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Purpose: This paper outlines the theoretical and empirical basis for compassion focused therapy (CFT) for psychosis, the gaps in the current knowledge and research, as well as some of the challenges for addressing gaps. It will guide the direction of future work and the steps needed to develop and advance this approach. Method: This paper reviews evidence of how evolutionary models such as social rank theory and attachment theory have greatly contributed to our understanding of psychosis and provide a clear rationale and evidence base for the mechanisms of change in CFT for psychosis. It reviews the evidence for outcomes of compassion training more generally, and early feasibility evaluations of CFT for psychosis. Results: The process evidence shows that people with psychosis have highly active social rank and threat systems, and the benefits of switching into attachment and care systems, which can support emotion regulation and integrative mind states. The outcomes evidence shows that compassion training impacts not only psychological outcomes, but also physiological outcomes such as neural circuits, immune system, and the autonomic nervous system. Within the psychosis field, outcomes research is still in the early days, but there are good indications of feasibility and a clear path forward for the next steps. Conclusions: CFT for psychosis is an approach that integrates biopsychosocial processes, an integration that's evidenced across each aspect of the model, from theoretical foundations (evolution‐informed) to interventions (e.g., body/breath training and relational techniques), to evaluation. Future RCTs are required to understand the effects on biopsychosocial outcomes for people with psychosis. [ABSTRACT FROM AUTHOR]

Plain language summary: A uterine transplant, or womb transplant, provides a potential treatment for women who cannot become pregnant or carry a pregnancy because they do not have a womb, or have a womb that is unable to maintain a pregnancy. This is estimated to affect one in 500 women. Options for those who wish to start a family include adoption and surrogacy, but these are associated with legal, cultural, ethical and religious implications that may not be appropriate for some women and their families. A womb transplant is undertaken when the woman is ready to start a family, and is removed following the completion of their family. Womb transplants have been performed all over the world, with more than 70 procedures carried out so far. At least 23 babies have been born as a result, demonstrating that womb transplants can work. While the procedure offers a different option to adoption and surrogacy, it is associated with significant risks, including multiple major surgeries and the need to take medications that help to dampen the immune system to prevent rejection of the womb. To date there has been a 30% risk of a transplant being unsuccessful. Although the number of transplants to date is still relatively small, the number being performed globally is growing, providing an opportunity to learn from the experience gained so far. This paper looks at the issues that have been encountered, which may arise at each step of the process, and proposes a framework for the future. However, long term follow‐up of cases will be essential to draw reliable conclusions about any overall benefits of this procedure. [ABSTRACT FROM AUTHOR]

The paper mulberry (Broussonetia papyrifera) leaf is rich in alkaloids and flavonoids, which has high medicinal and feeding value. We aimed to analyze the effects of B. papyrifera leaf extract on growth performance, antioxidant capacity, immune functions, and fecal microflora of weaned piglets. Thirty healthy, 28-day-old piglets were randomly assigned to three groups and fed with a basal diet supplemented with 0, 150, and 300 g/t B. papyrifera leaf extract for 42 days (control group, group I, and group II) separately. The result revealed that the final weight of piglets in group II was higher than the other groups, and the diarrhea rate in this group was 62.9% lower than in the control group. The feed conversion ratio in group I was significantly lower than the other two groups. Higher blood urine nitrogen concentration was noted in group II, higher glutathione peroxidase and catalase in group II, higher superoxide dismutase in the control group, and higher immune globulins (Ig) IgG, IgA, and IgM in group II. There was no significant difference in community richness and community diversity among the three groups of fecal samples. The relative level of Roseburia was higher in groups I and II, while Lactobacillus was higher in the control group. In conclusion, supplementation with B. papyrifera leaf extract at a certain dosage can increase growth performance and antioxidant capacity of weaned piglets, reduce the occurrence of diarrhea, enhance immune functions and disease resistance, and affect the composition of fecal microflora. [ABSTRACT FROM AUTHOR]

The paper mulberry (Broussonetia papyrifera) leaf is rich in alkaloids and flavonoids, which has high medicinal and feeding value. We aimed to analyze the effects of B. papyrifera leaf extract on growth performance, antioxidant capacity, immune functions, and fecal microflora of weaned piglets. Thirty healthy, 28-day-old piglets were randomly assigned to three groups and fed with a basal diet supplemented with 0, 150, and 300 g/t B. papyrifera leaf extract for 42 days (control group, group I, and group II) separately. The result revealed that the final weight of piglets in group II was higher than the other groups, and the diarrhea rate in this group was 62.9% lower than in the control group. The feed conversion ratio in group I was significantly lower than the other two groups. Higher blood urine nitrogen concentration was noted in group II, higher glutathione peroxidase and catalase in group II, higher superoxide dismutase in the control group, and higher immune globulins (Ig) IgG, IgA, and IgM in group II. There was no significant difference in community richness and community diversity among the three groups of fecal samples. The relative level of Roseburia was higher in groups I and II, while Lactobacillus was higher in the control group. In conclusion, supplementation with B. papyrifera leaf extract at a certain dosage can increase growth performance and antioxidant capacity of weaned piglets, reduce the occurrence of diarrhea, enhance immune functions and disease resistance, and affect the composition of fecal microflora. [ABSTRACT FROM AUTHOR]

Inflammation is an important driver of atherosclerosis, and the favourable outcomes of the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) trial revealed the large potential of anti-inflammatory drugs for the treatment of cardiovascular disease, especially in patients with a pro-inflammatory constitution. However, the complex immune reactions driving inflammation in the vascular wall in response to an atherosclerotic microenvironment are still being unravelled. Novel insights into the cellular processes driving immunity and inflammation revealed that alterations in intracellular metabolic pathways are strong drivers of survival, growth, and function of immune cells. Therefore, this position paper presents a brief overview of the recent developments in the immunometabolism field, focusing on its role in atherosclerosis. We will also highlight the potential impact of immunometabolic markers and targets in clinical cardiovascular medicine. [ABSTRACT FROM AUTHOR]

Simple Summary: Myeloid-derived suppressor cells (MDSCs) are immature cells that expand in the circulation of patients with cancer, sepsis or chronic inflammation, modulate the immune response against cancer (favoring tumor onset and progression) and promote neoangiogenesis. These premises suggest that MDSCs could be involved in the pathogenesis of primary myelofibrosis (PMF) (a myeloproliferative neoplasm characterized by chronic inflammation and extensive neoangiogenesis in bone marrow and spleen). In this paper, we found that (1) MDSCs are increased both in the circulation and in the spleen of PMF patients and strongly correlate with disease progression; and (2) reduced CXCR4 expression on MDSCs along with increased plasmatic SDF-1α can be involved in their mobilization. These findings suggest that circulating MDSCs can be considered a parameter of disease severity and set MDSCs as potential new targets for cancer therapy. Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by a chronic inflammatory state that plays a relevant role in the disease pathogenesis (as proven by high levels of inflammatory cytokines with prognostic significance and by a persistent oxidative stress) and by extensive neoangiogenesis in bone marrow (BM) and spleen. Myeloid-derived suppressor cells (MDSCs) are immature cells that expand in patients with cancer, sepsis or chronic inflammation, favoring tumor onset and progression mainly through the decrease in immune surveillance and the promotion of neoangiogenesis. In this paper, we evaluated the presence of circulating MDSCs in PMF patients, the plasmatic factors involved in their mobilization/expansion and the correlations with laboratory, genetic and clinical parameters. The data indicated that MDSCs could have a relevant role in PMF as a new pathogenic mechanism contributing to explaining the phenotypic diversity observed during the clinical course of the disease, or a potential new target for personalized treatment. [ABSTRACT FROM AUTHOR]

