted reaction

pathway, i.e. the protein molecule transform into β- sheet rich amyloid fibril via

formation of an oligomeric intermediate. However, the intriguing and interesting fact is

that the proteins maintain/attain some helical pattern in the oligomeric step. Raman

analyses established the distribution of residues in both helical and β-domain, possesses

similarity with molten globule like structure. However, in the fibrillar state, the protein

backbone attains anti-parallel β-sheet structure and several side-chain residues may be

exposed on the surface of the protein and it is evidenced in the Raman spectra of the

fibrils. The review particularly focuses on the aggregation and amyloid-like fibril

formation of hen egg-white lysozyme (HEWL) and discusses different aspects of fibril

formation mechanisms based on Raman spectroscopic data analysis.

Subject Index

Immunoinformatics and its Role in Vaccine Development

Immunoinformatics is currently an emerging field that has accelerated immunological research to a great extent. It is playing a significant role in antigen identification, immunodiagnostic development, and vaccine design. The arrival of genome sequencing with recent advancements in immunoinformatics has provided a lot of data that can be annotated using databases and tools to reduce the cost required for antibody and vaccine development, ultimately saving time, cost, and resources. The selection and identification of immunogenic regions from the pathogen genomes by computational methods play an important role in devising new hypotheses by a comprehensive examination of immunologic data composite, which is otherwise impossible to achieve by using traditional methods alone. Presently, many epitopebased vaccines, especially multi-epitope vaccines designed employing immunoinformatics approaches, are successfully trailed and being developed against pathogens. In this chapter, we provide an outline of the recent progress in the field of vaccinology and immunoinformatics, enlisted recent tools and databases available for epitopes prediction, validation, and vaccine design, and give a brief description of the role of immunoinformatics in vaccine design against recent COVID-19.

Nanotherapeutics in Cancer Treatment

Nanotherapeutics is an advancing technology and promising industry of the 21st century; with further development, it may hold secrets for the medical community and society as a whole. The development of nanotherapeutics into medicine is one of the newest developments in medical science that the scientific community has taken. The conventional approach of delivering anticancer drugs towards the targeted site is remained controversial and has numerous problems such as non-specific effects to the surrounding organs other than cancer affected, anticancer drug resistance, and chronic adverse effects. Recently, biomedical scientists have turned their attention towards nanocarriers possessing incredible activity to deliver anticancer drugs towards canceraffected areas without being disrupted by endogenous barriers, rendering lesser toxicity and promoting anticancer response. In this chapter, the overview of nanotherapeutic agents is thoroughly assessed in the treatment of cancers.

Subject Index

Phage Therapy as an Alternative Antibacterial Therapy

Antibiotic resistance is one of the growing concerns in healthcare settings. Most of the clinical and community (bacterial) strains have grown immune to almost all the available antibiotics. The discovery of new antibiotics or resurging of available antibiotics has failed to outcompete the growing resistance within the bacterial community. Thus, finding an alternative antibacterial modality to treat infectious diseases has become a significant objective among the scientific community around the globe. Phage therapy is one such an antibacterial therapy for the treatment of severe bacterial infections. The bacteriophages (or phage) are viruses that prey on bacteria for their multiplication and survival. Discovery of bacteriophage dates back to the early 1910s when Frederick W. Twort and Felix d'Herelle observed bacteriolytic activity. Before the discovery of antibiotics, phages were the choice of treatment against bacterial infections, but with the inconsistent research, phage therapy lost its importance in the therapeutics. With the emergence of antibiotic resistance, phage therapy and phage research has got a shape to revolutionize the growing bacterial infections. Phage therapy has shown promising results against severe bacterial infections in the circumstances where antibiotic treatment is ineffectual. This emergency has shed light on this forgotten therapy. This chapter will elucidate the history and fundamentals of phage biology and its significance in treating infectious diseases. With the special focus on advancements in phage research and their clinical outcomes which supports the use of phage therapy in humans. It also deals with the regulatory inputs required for phage therapy and the commercialization strategies undertaken by pharmaceuticals in the globalization of phage medicine. Besides, the authors would like to brief on the personalized phage therapy and their evolution from lab to bedside endpoints for treating the patients and other future perspectives that hold promise.

