Clozapine and Treatment-Refractory Illness
Ragy R. Girgis, Gary Brucato, Jeffrey A. Lieberman in Understanding and Caring for People with Schizophrenia, 2020
Gratefully, thanks to the efforts of researchers in the United States, the drug clozapine became available. Clozapine is as close to a “miracle drug” as possible for schizophrenia. It was developed in the 1960s and became available in Europe the following decade. It was quickly withdrawn from the market after numerous reports of agranulocytosis, which is characterized by an extremely low neutrophil count, and can be fatal if left untreated. The danger of the condition is that a low number of neutrophils leaves one highly susceptible to infection. There is a 1% chance of developing agranulocytosis in the first few months of treatment with clozapine. Fortunately, this risk decreases substantially after the first few months (4). Because of the potential for agranulocytosis, however, clozapine was relatively ignored until a landmark study was published in 1988 showing that clozapine is more effective than chlorpromazine, a standard antipsychotic medication, for individuals who had treatment-refractory schizophrenia (5). Since then, the FDA and other organizations have permitted the use of clozapine for treatment-refractory conditions, provided a patient’s absolute neutrophil count is measured weekly for six months, biweekly for six months, and then monthly thereafter.
Haematological system
Pankaj Desai in Pre-eclampsia, 2020
Most of the markers in modern medical science are expressed on the basis of numerical value. This means that if that particular cell concentration or a particular enzyme or hormone level is high, then the underlying process is active. To make this clear, a linear rise in the number of neutrophils indicates an acute infection. Similarly, a linear rise in levels of transaminases indicates deteriorating liver function. But this concept may be only partially accurate. Although rising neutrophils indicates a higher mobilisation of these leucocytes in the presence of acute infections, it is also true that the neutrophils become more efficient in their working in the presence of acute infection. It is quite likely that an increase in the number and competence both are essential for combating the acute infection. It is possible that a raised count of neutrophil to 13,000 per dL of blood may be shooting up to 20,000–25,000 had their competence too not improved concurrently.
Defences Against Infection
Jeremy R. Jass in Understanding Pathology, 2020
Neutrophils are generated within the bone marrow from myeloid precursors that give rise to other members of the granulocyte family (eosinophils and basophils). Once they enter the circulation, the half-life of neutrophils is a matter of hours. During pyogenic infections, the number of neutrophils rises sharply. Some of these will have been sequestered within the microvasculature of organs such as the spleen. Others will be maturing neutrophils that are released early from the marrow (recognised by their paucity of nuclear lobes). Neutrophils have a multilobated nucleus and finely granular cytoplasm. The granules are lysosomes containing a variety of enzymes including myeloperoxidase, lysozyme and cathepsin. The cell membrane has receptors for: (1) inflammatory mediators (e.g. components of complement such as C5a and platelet activating factor), (2) opsonised bacteria bearing the Fc portion of antibodies or the cleaved complement fragment C3b, and (3) adhesion molecules expressed by endothelial cells (the leukocyte integrin LFA-1 binds to intercellular adhesion molecule-1 (ICAM-1), while leukocyte receptors bearing the sialylated blood group Lewis X (SLex) bind to endothelial cell-leukocyte adhesion molecule-1 (ELAM-1) or E-selectin).
Exploring the role of neutrophils in infectious and noninfectious pulmonary disorders
Published in International Reviews of Immunology, 2023
Since a decade, the interest in understanding neutrophils, its functions and its role in pathogenesis and progression of various diseases is greatly emerging. This emerging interest is justified as the crucial role of these multinucleated cells in immune responses related to various respiratory diseases, be it infectious or noninfectious cannot be overlooked. Different stimulations from different environmental sources could result in activation and chemotaxis of neutrophils from peripheral blood toward the inflammation site. Neutrophils works in synchrony with other immune cells in order to control the infection. The task of recognition of the antigen/pathogen is accomplished with the help of various PRRs such as TLRs, NLRs etc. which recognize the conserved molecular patterns on the pathogens. Various cytokines and chemokines are produced and released by polymorphonuclear cells (PMNs) during infection which aids in onset of the pro-inflammatory responses like migration of a large number of different immune cell types toward the infection site. Certain antimicrobial peptides like elastase, cathepsins, serine proteases etc. are released by PMNs in order to kill the invading pathogen. Also, the increased oxidative burst due to increased production and release of ROS plays a major role in controlling and regulating the pathogen growth inside the host. In addition, neutrophils have also developed a unique trap system called as NETs.
Investigating Neutrophil-to-Lymphocyte and C-Reactive Protein-to-Albumin Ratios in Type 2 Diabetic Patients with Dry Eye Disease
Published in Ocular Immunology and Inflammation, 2023
Amani Y. Alhalwani, Rawan Baqar, Rawan Algadaani, Hala Bamallem, Rwzan Alamoudi, Shatha Jambi, Wessam Abd El Razek Mady, Naif S. Sannan, Muhammed Anwar Khan
NLR combines two major components of chronic inflammatory disease: high neutrophils and low lymphocytes. Inflammatory responses are related to neutrophils while immune pathway regulation is reflected by lymphocytes. They may be used to reflect systemic inflammation; innate immune responses are mediated by neutrophils, while adaptive immune responses are mediated by lymphocytes.24 Hence, NLR reflects systemic inflammation25 and is proposed as a novel marker of chronic inflammation.26 The NLR is a stable marker, easily available and cost-effective analytical parameter.27 Studies on diabetic patients reported that NLR was a dominant phenomenon.28 Previous research also showed that T2D-DED patients had increased NLR levels.29,30 Moreover, high neutrophil and low lymphocyte counts in peripheral blood indicated poor prognoses in some diseases such as DM. Therefore, NLR has been proposed as a prognostic and systemic inflammation indicator. Furthermore, NLR may be used to evaluate several ocular diseases where inflammatory pathogenesis occurs, such as DED.31
Immunopathology of COVID-19 and its implications in the development of rhino-orbital-cerebral mucormycosis: a major review
Published in Orbit, 2022
Tarjani Vivek Dave, Akshay Gopinathan Nair, Joveeta Joseph, Suzanne K Freitag
During infections, the first innate leukocytes that are activated are the neutrophils.36 The main function of neutrophils is the removal of pathogens and debris, which is achieved by phagocytosis.37 A well-regulated innate immune process recruiting macrophages and neutrophils is an early protective action against viral infections. Hyperglycemia, either due to steroid treatment or to insulin resistance, that develops following COVID-19 infection deactivates neutrophils. An additional immunologic role of neutrophils includes the release of the unique neutrophil extracellular traps (NETs). NETs are DNA fragments in association with granular antimicrobial proteins. Through reactive oxygen species (ROS)-independent mechanisms, NETs result in immediate entrapment of the viruses and render them inactive.38 They also help trigger cytokine production to restrict virus replication.36 At times, in severe COVID-19 associated cytokine storm, there is an overproduction of NETs. This leads to lung tissue damage by NETosis which involves microthrombosis and tissue necrosis.39–41