Abstract Background Our current understanding of the pathophysiology and management of sepsis is associated with a lack of progress in clinical trials, which partly reflects insufficient appreciation of the heterogeneity of this syndrome. Consequently, more patient-specific approaches to treatment should be explored. Aims To summarize the current evidence on precision medicine in sepsis, with an emphasis on translation from theory to clinical practice. A secondary objective is to develop a framework enclosing recommendations on management and priorities for further research. Sources A global search strategy was performed in the MEDLINE database through the PubMed search engine (last search December 2017). No restrictions of study design, time, or language were imposed. Content The focus of this Position Paper is on the interplay between therapies, pathogens, and the host. Regarding the pathogen, microbiologic diagnostic approaches (such as blood cultures (BCs) and rapid diagnostic tests (RDTs)) are discussed, as well as targeted antibiotic treatment. Other topics include the disruption of host immune system and the use of biomarkers in sepsis management, patient stratification, and future clinical trial design. Lastly, personalized antibiotic treatment and stewardship are addressed (Fig. 1). Implications A road map provides recommendations and future perspectives. RDTs and identifying drug-response phenotypes are clear challenges. The next step will be the implementation of precision medicine to sepsis management, based on theranostic methodology. This highly individualized approach will be essential for the design of novel clinical trials and improvement of care pathways. [ABSTRACT FROM AUTHOR]

Medulloblastoma (MB) is a highly malignant childhood brain tumor. Group 3 MB (Gr3 MB) is considered to have the most metastatic potential, and tailored therapies for Gr3 MB are currently lacking. Gr3 MB is driven by PRUNE-1 amplification or overexpression. In this paper, we found that PRUNE-1 was transcriptionally regulated by lysine demethylase LSD1/KDM1A. This study aimed to investigate the therapeutic potential of inhibiting both PRUNE-1 and LSD1/KDM1A with the selective inhibitors AA7.1 and SP-2577, respectively. We found that the pharmacological inhibition had a substantial efficacy on targeting the metastatic axis driven by PRUNE-1 (PRUNE-1-OTX2-TGFβ-PTEN) in Gr3 MB. Using RNA seq transcriptomic feature data in Gr3 MB primary cells, we provide evidence that the combination of AA7.1 and SP-2577 positively affects neuronal commitment, confirmed by glial fibrillary acidic protein (GFAP)-positive differentiation and the inhibition of the cytotoxic components of the tumor microenvironment and the epithelial–mesenchymal transition (EMT) by the down-regulation of N-Cadherin protein expression. We also identified an impairing action on the mitochondrial metabolism and, consequently, oxidative phosphorylation, thus depriving tumors cells of an important source of energy. Furthermore, by overlapping the genomic mutational signatures through WES sequence analyses with RNA seq transcriptomic feature data, we propose in this paper that the combination of these two small molecules can be used in a second-line treatment in advanced therapeutics against Gr3 MB. Our study demonstrates that the usage of PRUNE-1 and LSD1/KDM1A inhibitors in combination represents a novel therapeutic approach for these highly aggressive metastatic MB tumors. [ABSTRACT FROM AUTHOR]

Postbiotics are recognized as the most innovative, multidisciplinary biotechnological approach. Each year, the quantity of research results and patents grows. According to PubMed, around 250 research papers in the field of postbiotics were cited in 2023, followed by approximately 74 publications in early 2024. Concurrently, the global postbiotic market has grown significantly, becoming one of the most formidable markets in the biotic sector. Yet, there is no thorough analysis of the current progress of the postbiotics market or how research studies and discoveries can impact the quantity and quality of postbiotics. This review provides an insightful perspective on current consumer brands and highlights the latest therapeutic and non- therapeutic applications in the postbiotics market. In comparison to other therapeutic agents such as antibiotics, probiotics, and growth boosters, this review suggests that postbiotics are an effective and eco-friendly alternative therapy. Furthermore, postbiotics, an industrially sustainable technology, are highlighted, shedding light on the development of biotic markets. [Display omitted] • Postbiotics are a promising trend in both therapeutic and non-therapeutic markets. • Postbiotics enhance the immune system and strengthen defensive mechanisms against various disorders. • Postbiotics are an eco-friendly alternative to antibiotics and growth promoter therapies. • Postbiotic research enriches biotic markets by developing new detergents, biofuels, and artificial intelligence-based research tools. [ABSTRACT FROM AUTHOR]

In recent years, there has been growing interest in understanding the potential role of microbiota dysbiosis or alterations in the composition and function of human microbiota in the development of chronic rhinosinusitis with nasal polyposis (CRSwNP). This systematic review evaluated the literature on CRSwNP and host microbiota for the last ten years, including mainly nasal bacteria, viruses, and fungi, following the PRISMA guidelines and using the major scientific publication databases. Seventy original papers, mainly from Asia and Europe, met the inclusion criteria, providing a comprehensive overview of the microbiota composition in CRSwNP patients and its implications for inflammatory processes in nasal polyps. This review also explores the potential impact of microbiota-modulating therapies for the CRSwNP treatment. Despite variability in study populations and methodologies, findings suggest that fluctuations in specific taxa abundance and reduced bacterial diversity can be accepted as critical factors influencing the onset or severity of CRSwNP. These microbiota alterations appear to be implicated in triggering cell-mediated immune responses, cytokine cascade changes, and defects in the epithelial barrier. Although further human studies are required, microbiota-modulating strategies could become integral to future combined CRSwNP treatments, complementing current therapies that mainly target inflammatory mediators and potentially improving patient outcomes. [ABSTRACT FROM AUTHOR]

In this paper, a delayed cytokine-enhanced viral infection model incorporating nonlinear incidence and immune response is proposed and studied. The global stabilities of the equilibria of the model are characterized by constructing suitable Lyapunov functionals. The existence and properties of local Hopf bifurcation are discussed by regarding the immunity delay as the bifurcation parameter. Moreover, the global existence of Hopf bifurcation has been proved by regarding the immune delay as the bifurcation parameter. Numerical simulations are carried out to validate the obtained results. The results show that ignoring the cytokine-enhanced effect makes the infection risk underevaluated. The simulations show that increasing the immune delay destabilizes the model and generates a Hopf bifurcation and stability switches occurs. Moreover, it shows that immune delay may dominate the intracellular delays in such a viral infection model which means that the immune system of the host itself is complicated during virus infection. [ABSTRACT FROM AUTHOR]