Leptospirosis - A Complete Review

Leptospirosis is a rare but neglected bacterial infection that affects people and animals. It is caused by bacteria of the genus Leptospira. The disease was reported as early as 1886 by Adolf Weil. Leptospirosis may cause kidney damage, meningitis, liver failure, respiratory distress, and even death when it is not treated. Occupations at risk include surfers, slaughterhouse workers, farmers, sewer workers and, people working on derelict buildings. Amjad Islam et al. had reported that among Asian countries, its highest prevalence is found in India. In 2015, Federico Costa et al. estimated that leptospirosis causes 1.03 million cases worldwide each year. The pooled mortality rate is 25%. WHO has estimated that 0.1 to 1 per 100 000 people living in temperate climates are affected each year, with the number increasing to 10 or more per 100 000 people living in tropical climates. It is reported in all continents except Antarctica. Lesser availability of treatment resources is detrimental, and unfortunately, it is commonly reported in lower-middle-income group countries.

The current treatment modalities for milder cases of leptospirosis rely on antibiotic administration viz penicillin, ampicillin, cefmetazole, oxalactam, ceftizoxime, and cefotaxime.

Whereas, in severe cases, intravenous penicillin G has long been the drug of choice; the patients treated with penicillin for the management of this disease are to be monitored throughout the treatment to prevent the severe threat of potential Jarisch-Herxheimer reactions. In particular, this immune-mediated hypersensitivity reaction may occur within 4-5 h after administration of penicillins. Various kinds of human leptospirosis vaccines have been developed, including inactivated whole-cell, outer-envelope, and recombinant vaccines. Of these, only a multivalent inactivated leptospirosis vaccine (killed vaccine) is available in China, Japan, and Vietnam. However, human vaccines for leptospirosis are serovar-specific and require yearly boosters. So there is a need for the development of novel compounds which have leptospirocidal activity. Notably, drugs for treating leptospirosis are minimum; the present research for the development of novel lead compounds for this pathogen is very limited.

This review aims to summarize the most recent literature on synthetic lead molecules, natural products for its treatment, drug targets, etc., and provide recommendations to researchers who may encounter difficulties in finding details on the subject.

Reverse Vaccinology Approaches for Rapid Vaccine Design Against Emerging Infectious Diseases

Reverse vaccinology uses computational approaches to identify potential vaccine candidates. With the increasing pace of genome sequencing, it is possible to identify all potential antigens from any sequenced pathogen. Reverse vaccinology uses computational data to identify potential antigens, express those potential antigens, and then screen them further for protective immune response. Thus, reverse vaccinology offers several advantages and enables identifying novel antigens even if the expression level is low or not abundant. Besides, reverse vaccinology approaches offer reduced time and reduced cost for the development of vaccines compared to conventional vaccination methods. Such a timely, speedy, and economical process for developing vaccines without compromising safety and immunogenicity is the urgent need of the hour to combat many emerging pathogens, including SARS-CoV-2. This chapter summarizes approaches and challenges in developing vaccines against many emerging pathogens, including SARS-CoV-2, by employing this innovative strategy.

Unusual Clinical Aspects of Vitamin Hypersensitivity

Although immediate-type hypersensitivity and allergic contact dermatitis have been mainly reported following vitamins or multivitamins intake and exposure respectively, more rarely unusual immune-mediated adverse reactions such as fixed drug eruption and other more serious hypersensitivity syndrome are described in the literature, but their diagnostic approach is more difficult because skin tests in severe cutaneous adverse reactions are validated for few drugs as anti-convulsivant agents.

Subject Index

Neurosurgery

This chapter will provide a broad overview of the more common pediatric neurosurgical conditions seen in a children’s hospital setting, with the exception of trauma. Emphasis will be placed on conditions in which the pediatric surgeon and neurosurgeon interface in the care of the child. Also, tips on what to do when a neurosurgeon is not available will be discussed. Extra effort will be spent explaining the various devices pediatric neurosurgeons implant that can very well complicate anticipated or unanticipated general surgical procedures.

Abdomen

In this chapter we discuss common and unusual conditions of the abdomen that are treated surgically, related to the stomach, small intestine and colon. Such as Hypertrophic pyloric stenosis, is one of the most common surgical conditions of the newborn. Congenital intestinal obstruction occurs in approximately 1 in 2000 live births and is a common cause of admission to a neonatal surgical unit. Normal rotation of the intestine requires transformation from a simple, straight alimentary tube into the mature fixed and folded configuration normally present at birth. Through precise embryologic events, the duodenojejunal junction become fixed in the left upper abdomen while the cecum is anchored in the right lower quadrant. The midgut, defined as the portion of the intestine supplied by the superior mesenteric artery (SMA), is thus suspended from a wide mesenteric base.