Simple Summary: The incidence of gastric cancer (GC) is increasing. Many people receive an advanced diagnosis of GC. Furthermore, a large number of patients are surgically inoperable and are unresponsive to preoperative chemotherapy. Patients with GC do not currently have an immunotherapy option. Our study's objective was to provide insight into extracellular vesicles (EVs) and GC. EVs in GC can be studied, as this article explains. EVs screening, which is available for all patients, is an option for combatting GC. Extracellular vesicles, or EVs, are membrane-bound nanocompartments produced by tumor cells. EVs carry proteins and nucleic acids from host cells to target cells, where they can transfer lipids, proteomes, and genetic material to change the function of target cells. EVs serve as reservoirs for mobile cellular signals. The collection of EVs using less invasive processes has piqued the interest of many researchers. Exosomes carry substances that can suppress the immune system. If the results of exosome screening are negative, immunotherapy will be beneficial for GC patients. In this study, we provide an update on EVs and GC based on ongoing review papers and clinical trials. [ABSTRACT FROM AUTHOR]

Contracting cancer typically induces a state of terror among the individuals who are affected. Exploring how chemotherapy and anxiety work together to affect the speed at which cancer cells multiply and the immune system's response model is necessary to come up with ways to stop the spread of cancer. This paper proposes a mathematical model to investigate the impact of psychological scare and chemotherapy on the interaction of cancer and immunity. The proposed model is accurately described. The focus of the model's dynamic analysis is to identify the potential equilibrium locations. According to the analysis, it is possible to establish three equilibrium positions. The stability analysis reveals that all equilibrium points consistently exhibit stability under the defined conditions. The bifurcations occurring at the equilibrium sites are derived. Specifically, we obtained transcritical, pitchfork, and saddle-node bifurcation. Numerical simulations are employed to validate the theoretical study and ascertain the minimum therapy dosage necessary for eradicating cancer in the presence of psychological distress, thereby mitigating harm to patients. Fear could be a significant contributor to the spread of tumors and weakness of immune functionality. [ABSTRACT FROM AUTHOR]

Simple Summary: The B cell receptor (BCR) is a membrane-bound protein complex that is required for the normal development of B cells. BCR signalling is also involved in the pathogenesis of B cell cancers. While there is substantial literature on genomic analyses of the BCR, there are limited proteomic studies of receptor structure and its interactions with neighbouring proteins. This is partly due to the location of the BCR in the surface-membrane lipid environment that has limited the ability to enrich the complex for proteomic analysis. Here, we report an enrichment technique that can be used for mass spectrometry analyses of the BCR from live B cells. B cells are central to the adaptive immune response and provide long-lasting immunity after infection. B cell activation is mediated by the surface membrane-bound B cell receptor (BCR) following recognition of a specific antigen. The BCR has been challenging to analyse using mass spectrometry (MS) due to the difficulty of isolating and enriching this membrane-bound protein complex. There are approximately 120,000 BCRs on the B cell surface; however, depending on the B cell activation state, there may be hundreds-of-millions to billions of proteins in a B cell. Consequently, advanced proteomic techniques such as MS workflows that use purified proteins to yield structural and protein-interaction information have not been published for the BCR complex. This paper describes a method for enriching the BCR complex that is MS-compatible. The method involves a Protein G pull down on agarose beads using an intermediary antibody to each of the BCR complex subcomponents (CD79a, CD79b, and membrane immunoglobulin). The enrichment process is shown to pull down the entire BCR complex and has the advantage of being readily compatible with further proteomic study including MS analysis. Using intermediary antibodies has the potential to enrich all isotypes of the BCR, unlike previous methods described in the literature that use protein G-coated beads to directly pull down the membrane IgG (mIgG) but cannot be used for other mIg isotypes. [ABSTRACT FROM AUTHOR]

The cells presented in this work are not classified as cells that make up the immune system. They, however, present functions and molecules, which are characteristic of immune cells. These characteristic functions are, for example, sensing threat, performing phagocytosis, presentation of foreign antigens, cytokine release or enhancing immune memory. The enlisted immune response mechanisms are carried out by the possession of molecules such as Toll‐like receptors, receptors for the Fc fragment of IgG, major histocompatibility complex class II molecules, costimulatory CD80/CD86 proteins and molecules needed for NLRP3 (NOD‐like family pyrin domain containing 3) inflammasome activation. Thanks to these properties, the described nonimmune cells play an important role in the local immune response and support of the entire body in the fight against pathogens. They constitute the first line of defense of tissues and organs against pathogens and molecules recognized as harmful. The cells described in this article are particularly important in immunologically privileged places (e.g. the Bowman's capsule in the kidney), where "typical" immune cells normally do not have access. In this paper, we present immune‐like functions and molecule suites of resident kidney cells (podocytes and mesangial cells), cochlear resident cells, fibrocytes and fibroblasts, as well as some stem cells (mesenchymal stem cells and umbilical cord Wharton's jelly–derived cells). [ABSTRACT FROM AUTHOR]

In this paper, we present a review of several selected talks presented at the CTTACC conference (Cellular Therapies in Trauma and Critical Care) held in Scottsdale, AZ in May 2023. This conference review highlights the potential for cellular therapies to "reset" the dysregulated immune response and restore physiologic functions to normal. Improvements in medical care systems and technology have increasingly saved lives after major traumatic events. However, many of these patients have complicated post-traumatic sequelae, ranging from short-term multi-organ failure to chronic critical illness. Patients with chronic critical illness have been found to have dysregulated immune responses. These abnormal and harmful immune responses persist for years after the initial insult and can potentially be mitigated by treatment with cellular therapies. The sessions emphasized the need for more research and clinical trials with cellular therapies for the treatment of a multitude of chronic illnesses: post-trauma, radiation injury, COVID-19, burns, traumatic brain injury (TBI) and other chronic infections. [ABSTRACT FROM AUTHOR]

Among the properties melatonin is claimed to possess, are the immuno-inflammation inductive capacities that would be responsible of some of the paramount of activities melatonin is reported to have in most of the human pathological conditions. In the present paper, we measured the effect of melatonin on established cellular models of immuno-inflammation, and found none. The discrepancies are discussed, especially because those properties are reported at pharmacological concentration (1 μM and beyond) at which the melatonin receptors are desensitized by internalization, leading to putative non-receptor-dependent mechanism of action. • The melatonin enthusiasts are ruining Science reputation, by claiming facts that are often wishful thinking. • Melatonin is not able to boost most of the actors of the immune system, even at pharmacological concentrations. • We hope to be able to show that some of the activities of melatonin are pure fantasies. [ABSTRACT FROM AUTHOR]

In the pursuit of point-of-care systems that present high sensitivity and fast turnaround time, lateral flow is considered a remarkable promising class of in vitro diagnostics, and popularized by the pregnancy tests. A variety of lateral flow tests have emerged able to provide cardiac panels in emergency conditions, infectious disease screening, drug abuse, among others. However, most commercial tests only provide qualitative results, limiting their applicability for quantification thresholds of most biomarkers. In this paper, we propose a novel detection architecture for quantification of biomolecules labeled with magnetic nanoparticles employing two spin valve sensors. The main goal of this paper is to demonstrate that this architecture can detect and monitor MNPs flowing in a LFT strip for detection and quantification of different solutions varying in MNP concentration. In addition, we present preliminary analytical results that support our strategy for achieving biomolecular quantification using the proposed solution. [ABSTRACT FROM AUTHOR]

The adaptive immune system has two types of plasma cells (PC), long-lived plasma cells (LLPC) and short-lived plasma cells (SLPC), that differ in their lifespan. In this paper, we propose that LLPC is crucial to the clearance of viral particles in addition to reducing the viral basic reproduction number in secondary infections. We use a sequence of within-host mathematical models to show that, CD8 T cells, SLPC and memory B cells cannot achieve full viral clearance, and the viral load will reach a low positive equilibrium level because of a continuous replenishment of target cells. However, the presence of LLPC is crucial for viral clearance. [ABSTRACT FROM AUTHOR]

Abstract: Paper supports were used to develop a simple, inexpensive, fast and sensitive electrochemical immunosensor for the analysis of antibiotic residues in milk samples, where single-walled carbon nanotubes (SWNTs) and a simple dip–dry coating method were employed to prepare the highly sensitive biosensor. Well-dispersed SWNTs were impregnated with an antibody against neomycin to obtain a composite coating solution, followed by dipping the filtration paper in the solution to fabricate the sensitive biosensor which had high electrical conductivity. Based on the impedance change in the entire paper supported biosensor with increased concentrations of neomycin, the limit detection of the optimized method was 0.04ngmL−1 and a linear detection range from 0.2 to 125ngmL−1, well below the European Union regulations for neomycin in this matrix. This paper supported biosensor was applied to determine neomycin in milk samples after a simple sample treatment, with spiked recoveries which ranged from 93.25 to 110.47%. A variety of antibiotic residues in milk samples could be determined following similar sensor preparation. [Copyright &y& Elsevier]

Rheumatoid arthritis (RA) is a chronic autoimmune condition frequently found in rheumatological patients that sometimes raises diagnosis and management problems. The pathogenesis of the disease is complex and involves the activation of many cells and intracellular signaling pathways, ultimately leading to the activation of the innate and acquired immune system and producing extensive tissue damage. Along with joint involvement, RA can have numerous extra-articular manifestations (EAMs), among which lung damage, especially interstitial lung disease (ILD), negatively influences the evolution and survival of these patients. Although there are more and more RA-ILD cases, the pathogenesis is incompletely understood. In terms of genetic predisposition, external environmental factors act and subsequently determine the activation of immune system cells such as macrophages, neutrophils, B and T lymphocytes, fibroblasts, and dendritic cells. These, in turn, show the ability to secrete molecules with a proinflammatory role (cytokines, chemokines, growth factors) that will produce important visceral injuries, including pulmonary changes. Currently, there is new evidence that supports the initiation of the systemic immune response at the level of pulmonary mucosa where the citrullination process occurs, whereby the autoantibodies subsequently migrate from the lung to the synovial membrane. The aim of this paper is to provide current data regarding the pathogenesis of RA-associated ILD, starting from environmental triggers and reaching the cellular, humoral, and molecular changes involved in the onset of the disease. [ABSTRACT FROM AUTHOR]

Tumor–immune system interactions are very complicated, being highly nonlinear and not well understood. A large number of tumors can potentially weaken the immune system through various mechanisms such as secreting cytokines that suppress the immune response. In this paper, we propose a tumor–immune system interaction model with a nonmonotonic immune response function and adoptive cellular immunotherapy (ACI). The model has a tumor-free equilibrium and at most three tumor-presence equilibria (low, moderate and high ones). The stability of all equilibria is studied by analyzing their characteristic equations. The consideration of nonmonotonic immune response results in a series of bifurcations such as the saddle-node bifurcation, transcritical bifurcation, Hopf bifurcation and Bogdanov–Takens bifurcation. In addition, numerical simulation results show the coexistence of periodic orbits and homoclinic orbits. Interestingly, along with various bifurcations, we also found two bistable scenarios: the coexistence of a stable tumor-free as well as a high-tumor-presence equilibrium and the coexistence of a stable-low as well as a high-tumor-presence equilibrium, which can show symmetric and antisymmetric properties in a range of model parameters and initial cell concentrations. The new findings indicate that under ACI, patients can possibly reach either a stable tumor-free state or a low-tumor-presence state in the presence of nonmonotonic immune response once the immune system is activated. [ABSTRACT FROM AUTHOR]

Simple Summary: Simple Summary: The infectious bursal disease virus (IBDV) is a major pathogen in the poultry industry due to its profound impact on the immune systems of young chickens. Various genetic types with distinct biological characteristics have been described. In this study, we evaluated the expression of different cytokines in the bursa of Fabricius and thymus over a 28-day experimental infection with two strains from the G1a (Classical) and G6 (ITA) genogroups. The G6 strain appeared to induce a more immediate immunosuppression, and unlike the G1a strain, did not show signs of gene expression recovery by the end of the study. This finding aligns with the higher replication level previously reported for the G6 and with the clinical outcome, as this genotype, although subclinical, has often been considered more immunosuppressive. Unlike other studies that focused on shorter periods post-infection, the patterns observed in this study were highly variable and complex, depending on the strain, tissue, and time point. Therefore, this study not only confirms the effect of strain/genogroup on immune system modulation but also highlights the importance of extended monitoring post-infection to better understand the intricate patterns and interactions with the host response. Infectious bursal disease virus (IBDV) is a significant burden for poultry production and market due to both direct disease and induced immunosuppression. In the present study, the expression of different cytokines in the bursa of Fabricius and thymus was evaluated during a 28-day-long experimental infection with two strains classified in the G1a (Classical) and G6 (ITA) genogroups. Although both strains significantly affected and modulated the expression of different molecules, the G6 strain seemed to induce a delayed immune response or suppress it more promptly. A recovery in the expression of several mediators was observed in the G1a-infected group at the end of the study, but not in the G6 one, further supporting a more persistent immunosuppression. This evidence fits with the higher replication level previously reported for the G6 and with the clinical outcome, as this genotype, although subclinical, has often been considered more immunosuppressive. However, unlike other studies focused on shorter time periods after infection, the patterns observed in this paper were highly variable and complex, depending on the strain, tissue, and time point, and characterized by a non-negligible within-group variability. Besides confirming the strain/genogroup effect on immune system modulation, the present study suggests the usefulness of longer monitoring activities after experimental infection to better understand the complex patterns and interactions with the host response. [ABSTRACT FROM AUTHOR]

Time of day affects how well the immune system responds to viral or bacterial infections. While it is well known that the immune system is regulated by the circadian clock, the dynamic origin of time-of-day-dependent immunity remains unclear. In this paper, we studied the circadian control of immune response upon infection of influenza A virus through mathematical modeling. Dynamic simulation analyses revealed that the time-of-day-dependent immunity was rooted in the relative phase between the circadian clock and the pulse of viral infection. The relative phase, which depends on the time the infection occurs, plays a crucial role in the immune response. It can drive the immune system to one of two distinct bistable states, a high inflammatory state with a higher mortality rate or a safe state characterized by low inflammation. The mechanism we found here also explained why the same species infected by different viruses has different time-of-day-dependent immunities. Further, the time-of-day-dependent immunity was found to be abolished when the immune system was regulated by an impaired circadian clock with decreased oscillation amplitude or without oscillations. [ABSTRACT FROM AUTHOR]