Differential Diagnosis of COVID-19

Differential diagnosis is a key step to treat and prevent any disease at current. Differential identification becomes more inevitable in diseases that become pandemic while their signs and symptoms overlap with many diseases. Coronavirus disease-19 shows resemblance in its pneumonic presentation with related coronaviruses (SARS virus, and MERS virus), adenovirus, influenza virus, human Metapneumovirus, parainfluenza, Respiratory Syncytial Virus, rhinovirus, bacterial pneumonia (Streptococcus pneumonia, Haemophilus influenza pneumonia, Moraxella catarrhalis pneumonia, and Chlamydia pneumonia), and Mycoplasma pneumonia. Contrary to the discussion of only diagnostic findings, a comprehensive approach of differences in aetiologies, transmission/epidemiology, pathogeneses, clinical signs, and response therapy is necessary to resolve pandemic corona infection. Additionally, mathematical predictive models calculate the reproductive number (R0) to show the epidemic nature of the disease in comparison to other conditions, thus aids therapeutic and prevention measures. The current chapter differentiates minor and major differences of COVID-19 compared to viral and bacterial diseases that show similar signs and symptoms.

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.

Subject Index

Cerebrospinal Fluid (CSF)

Learning objectives:

1. Describe all characteristics of Cerebrospinal fluid.

Various Body Fluids

Learning objectives:

1. Describe Cerebrospinal fluid.

2. Discuss Synovial fluid.

3. Explain different exudates in body.

Azadirachta Indica (Neem) in Various Infectious Diseases

The 21st century is witnessing a war between mankind and microorganisms. The worldwide outbreak of infectious diseases is responsible for morbidity and mortality. The pharmaceutical industry has limited drugs in the pipeline against infectious diseases. Resistance of microorganisms against already available drugs is another concern. An initiative from researchers to search for new ways to prevent or treat infectious diseases is necessary. Many herbal drugs are known to be effective against pathogenic organisms from ancient times. Repurposing of herbal medicines for infectious diseases is a prodigious initiative. Azadirachta indica, commonly known as neem, is known to be effective against infectious diseases from ancient times. It is a member of the Meliaceae family. Leaves, seeds, fruits, and roots of this plant are reported to be effective according to Chinese, Ayurvedic, and Unani medicine. The plant has antiviral, antibacterial, and antifungal properties. The principal component of neem is azadirachtin. Other constituents, namely nimbolinin, nimbin, nimbidin, nimbidol, are also known to be having medicinal properties. Antibacterial and antifungal properties can be attributed to azadirachtin, quercetin, ß-sitosterol, gedunin, and polyphenolic flavonoids. Many pharmacological studies report antimicrobial efficacy of Azadirachta indica. The present chapter will explain the link between phytochemical constituents of neem to antimicrobial activity along with possible underlying mechanisms and pathways. Clinical studies on neem are also discussed in great detail to highlight the emergence of this traditional medicine into modern medicine in the battle against infectious diseases.

Subject Index

Renal Functions

Obstacles and Challenges in the Use of Probiotics

Probiotics are helpful microorganisms that are resistant to biliary, gastric, and pancreatic secretions and can attach to the epithelial cells and colonize the surface of the intestinal cells. These capabilities are the main mechanisms of probiotics that allow them the adaptation to gut conditions. Probiotic cells attach to the intestinal cells and inhibit the attachment of enteric pathogenic germs to the intestinal mucosa by producing growth-inhibitory elements such as short-chain fatty acids, bacteriocin, and toxic oxygen metabolites. Attaching to the mucosal layer is essential for their functions, but it can increase the possibility of translocation and pathogenicity. On the other hand, there are also concerns about the possible transmission of antimicrobial resistance properties from probiotic strains to pathogenic bacteria in the gut environment. Consequently, the use of probiotics is entirely safe only in healthy people, and also it should be used with caution in children, the elderly, pregnant women, and immunocompromised patients. In recent years, scientists take a new approach to using probiotics in a non-viable form (currently known as postbiotics) to overcome the technological, economic, and clinical problems regarding the application of live probiotics. Hence, this chapter provides an overview of the nutritional and clinical concerns caused by probiotic intake in vulnerable patients, with emphasis on the application of a non-viable form of probiotics as a promising alternative.

Clinical Presentation and Comorbidities

Presently, the whole world is going through a historic yet a troublesome situation following COVID-19 outbreak. The clinicians have observed a wide variety of respiratory and non-respiratory clinical manifestations in COVID-19 patients. Accumulating reports revealed that the clinical features of COVID-19 may include asymptomatic/mild symptoms, neurological, cardiovascular complications, severe pneumonia and mortality. The most common features noticed are fever, dry cough, sore throat, shortness of breath, sputum production, fatigue, and myalgia. Recently, US health protection agency has also reported repeated shaking along with chills, loss of taste and smell in new case studies as additional symptoms. In addition to this, COVID-19 patients may show clinical signs like persistent pressure and pain in the chest, blue lips or face, confusion and GIT disturbances (diarrhea, nausea, vomiting and abdominal discomfort). The current ongoing pandemic has remarkably affected almost every age group of humans, starting from infants less than 3 months, adults, elder and older patients. Furthermore, the clinical presentations in these groups of COVID-19 infected patients were found to show considerable inter-individual variations. The findings also suggested that the comorbid conditions (heart injury, hyperglycemia, hypertension, neurodegenerative diseases) in elder/older patients further complicate the health of COVID-19 patients.