Severe acute pancreatitis (SAP) begins with premature activation of enzymes, promoted by the immune system, triggering a potential systemic inflammatory response that leads to organ failure with increased mortality and a bleak prognosis. Interleukin-22 (IL-22) is a cytokine that may have a significant role in SAP. IL-22, a member of the IL-10 cytokine family, has garnered growing interest owing to its potential tissue-protective properties. Recently, emerging research has revealed its specific effects on pancreatic diseases, particularly SAP. This paper provides a review of the latest knowledge on the role of IL-22 and its viability as a therapeutic target in SAP. Highlights: 1. Interleukin-22 (IL-22) is a member of the IL-10 family of cytokines. 2. IL-22 is a potential indicator for monitoring organ dysfunction and severity of severe acute pancreatitis (SAP). 3. IL-22 acts as a protective factor against acinar cell damage by suppressing autophagy and reducing the infiltration of inflammatory cells. 4. IL-22 alleviate SAP-induced multiorgan injury. 5. IL-22 protect SAP-induced intestinal barrier damage. [ABSTRACT FROM AUTHOR]

In this paper, we study a delayed HIV infection model with nonmonotonic immune response and perform stability and bifurcation analysis. Our results show that the delayed HIV infection system with nonmonotonic immune response has bistability and stable periodic solution appear. We find that both the uninfected and immune-free equilibria are globally asymptotically stable under certain conditions which are not affected by time delay. However, the time delay makes one immune equilibrium always unstable for τ ≥ 0 and also makes another immune equilibrium appear stability switches; meanwhile, the system will exhibit local Hopf bifurcation, global Hopf bifurcation, and saddle-node-Hopf bifurcation. Numerical simulations are carried out to verify our results. [ABSTRACT FROM AUTHOR]

Simple Summary: Endometrial cancer is the sixth most common cancer among women worldwide, with an increasing mortality rate. The standard treatment of patients with advanced or recurrent endometrial cancer has not changed significantly in recent decades. However, in recent years, immunotherapy has emerged as a promising strategy that harnesses the body's immune system against cancer, particularly in advanced or recurrent cases, offering patients the possibility of better results and longer survival. Our critical review analyses recent findings in the literature in this field, focusing on the role of immunotherapy in the treatment of this disease. In particular, it focuses on the importance of molecular biology and highlights how this can change the choice of treatment, providing insights for future therapeutic strategies. The Cancer Genome Atlas (TCGA) has radically changed the history of endometrial cancer by outlining a new classification, based on its molecular characteristics. In the field of oncology, we are approaching the new era of molecular biology, particularly regarding endometrial cancer, with the increasing importance of targeted therapy. This paper is a review of phase III randomized controlled trials published in English between January 2019 and December 2023, comparing drugs of interest with standard adjuvant treatment and molecular subtypes in endometrial cancer. The use of immunotherapy alone or in combination with chemotherapy as therapy in patients with recurrent or advanced primary or metastatic endometrial cancer significantly improves the prognosis of these patients. The results show greater efficacy of all proposed treatments for mismatch repair deficiency (dMMR/MSI-H) patients compared to mismatch repair proficiency (pMMR) patients. Progression-free survival (PFS) and overall survival (OS) are better in dMMR patients in all studies analysed. Immunotherapy has the potential to revolutionize the gynaecological cancer treatment landscape, offering a new pathway and new hope for endometrial cancer patients, improving their outcomes in the future. Given the exciting results obtained in dMMR/MSI-H patients, MMR status should be investigated in every patient with advanced endometrial cancer at the time of diagnosis. [ABSTRACT FROM AUTHOR]

Simple Summary: The microenvironment of hepatocellular carcinoma is a really complex milieu, containing a wide variety of cells with specific tasks, belonging to both the mesenchimal and immunitary systems, the extracellular matrix, growth factors, proinflammatory cytokines, and translocated bacterial products. This intricate environment represents a source of potential targets in order to establish a wide and multitask therapeutic strategy for hepatocellular carcinoma. Hepatocellular carcinoma is a malignant tumor that originates from hepatocytes in an inflammatory substrate due to different degrees of liver fibrosis up to cirrhosis. In recent years, there has been growing interest in the role played by the complex interrelationship between hepatocellular carcinoma and its microenvironment, capable of influencing tumourigenesis, neoplastic growth, and its progression or even inhibition. The microenvironment is made up of an intricate network of mesenchymal cells, immune system cells, extracellular matrix, and growth factors, as well as proinflammatory cytokines and translocated bacterial products coming from the intestinal microenvironment via the enterohepatic circulation. The aim of this paper is to review the role of the HCC microenvironment and describe the possible implications in the choice of the most appropriate therapeutic scheme in the prediction of tumor response or resistance to currently applied treatments and in the possible development of future therapeutic perspectives, in order to circumvent resistance and break down the tumor's defensive fort. [ABSTRACT FROM AUTHOR]

Introduction: Understanding the complex link between our gut health and general well-being has drawn more attention in recent years. Prebiotics can promote mineral absorption, influence metabolism, improve immune system regulation, and fight infections. Aim: This article focuses into the evolving paradigms in prebiotics research, highlighting their regulation, diverse applications, impact on diseases, and their growth on the global market. Discussion: Prebiotics are Generally Recognized as Safe (GRAS), novel foods and food additives by the Food and Drug Administration (FDA), EU and Japan, respectively. The multifaceted applications of prebiotics go across various sectors, ranging from functional foods and dietary supplements to cosmetics. A comprehensive review of prebiotics' effects on human health and illness prevention is a significant strength of the paper. Prebiotics support a healthy microbiome by feeding helpful gut flora, which may reduce the risk of a variety of illnesses and improve general health. In parallel, it covers an overview of the prebiotics industry in the world, considering aspects including consumer knowledge of gut health and growing prebiotic demand. Conclusion: Prebiotics are anticipated to have a significant role in determining the direction of nutrition and preventive healthcare as research advances and consumer demand for natural health solutions rises. [ABSTRACT FROM AUTHOR]

Atopic Dermatitis (AD), recognized as one of the most prevalent chronic inflammatory skin disorders among children, is characterized by skin barrier dysfunction and immune system abnormalities. Historically viewed as a childhood condition, recent findings underscore a notable prevalence of AD in adults, prompting a critical examination of this demographic. Diagnosis hinges largely on subjective clinical assessments due to the absence of universally accepted biomarkers. Consequently, efforts are underway to identify dependable biomarkers to enhance diagnostic precision. This paper underscores the scarcity of AD diagnoses in adults despite its pediatric prominence, emphasizing the need for heightened awareness and tailored diagnostic approaches in adult populations. Severity scores such as SCORing Atopic Dermatitis (SCORAD) and dermatological life quality index (DLQI) play pivotal roles in evaluating disease severity and its impact on quality of life, guiding the development of personalized treatment strategies for adult AD patients. In this study, we aim to present four compelling cases of adult-onset atopic dermatitis, each offering unique insights into this increasingly recognized phenomenon. What makes these cases particularly noteworthy is the absence of any prior atopic history in two out of four patients, challenging the conventional understanding of AD as a condition predominantly linked to childhood. Moreover, the clinical presentation in all four cases was markedly atypical, underscoring the elusive nature of adult-onset AD diagnosis. In our investigation, interleukin 4 (IL-4), interleukin 13 (IL-13), and Immunoglobulin E (IgE) were utilized as diagnostic biomarkers for our patient cohort. Given the established pivotal roles of IL-4 and IL-13 in AD pathogenesis, elevated serum levels of these biomarkers, although not universally endorsed, hold potential for diagnostic utility. Furthermore, heightened levels of IgE, indicative of allergic responses and inflammation inherent to the condition, emphasize its significance as a key biomarker and therapeutic target in AD management. [ABSTRACT FROM AUTHOR]

The alternative pathway of the complement system is implicated in the etiology of age-related macular degeneration (AMD). Complement depletion with pegcetacoplan and avacincaptad pegol are FDA-approved treatments for geographic atrophy in AMD that, while effective, have clinically observed risks of choroidal neovascular (CNV) conversion, optic neuritis, and retinal vasculitis, leaving room for other equally efficacious but safer therapeutics, including Poly Sialic acid (PSA) nanoparticle (PolySia-NP)-actuated complement factor H (CFH) alternative pathway inhibition. Our previous paper demonstrated that PolySia-NP inhibits pro-inflammatory polarization and cytokine release. Here, we extend these findings by investigating the therapeutic potential of PolySia-NP to attenuate the alternative complement pathway. First, we show that PolySia-NP binds CFH and enhances affinity to C3b. Next, we demonstrate that PolySia-NP treatment of human serum suppresses alternative pathway hemolytic activity and C3b deposition. Further, we show that treating human macrophages with PolySia-NP is non-toxic and reduces markers of complement activity. Finally, we describe PolySia-NP-treatment-induced decreases in neovascularization and inflammatory response in a laser-induced CNV mouse model of neovascular AMD. In conclusion, PolySia-NP suppresses alternative pathway complement activity in human serum, human macrophage, and mouse CNV without increasing neovascularization. [ABSTRACT FROM AUTHOR]

In a bounded smooth domain Ω ⊂ R 3 and with a positive parameter χ > 0 , this paper is devoted to investigating the global boundedness and asymptotic behavior of solutions to a immune chemotaxis system. By establishing the uniform boundedness of L ∞ -norm for immune cells and the uniform boundedness of L q -norm with q ∈ (3 , ∞) for the chemokines gradient, it is possible to identify a smallness condition on chemosensitivity χ that ensures global existence of classical solution to the model in a three-dimensional bounded domain. Moreover, to get exponential decay rate the smallness of (‖ M 0 ‖ L ∞ , ‖ A 0 ‖ L ∞) is pivotal, we shall see that the system still admits an energy type inequality, and an analysis thereof will show that any nontrivial solution approaches exponentially fast with respect to the topology in L ∞ (Ω) . [ABSTRACT FROM AUTHOR]

The purpose of this research is to examine whether Buddhist ethics can improve the health and well-being of Buddhist practitioners during pandemics like COVID-19. It is hypothesized that diseases are part of suffering, and Buddhist teachings aim to eliminate the suffering of all beings. Buddhism also offers ethical codes of conduct for its practitioners to improve their health and well-being. So, the Buddha's teaching or Buddhist ethics, when practiced seriously, should be able to improve one's health, physically and mentally, enhancing the well-being of all Buddhist practitioners during the spread of all pandemics including COVID-19. The present study found that Buddhist ethical practices like the chanting of Buddhist suttas and the development of mindfulness, concentration/meditation, and insight (vipassanā) can improve both physical and mental health, which are important for dealing with any pandemic, tremendously. If the cores of Buddhist ethics (morality, meditation, and wisdom) are perfectly practiced, not only will one live with good physical and mental health but one also will be able to eliminate all the mental defilements that are the root causes of all illnesses and thus enter nibbāna, the state of mind that is beyond all sources of suffering including pandemics/epidemics. More specifically, this paper highlights a set of Buddhist practices, called four bhāvanās (types of development), that can be used to improve health and well-being during any pandemic. [ABSTRACT FROM AUTHOR]

DNA oncoviruses represent an intriguing subject due to their involvement in oncogenesis. These viruses have evolved mechanisms to manipulate the host immune response, facilitating their persistence and actively contributing to carcinogenic processes. This paper describes the complex interactions between DNA oncoviruses and the innate immune system, with a particular emphasis on the cGAS-STING pathway. Exploring these interactions highlights that DNA oncoviruses strategically target and subvert this pathway, exploiting its vulnerabilities for their own survival and proliferation within the host. Understanding these interactions lays the foundation for identifying potential therapeutic interventions. Herein, we sought to contribute to the ongoing efforts in advancing our understanding of the innate immune system in oncoviral pathogenesis. [ABSTRACT FROM AUTHOR]

Tumor-associated macrophages (TAMs) are a key component of the immunosuppressive cell and cytokine network. They play a critical role in allowing tumors to evade the immune system. To successfully combat cancer through immunotherapy, it is essential to re-educate TAMs. This study introduces a TAM-targeting nanoreporter that can reshape the tumor immune microenvironment, enhancing cancer immunotherapy. Additionally, the nanoreporter allows for the monitoring of TAM immune activation through protease-responsive photoacoustic/fluorescent imaging. [Display omitted] • This paper described a non-invasive optical imaging technique for tracing the immune activation of tumor-associated macrophages. • This nanoreporter could target TAMs and achieve precise controlled release of TLR agonists. • This "all-in-one" nanoplatform shows promise in cancer diagnosis, treatment and prognosis assessment. Tumor-associated macrophages (TAMs) are vital in the tumor microenvironment, contributing to immunosuppression and therapy tolerance. Despite their importance, the precise re-education of TAMs in vivo continues to present a formidable challenge. Moreover, the lack of real-time and efficient methods to comprehend the spatiotemporal kinetics of TAMs repolarization remains a significant hurdle, severely hampering the accurate assessment of treatment efficacy and prognosis. Herein, we designed a metal–organic frameworks (MOFs) based Caspase-1 nanoreporter (MCNR) that can deliver a TLR7/8 agonist to the TAMs and track time-sensitive Caspase-1 activity as a direct method to monitor the initiation of immune reprogramming. This nanosystem exhibits excellent TAMs targeting ability, enhanced tumor accumulation, and stimuli-responsive behavior. By inducing the reprogramming of TAMs, they were able to enhance T -cell infiltration in tumor tissue, resulting in inhibited tumor growth and improved survival in mice model. Moreover, MCNR also serves as an activatable photoacoustic and fluorescent dual-mode imaging agent through Caspase-1-mediated specific enzyme digestion. This feature enables non-invasive and real-time antitumor immune activation monitoring. Overall, our findings indicate that MCNR has the potential to be a valuable tool for tumor immune microenvironment remodeling and noninvasive quantitative detection and real-time monitoring of TAMs repolarization to immunotherapy in the early stage. [ABSTRACT FROM AUTHOR]