In the present book chapter, the clinical presentation of COVID-19 in pediatric, adults and geriatric group of population will be emphasized along with the higher susceptibility of COVID-19 in comorbid patients.

Solid Lipid Nanoparticles and Nanostructured Lipid Carriers for Drug Delivery Applications

Lipid nanoparticles, such as solid lipid nanoparticles and nanostructured lipid carriers, are drug delivery systems in which solid lipids are dispersed in an aqueous phase stabilized by a surfactant layer. The great interest in these nanocarriers in the latest years is due to the biocompatible lipid matrix, associated with the potential for sustained drug release, and easy transposition to the industrial scale. Moreover, these lipid systems present the ability to prevent drug degradation, and to enhance cell uptake, usually increasing drug efficacy. This chapter will provide an overview of the recent literature on solid lipid nanoparticles and nanostructured lipid carriers for drug delivery applications. Thus, some background information on the origins, composition, characterization parameters and biological applications of these nanocarrier systems will be presented.

Artificial Intelligence (AI) in Cancer Diagnosis and Prognosis

Cancer is a disorder with aggressive, low-median survival. Unfortunately, the healing time is long and expensive owing to high recurrence and mortality rates. It is essential to increase patient survival. Over the years, mathematical and computer engineering advancements have inspired numerous scientists to use quantitative methods to evaluate disease prognosis, such as multivariate statistical analysis, and the precision of these studies is considerably higher than that of observational predictions. However, as artificial intelligence (AI) has found widespread applications in clinical cancer research in recent years, especially machine learning and deep learning, cancer prediction output has reached new heights. The literature on the use of AI for cancer diagnosis and prognosis is discussed in this part. We discuss how AI supports the diagnosis of cancer, especially in terms of its unparalleled precision. We also illustrate forms in which these approaches progress the field. Opportunities and problems are addressed in the clinical application of AI.

Explaining 6G Spectrum THz, mmWave, Sub 6, and Low-Band

This chapter aims to provide readers with a general vision of 6G. Firstly, we give a simple overview of various aspects related to 6G, including inevitability of 6G research, international organizations for standardization, and also 6G research progress of some countries/regions. Then, 6G spectrum compositions are discussed in detail with emphasis on SUB-6, mmWAVE, and Terahertz (THz).

Advances in Experimental Animal Models Provide Insights into Different Etiology and Mechanism of Multiple Sclerosis to Design Therapeutics

Myelin covering of axons in the central and peripheral nervous system helps in faster propagation of neuronal action potentials. Demyelination is a neurodegenerative process in which the axons lose their myelin coverings, exposing the axons to surroundings and leading to a reduction in neuron-to-neuron communication. Several demyelinating diseases exist in humans, and one of the most frequently occurring demyelinating disease of the CNS is multiple sclerosis (MS). Although more than 2.3 million people suffer from MS globally, the disease etiology is still unknown, impeding the development of effective therapeutics. The available treatments are based on disease-modifying therapy to reduce or moderate the symptoms and slow the disease progression; however, none can cure the disease. One key to better design therapeutics is to understand the cellular and molecular mechanisms of MS by developing reliable model systems. Human studies have their own limitations, such as limited access to patient tissues. Moreover, genetic variability makes it difficult to identify the triggers of MS. This calls for the development of reliable experimental animal models to understand MS pathogenesis better. There is no exclusive experimental model that covers the entire gamut of the disease. In this chapter, we will discuss experiment autoimmune encephalomyelitis (EAE), Theiler’s murine encephalomyelitis virus (TMEV), and mouse hepatitis virus (MHV)-induced models of demyelination that mimic specific histopathological and neurobiological aspects of multiple sclerosis. The present understanding of MS as an autoimmune disease mediated by self-reactive T-cells comes mainly from studies on the EAE model. Further, viral-induced demyelination models have provided valuable insights into a better understanding of MS. Studies in the TMEV model have demonstrated molecular mimicry and epitope spreading as major mechanisms of virus-induced neuroinflammation. Our knowledge of immune-mediated CNS damage has been further enhanced by studies on MHV-induced neuroinflammatory demyelination, suggesting macrophage-mediated myelin stripping in neurodegeneration. While the limitations of these models of MS are obvious, appropriate use of this model has led to the development of clinically useful drugs for the treatment of this devastating disease.

Origin, Proliferation and Development of Vertebrate Pigment Cells-Melanophores and Melanocytes

Skin color in vertebrates predominantly depends on the presence of specialized cells that produce pigment. These special cells absorb or reflect light in a specific way to impart color to the skin and are called as chromatophores. Chromatophores are grouped into melanophores, erythrophores, xanthophores, leucophores and iridophores which largely depend on the pigment they produce. Melanophores are the most important type of chromatophores responsible for dorsal pigmentation in many vertebrates including fishes, amphibians and reptiles. In birds and mammals, melanophores are called melanocytes. All melanophores or melanocytes store thousands of dark brown/black biopolymer pigment melanins, packaged into membrane bound intra-cytoplasmic vesicles called as melanosomes. Melanophores or melanocytes originated from the neural crest cells, induced by several extracellular signals. Melanoblasts, precursor of melanocytes migrate, proliferate, differentiate and spread to their final destination in the basal layer of epidermis and hair follicles, however, distribution of melanocytes varies among different species. The embryonic development of melanocytes offers an opportunity to better understand the concept of vertebrate pigmentation. Thus the present chapter provides siginificant knowledge on the vertebrate pigment cells from origin to different stages of their development.

COVID-19 Vaccine Development: Challenges and Current Scenarios

The ongoing situation of COVID-19 pandemic entails us towards the development of a prophylactic vaccine as a public health priority. The emergence of SARS-CoV-2 in Wuhan, China during December 2019 marked the third introduction of a highly pathogenic Coronavirus into human population in the twenty-first century. Knowledge from the former vaccine candidates of SARS-CoV and MERS-CoV has unlocked the door for the developers to accelerate the global vaccine development pathway for ongoing COVID-19 pandemic, soon after the online publication of SARSCoV- 2 genomic sequence. The vaccine development pipeline for COVID-19 shows a promising result by utilizing various platforms (nucleic acid, viral vector, recombinant protein, live attenuated viruses, inactivated viruses and virus like particles) with different strategies. Surprisingly till now, we have about 190 vaccine candidates in the clinical and pre-clinical pipeline till 31st August 2020. Approximately, 39 of these vaccine candidates are impending into the human clinical trials after showing significant safety data in preclinical studies of which, 8 vaccine candidates are running in final phase3 stage. Three of them have got an emergency approval for limited or early use. At least 8 candidate vaccines have been developed from India, from which 2 of them have entered phase2 trials. Already existing tuberculosis vaccines are also being tested in clinical trials bridging the gap before a potential COVID-19 vaccine is developed. This chapter highlights the obstacles for implementation of vaccine development for SARS-CoV-2. One of the impediments is identification of high-risk population including frontline health care workers, elderly individuals and persons with pre-existing chronic diseases. We have also provided a comprehensive overview about the COVID-19 vaccine candidates that are in preclinical and clinical stages of development. Thus, fast track clinical trials of many candidates are implemented in different geographical regions promising a prophylactic vaccine against SARS-CoV-2.

Diabetes and Ocular Infections

This chapter will review some of the infections that can be seen in and around the eye in diabetic patients. Specifically, six cases of infection will be highlighted and discussed.

Microbial Pollution Control through Biogenically Synthesized Silver Nanoparticles (Bacillus Spp)

Microbes are omnipresent in nature, and have both beneficial and nonbeneficial activities for humans. In the system we live in is getting worse, due to microbes, that obviously end up in pandemic diseases like Covid-19. This chapter made an attempt to control pathogenic microorganisms either in the form of a spray or incorporated in disinfecting agents. Nanotechnology deals with the synthesis, characterization, and manipulation of metals at the nanoscale. The nanoparticles are precisely used due to their smaller size, physical properties, etc. which have shown a change in other materials that are in contact with these tiny particles. They are synthesized through various methods such as physical, chemical, and biological means. This study is aimed at the use of biological, eco-friendly, and green synthetic nanoparticles due to their less time consumption and ease. The visual observation was made with the color change indicated by the synthesized nanoparticles. They were further characterized by UV-Visible Spectrophotometer, XRD, EDAX, Zeta analysis, and FESEM. The size of nanoparticles was about 5.49 ± 2.10 nm. The synthesized nanoparticles showed significant results in control of S. aureus and P. aeruginosa with the zone of inhibition having a size of 16 mm and 18 mm, respectively. The green synthesized nanoparticles were based on the minimal inhibitory concentration and minimal bactericidal concentration.