Simple Summary: Therapeutic options for GEP-NETs are very limited, and at the same time, the incidence of these cancers is increasing. The evidence has shown that multiple neoplasms can be successfully treated with immune checkpoint inhibitors such as PD-1/PD-L1 inhibitors. Crucial to determining a patient's response to immunotherapy is access to the tumor microenvironment. Currently, there is no consistency regarding the future role of TME and immunotherapy in GEP-NETs. Thus, this review points to the solution in selecting a concrete patient group that, based on tumor features can benefit from immunotherapy. Neuroendocrine neoplasms (NENs) are a heterogenous and recurrent group of malignancies originating from neuroendocrine secretory cells diffused on all parts of the human body. Gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) account for most NENs. Considering the abundance of possible origins, locations, and tumor specifications, there is still no consensus about optimal treatment options for these neoplasms. In light of the escalating immunotherapeutic approaches, it is crucial to define indications for such therapy in GEP-NETs. Bearing in mind the significance of pathophysiological mechanisms and tumor microenvironment (TME) impact on carcinogenesis, defining TME structure and correlation with the immune system in GEP-NETs appears essential. This paper aimed to assess the characterization of the tumor immune microenvironment for a better understanding of the possible therapeutic options in GEP-NETS. The authors performed a systematic review, extracting papers from the PubMed, Web of Science, and Scopus databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Among 3800 articles identified through database searching, 292 were assessed for eligibility. Ultimately, 28 articles were included in the qualitative synthesis. This paper sums up the research on the immune cell infiltrates, immune checkpoint expression, cytokine profile, neoangiogenesis, and microbiome in the TME of GEP-NETs. [ABSTRACT FROM AUTHOR]

Abstract: The level of T-cell receptor excision circles (TREC), which decline with advancing age in normal individuals, has recently gained interest as a reference marker for studies on premature or early immunosenescence under particular health conditions. In order to facilitate translational studies at population and clinical levels, essential for the understanding of how changes in TREC levels are associated with responsiveness of the immune system, we have developed and optimized a real-time polymerase chain reaction (qPCR) assay which quantifies the TREC ratio from dried blood spot (DBS) samples. The present study considers a fully automated procedure to purify DNA and amplify sequences of interests by means of qPCR from DBS samples collected in healthy adults. Both TREC:PBMC (peripheral blood mononuclear cell) and TREC:T-cell ratios were compared for intra- and inter individual reproducibility. Furthermore, the impact of the length of storage on the quality of the DNA generated was also analyzed. In conclusion we describe a fully automated procedure for extracting DNA and qPCR set up, which offers a high-precision, robust qPCR assay for the quantification of both TREC:T-cell ratio and TREC:PBMC from DBS samples. [Copyright &y& Elsevier]

The amyloid hypothesis has so far been at the forefront of explaining the pathogenesis of Alzheimer's Disease (AD), a progressive neurodegenerative disorder that leads to cognitive decline and eventual death. Recent evidence, however, points to additional factors that contribute to the pathogenesis of this disease. These include the neurovascular hypothesis, the mitochondrial cascade hypothesis, the inflammatory hypothesis, the prion hypothesis, the mutational accumulation hypothesis, and the autoimmunity hypothesis. The purpose of this review was to briefly discuss the factors that are associated with autoimmunity in humans, including sex, the gut and lung microbiomes, age, genetics, and environmental factors. Subsequently, it was to examine the rise of autoimmune phenomena in AD, which can be instigated by a blood-brain barrier breakdown, pathogen infections, and dysfunction of the glymphatic system. Lastly, it was to discuss the various ways by which immune system dysregulation leads to AD, immunomodulating therapies, and future directions in the field of autoimmunity and neurodegeneration. A comprehensive account of the recent research done in the field was extracted from PubMed on 31 January 2022, with the keywords "Alzheimer's disease" and "autoantibodies" for the first search input, and "Alzheimer's disease" with "IgG" for the second. From the first search, 19 papers were selected, because they contained recent research on the autoantibodies found in the biofluids of patients with AD. From the second search, four papers were selected. The analysis of the literature has led to support the autoimmune hypothesis in AD. Autoantibodies were found in biofluids (serum/plasma, cerebrospinal fluid) of patients with AD with multiple methods, including ELISA, Mass Spectrometry, and microarray analysis. Through continuous research, the understanding of the synergistic effects of the various components that lead to AD will pave the way for better therapeutic methods and a deeper understanding of the disease. [ABSTRACT FROM AUTHOR]

Chemotaxis plays a crucial role in a variety of processes in biology and ecology. Quite often it acts to improve efficiency of biological reactions. One example is the immune system signalling, where infected tissues release chemokines attracting monocytes to fight invading bacteria. Another example is reproduction, where eggs release pheromones that attract sperm. A macro scale example is flower scent appealing to pollinators. In this paper we consider a system of PDEs designed to model such processes. Our interest is to quantify the effect of chemotaxis on reaction rates compared to pure reaction-diffusion. We limit consideration to surface chemotaxis, which is well motivated from the point of view of many applications. Our results provide the first insight into situations where chemotaxis can be crucial for reaction success, and where its effect is likely to be limited. The proofs are based on new analytical tools; a significant part of the paper is dedicated to building up the linear machinery that can be useful in more general settings. In particular, we establish precise estimates on the rates of convergence to the ground state for a class of Fokker--Planck operators with potentials that grow at a logarithmic rate at infinity. These estimates are made possible by a new sharp weak weighted Poincaré inequality. [ABSTRACT FROM AUTHOR]

The article presents the 2009 issue of the "World Allergy Organization." It discusses the use of sub-lingual immunotherapy (SLIT) in medical care particularly its clinical application for physicains who are focusing on the development of immune system resistance. Moreover, it also provides an overview on the functions of subcutaneous immunotherapy and other routes of immunotherapy administration in treating severe diseases due to allergens.

Offers the best practice guideline for the routine pathology evaluation of the immune system. Assessment of clinical pathology; Semiquantitative description of lymphoid tissue changes; Examination of lymphoid tissue by compartments.