Subject Index

BCG Vaccination

The BCG vaccine is derived from the Bacillus Calmette-Guérin (BCG) and is the most utilized vaccine in the history of humankind. Calmette and Guérin developed it in the Pasteur Institute from an original strain of Mycobacterium bovis.

The use of BCG vaccine is limited to the prevention of disseminated and meningeal TB, the most severe forms of the disease in children. BCG vaccination is recommended in countries or settings with a high incidence of TB. A single dose of BCG vaccine should be given to all healthy neonates at birth. The standard dose of BCG vaccine is 0.05 mL for infants aged less than one year and 0.1 mL for those aged one year and older. Studies have shown minimal or no evidence of additional benefits of repeat BCG vaccination against TB.

BCG vaccination is not recommended during pregnancy and it is contraindicated for individuals with immunodeficiency. HIV-infected children, when vaccinated with BCG at birth, are at increased risk of developing disseminated BCG disease.

An effective vaccine preventing pulmonary TB in adults is urgently needed but has long been considered by the TB community as an elusive goal. The slight decrease in the global incidence of TB and the rise in multidrug-resistant TB (MDR-TB) are elements that show the critical state of the TB epidemic and emphasize the need for the development of new tools, including candidates for an effective vaccine.

Treatment of Drug-Resistant Tuberculosis

The presence of drug resistance should always be suspected when there are risk factors for it and must be confirmed by bacteriological or molecular tests for standardized drug sensitivity. Any regimen for drug-resistant TB is more likely to be effective if its composition is based on information from reliable drug susceptibility testing.

The presence of drug-resistant tuberculosis should be suspected in patients who are failing treatment, in patients with TB relapse, in subjects coming from regions with a high prevalence of MDR-TB, and in contacts of known cases of MDR-TB. Although there are multiple reasons why treatment may fail, the most frequent is the lack of adherence to the regimen.

The most common causes of relapse include lack of adherence to treatment with the development of acquired drug resistance, treatment with an inadequate therapeutic regimen, malabsorption of drugs, and exogenous reinfection with a different strain of M. tuberculosis.

In patients with confirmed rifampicin-susceptible and isoniazid-resistant tuberculosis, treatment with rifampicin, ethambutol, pyrazinamide, and levofloxacin is recommended for a duration of 6 months.

One general WHO recommendation is that all patients with rifampin-resistant TB (even those with monoresistance to rifampin) should be treated with an MDR-TB drug regimen. There are three options for the treatment of RR/MDR/XDR TB. Two are recommendations for programmatic management (the short and longer regimens) and one for operational research (the BPaL regimen).

Tuberculosis in Persons Living with HIV

The lifetime risk of developing active TB in subjects with latent tuberculosis infection without the human immunodeficiency infection (HIV) co-infection is 5-10%; for people living with HIV (PLWHIV), the annual risk is 3-16% per year.

The interaction of these two pathogens is complex: HIV-1 co-infection is the most significant risk factor for developing active tuberculosis, while M. tuberculosis coinfection leads to increased viral replication and disease progression.

Clinical presentation will vary depending on the degree of immunodeficiency. Patients with higher CD4 cell counts can present with the classic symptoms, while the clinical presentation of TB in patients with advanced immunodeficiency (less than 200 cells/mm3) is usually atypical. Extrapulmonary tuberculosis is more frequent among co-infected individuals regardless of the CD4 cell counts, occurring in up to 70% of patients with CD4 counts of ≤100 and about 30% of subjects with counts of >300 cells/mm3.

The diagnostic approach in subjects with TB-HIV-1 co-infection is the same as that of patients without HIV infection, with the goal being the microbiologic confirmation of the diagnosis.

Antiretroviral (ART) should be started in all TB patients living with HIV regardless of their CD4 cell count. Antituberculosis treatment should be initiated first, followed by ART as soon as possible within the first 8 weeks of treatment. Unfortunately, the restoration of the immune response sometimes has an undesirable effect known as immune reconstitution inflammatory syndrome (IRIS).

Childhood Tuberculosis

Traditionally little attention has been paid to pediatric tuberculosis by clinicians, researchers, decision-makers, and even by national tuberculosis programs. According to the World Health Organization (WHO) Global Report for the year 2018, 10 million people developed TB in 2017, with 1 million of those being children under15 years of age. In the same year, there were 1.3 million deaths due to tuberculosis among HIV-negative people; children accounted for 15% of all deaths from TB, a percentage higher than their share of estimated cases.

Clinical presentation of pulmonary TB varies according to the age of the patient. Infants frequently will present with reduced playfulness, fever, dry cough, and dyspnea; children usually have dry cough as the only symptom, whereas in adolescents, the clinical manifestations are very similar to those of adults with fever and productive cough.

Lymphadenopathy is the most common type of extrapulmonary TB in children. The most commonly involved sites are the anterior cervical, posterior cervical triangle, submandibular, and supraclavicular lymph nodes.

BCG is the only vaccine available for clinical use in TB worldwide. Its overall efficacy for preventing tuberculosis is around 50% (range 0-80%). It is especially useful in the prevention of severe forms of the disease in children, including disseminated disease and meningeal tuberculosis. It does not prevent pulmonary tuberculosis effectively.

Tuberculosis in Special Situations: Liver and Renal Disease, Pregnancy, Extrapulmonary Tuberculosis, Tuberculosis in Immunosuppressed Individuals other than HIV, Tuberculosis, and Diabetes

Although the underlying general principles of management of tuberculosis are the same for all cases, there are certain special situations in which the treatment regimen must be modified.

Uremia and post-renal transplant are both risk factors for tuberculosis due to the underlying immunodeficiency. Patients undergoing dialysis have a 10-25-fold higher risk of developing the disease than the general population.

Many antituberculosis drugs are hepatotoxic. If aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are increased more than three times the upper limit of normal in the presence of symptoms of hepatitis or >5 times the upper limit of normal, even if the patient is asymptomatic, all hepatotoxic drugs should be discontinued.

First-line drugs (HREZ) are safe during pregnancy, and regimen doses and duration are the same as in non-pregnant individuals. Pyridoxine (50 mg, vitamin B6) should be added to the regimen to prevent neuropathy in the mother and seizures in the fetus.

There is an increased risk of progression to active TB in subjects with latent infection TB and diabetes in comparison with the infected nondiabetic population. Also, outcomes for patients with TB and diabetes are worse than for TB patients without diabetes, and diabetes also increases the risk of drug-resistant TB.

Risk factors for extrapulmonary TB (EPTB) include advanced age, female gender, immunosuppression (including HIV) and chronic comorbidities. Symptoms and signs are usually non-specific, and except for miliary forms, the chest radiograph might be normal; therefore, the diagnosis of EPTB is frequently delayed with the consequent increase in morbidity and mortality.

Laboratory Diagnosis of Tuberculosis

Although sputum microscopy remains the most widely used diagnostic method worldwide, given its low sensitivity (50-80%) and specificity (it does not distinguish M. tuberculosis from nontuberculous mycobacteria), more rapid, sensitive, and specific methods are required nowadays. Culture for mycobacteria continues to be the gold standard due to its higher sensitivity and specificity, and because it also allows the detection of strains resistant to antituberculosis drugs; however, even with liquid culture media, at least one month of processing is required to obtain results. Therefore, rapid genotyping methods (e.g., Xpert and line-probe assays known as LPAs) have replaced phenotypic methods by allowing the identification of species and the presence of mutations associated with resistance in less than 24 hours. The Xpert, an automated real-time PCR system, can identify the presence of mutations associated with rifampin resistance in less than two hours, with a sensitivity higher than 70% in patients with negative microscopy. LPAs allow species identification and the presence of mutations associated with resistance to isoniazid, rifampin, fluoroquinolones, and second-line injectables in less than 24 hours. Progressively, the complete sequencing of the Mycobacterium tuberculosis genome has been integrated into the diagnostic protocol, allowing the identification of all mutations associated with resistance for all antituberculosis drugs. Phenotypic methods (microscopy and cultures) continue to play an essential role in the follow-up of patients who are already under treatment.

Imaging in Tuberculosis

Tuberculosis is an excellent simulator and can mimic virtually any disease. Clinically, it has been divided into primary and post-primary tuberculosis. Primary tuberculosis usually refers to patients not previously exposed to M. tuberculosis. Primary tuberculosis is more frequent in children, with its highest prevalence in children under five years, although the frequency of primary forms in adults is increasing. The primary disease has four main presentations at imaging: chest lymphadenopathy, pneumonia, miliary disease, and pleural effusion. Post-primary TB (also known as reactivation or secondary TB) most commonly involves the lungs in the apical and posterior segments of the upper lobes and the apical segment of the lower lobes. Initially, there are parenchymal consolidations, that if they are not diagnosed and treated, usually progress to necrosis and cavitation. Unilateral lung destruction is a serious complication of pulmonary TB that occurs in chronic advanced cases. Although TB is mostly limited to the lungs, it can happen in any other tissue or organ, especially in the immunocompromised host.

Clinical Diagnosis of Tuberculosis

Symptoms and signs of active tuberculosis (TB) depend on its anatomical location. Pulmonary disease is the most common presentation of tuberculosis in the adult patient (more than 80% of the cases in the immunocompetent patient). Signs and symptoms can appear after just a few weeks from the primary infection, or many years later due to the reactivation of latent disease anywhere in the body.

Symptoms of pulmonary tuberculosis are nonspecific and may occur in many other pulmonary conditions; however, in high-burden regions, they remain a valuable tool for initial screening.

Signs and symptoms of extrapulmonary tuberculosis (EPTB) are protean, and chest xrays of the chest frequently do not show abnormalities. TB lymphadenitis is the most common form of EPTB, especially in children and young individuals.

Miliary tuberculosis is characterized by the presence of disseminated innumerable small nodules. It is secondary to the hematogenous spread of the bacilli throughout the body after the primary infection or the reactivation of a latent focus.

Although TB can involve any segment of the gastrointestinal tract, the ileocecal region is the most frequently affected. It is due to the ingestion of milk or milk products contaminated with M. bovis, the swallowing of secretions infected with M. tuberculosis, hematogenous dissemination of active TB disease, or from direct spread from contiguous organs.

Central nervous system tuberculosis is a consequence of hematogenous dissemination and the most severe form of the disease, with high morbimortality.

Microbiology of Tuberculosis

Mycobacterium tuberculosis (MTB) is the primary etiological agent of tuberculosis in humans (since the disease may be due to other mycobacteria of the MTB complex such as M. bovis). It belongs to the order of the Actinomycetales and the Mycobacteriaceae family. It is a bacillus that lacks capsule or flagella and does not produce spores or toxins; it measures 0.5 by four microns. Its generation time is prolonged (up to 24 hours). It is an aerobic bacillus that, if necessary, can persist under anaerobic conditions.

It has a cell wall of extremely complex composition, with great strength and thickness, constituted up to 60% by lipids, generally known as mycolic acids that form complexes with polysaccharides such as arabinogalactan and peptidoglycan; these lipids determine their resistance to discoloration by alcohol-acid after they have been stained with carbol fuchsin (hence the term acid-fast bacilli acid or AFB). A distinctive feature of the MTB cell wall is its content of N-glycolimuranic acid instead of N-acetylmuramic acid found in most bacteria.

The unusual cell wall of MTB also allows it to survive initially in the macrophage. The cell wall also constitutes a robust and highly impermeable barrier to harmful compounds and drugs. MTB can sense when the local tissue conditions are inadequate for survival (low oxygen tension and nutrient depletion), as in the macrophages and granulomas, responding by the activation of a dormant state, in which the bacilli stop multiplying, down-regulates its metabolism and activates anaerobic metabolism.

Molecular Mechanism of Nervous System Disorders and Implications for New Therapeutic Targets

The nervous system has a very good defence mechanism. The brain is protected by the skull, the spinal cord is shielded by vertebrae and thin membranes. The brain and spinal cord are buffered by cerebro-spinal fluid (CSF). The nervous system is susceptible to assorted disorders. It can be damaged by the structural defects, autoimmune disorders, infection, degeneration disorders, trauma, blood flow interference or tumors. At present, there is no treatment that can alleviate the disorders of the nervous system completely. In recent years, progress has been made in treating nervous system disorders symptomatically but still new product development is lagging behind in treating the disorders originating in the nervous system. This is due to several factors, including the intricacy of a particular disease or efficacy of the drug or delivering system to cross the blood-brain barrier (BBB). This chapter examines the modern state of major nervous system disorders like infection (meningitis), functional disorders (epilepsy, neuralgia), structural disorders (Bell’s palsy, Guillain-Barre syndrome) and degeneration disorder (Huntington disease). The discussion topics include analysis of biological machinery underlying each disease, cytokine expression involved in each disease and how it is regulated in particular disease along with its involvement in targeted therapy, approved pharmaceutical drugs and the development of new therapeutic technologies or customized approaches for drug delivery to particular target (epigenetics, Gene therapy, stem cell therapy). We suppose that with the intensification of modern science, the mobility of nervous system disorders will decline.

Natural Products with Antimicrobial Activity for Mycobacterium tuberculosis

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis. TB is one of the top ten causes of death in the world and it is highly prevalent, characterized by the constant occurrence of drug-resistant cases, and confounded by the incidence of respiratory diseases caused by nontuberculous mycobacteria (NTM). The anti-TB drugs commonly used are insufficient and have multiple adverse effects. Therefore, a new strategy to eradicate this infectious disease is required. The implementation of new anti-TB drugs together with host-directed therapy (HDT) can decrease the duration of treatment and improve the TB patients’ health. It is proposed that natural products are an enormous source of bioactive compounds to treat TB. They can be new anti-TB drugs or agents for HDT.