Antiphospholipid Antibodies in Children with Age-Dependent Epileptic Encephalopathy.Purpose:Antiphospholipid antibodies (aPLs) have been found in the serum of patients with several neurologic disorders. Serum aPLs were detected in 19–26% of adult patients both with chronic epilepsy and with newly diagnosed seizure disorders. In children with partial epilepsy, Angelini et al. (1998) found aPLs in 13% of these cases. We studied the serum aPLs in 31 children with age-dependent epileptic encephalopathy: early infantile epileptic encephalopathy with suppression burst (EIEE), West syndrome (WS), and Lennox–Gastaut syndrome (LGS).Methods:Two children with EIEE, 20 with WS, and nine with LGS in the Pediatric Unit of Nihon University Itabashi Hospital were enrolled in the study. Inclusion criteria were (a) reliable diagnosis of age-dependent epileptic encephalopathy, (b) no signs or symptoms consistent with clinical immune system disorders and collagen diseases, and (c) negative for anticardiolipinβ2-glycoprotein I antibodies. Anticardiolipin antibodies (aCLs) of serum immunoglobulin G (IgG class) were measured with the enzyme-linked immunosorbent assay (ELISA) method. A value of aCL<10 U/ml is within normal limits. All of the subjects were classified in two groups. The patients in group A were diagnosed within 3 years, and those in group B were diagnosed beyond 3 years.Results:In the two patient with EIEE, the peak values of aCL were 57.9 and 35.6 U/ml. In patients with WS, the positive rate for the peak aCL levels was 91.7%, and the mean (±SD) level was 40.4± 39.2U/ml in group A, whereas the corresponding figures were 25% and12.7± 17.0 U/ml in group B. In patients with LGS, the positive rate for the peak aCL levels was 100%, and the mean level was 20.3± 6.6U/ml in group A, whereas the corresponding figures were 50% and 11.0± 12.2 U/ml in group B. We divided all the patients into a seizure-free group and a seizure-uncontrolled group. The mean peak value was 15.2± 17.8 in the seizure-free group and 38.8± 35.1 in the seizure-uncontrolled group.Discussion:A high positive rate of aPLs was found among patients with WS, characterized by early onset and long duration of epilepsy. These patients were poor responders to antiepileptic drugs (AEDs). Immunomodulatory therapies (intravenous Igs) have been shown to be effective in some children with this type of intractable epilepsy. Conversely, aPLs were more frequent among patients with localization–related epilepsies than in those with idiopathic generalized epilepsies. Several AEDs such as carbamazepine and phenytoin have been implicated as activators of antinuclear antibody production and drug-induced systemic lupus erythematosus. These antibodies are usually associated with autoimmune disorders such as primary antiphospholipid syndrome in rheumatic and connective tissue disorders. Two main pathogenic mechanisms have been proposed to explain the relationship between positive aPLs and neurologic symptoms (i.e., thrombotic and ischemic events within the CNS, and immune-mediated cellular damage from neuronal synaptic membrane attack). It has been shown that aPLs can disrupt neuronal function by directly acting on nerve terminals and reducingγ-aminobutyric acid-receptor–mediated chloride currents, suggesting a direct and reversible mechanism through which aPLs might lower the seizure threshold. It has also been postulated that antibodies to endothelium frequently coexist with aPLs and may induce apoptosis within the CNS. The high prevalence of positive aPLs in children with epilepsy indicates that immunologic dysfunction is associated with epilepsy, in at least some children. Conversely, aCL may appear after viral infections, and we speculate that some viral infections may be related to the age-dependent epileptic encephalopathyConclusions:The level of aPLs is related to disease severity and seizure frequency in patients with age-dependent epileptic encephalopathy, and aPLs may be useful to indicate prognosis and treatment effect. Regional Hyperperfusion in Temporal Lobe Seizures with Dystonic Posturing, Evaluated by Ictal–Interictal Subtraction SPECT.Purpose:Ictal hyperperfusion areas evaluated by multimodality registration methods may demonstrate anatomic localization of ictal symptoms. Dystonic posturing (DP) is one of the most reliable lateralizing indicators for temporal lobe epilepsy (TLE). Areas of regional hyperperfusion associated with DP in TLE were evaluated by using ictal–interictal subtraction single-photon emission computed tomography (SPECT).Methods:Twenty-three patients were randomly selected from 97 TLE patients who underwent operations between 1988 and 2000 in Shizuoka Medical Institute of Neurological Disorders (National Epilepsy Center). All ictal events were noted by reviewing long-term video-EEG monitoring records (by Y.I. and M.M.). The patients were divided into three groups according to the ictal symptoms: group D with unilateral DP, group H with elevated muscle tonus but without DP, and group N without DP or alternation of muscle tonus. For SPECT (Headtome set-070, Shimazu, Tokyo) sampling, each patient was injected with the same tracer during the ictal and interictal periods. Ictal and interictal SPECT and thin-slice magnetic resonance imaging (MRI; Sierra 1.5-T; General Electric, Milwaukee, WI, U.S.A.) were input into the automatic multimodality registration program (Dr. View/Linux, Asahikasei, Tokyo) to generate ictal–interictal subtraction images of SPECT on MRI for individual patients. Ictal hyperperfusion areas were evaluated by K.M. and M.T.Results:Six patients belonged to group D, nine patients to group H, and eight patients to group N. Statistically significant hyperperfusion was observed in the putamen (five patients in group D, two in group H and group N; p<0.01). Other ictal symptoms (such as autonomic symptoms, oral automatism, ocular or head deviation or both) showed no statistically significant differences except unilateral upper-limb automatism (four patients in group D, one in group H, and none in group N; p<0.01). Other factors such as age, sex, duration of illness, presence of MRI lesion or SPECT tracer (nine patients with[123I]-IMP and 14 with[99mTc]-ECD) were not statistically significant.Conclusions:A strong correlation between DP and putaminal hyperperfusion was demonstrated. Some patients showed a wide hyperperfusion area extending from the mesial temporal lobe to the putamen that may correspond to the propagation of epileptic discharges. Hyperactivity of the putamen is suggested to be associated with contralateral dystonic posturing. Epilepsy with Psychosis: Endocrine Psychic Syndrome.Case 1:A 9-year-old girl has had paroxysmal episodes of microspia and complex partial seizures without aura since age 8 years. She experienced visual hallucinations such as the strange face of an old lady and six moving ballerinas at age 9 years. In addition, she experienced auditory hallucination of a voice, something invisible coming close to her, and the feeling of fear. She broke her sister's comic book in a quick temper. Electroencephalogram (EEG) showed repetitive spikes on the left occipital and posterotemporal regions during both the psychotic state and remission. Brain magnetic resonance imaging (MRI) showed no definite abnormality. Brain single-photon emission computed tomography (SPECT) showed a subtle change in hypoperfusion in the left hemisphere. No definite differences were found during both states in EEG or SPECT. Her psychotic symptoms appeared after a lucid period of 30 min to 2 days and are followed by habitual complex partial seizures. It seemed that the psychotic symptoms of case 1 developed after seizures. We therefore considered that her symptoms correlated with the postictal stage, so-called postictal psychosis. However, her biochemical studies showed hyperthyroidism. Her psychotic symptoms disappeared soon after taking thiamazole.Case 2:A 21-year-old woman experienced complex partial seizures and secondarily generalized tonic–clonic seizures since age 2 years. She was admitted to the pediatrics department for recurrent vomiting. After admission, she complained that a ghost disturbed her eating. She experienced hearing voices of neighbors, delusions of reference and persecution, and delusions of speech with bizarre and grotesque features. In addition, she showed irritation, agitation, and violent behavior to her family. The EEG showed theta waves on bilateral frontocentroparietotemporal regions during psychosis. The same findings of EEG were observed during remission. Brain MRI showed a high-intensity area in the right cingulate gyrus. Brain SPECT showed hypoperfusion in the right mesial and lateral temporal regions during both states. However, hyperperfusion in bilateral frontal cortex were observed during psychosis. No correlation was noted between her psychotic symptoms and seizure activity or medication. We therefore considered that her psychotic symptoms resembled interictal chronic psychosis. However, her biochemistry data and the Ellsworth-Howard test showed pseudohypoparathyroidism type II. Her psychotic symptoms disappeared after treatment with a vitamin D analogue. We were able to discontinue all antipsychotic drugs.Conclusions:More than 150 years ago, von Basedow first described psychotic illness in a patient with exophthalmic goiter. Brownlie et al. reported psychosis associated with thyrotoxicosis. Eight among their 18 patients experienced hallucination, and 10 cases, including two schizophreniform cases, had good prognosis after an adequate treatment. Conversely, Hey et al. reported a case of Capgras syndrome in association with pseudohypoparathyroidism. This patient had mental retardation, epilepsy, and schizophrenia-like symptoms. Because of psychosis, he had a history of electroconvulsive therapy. Pollard et al. reported a 13-year-old Asian girl who showed hysterical paralysis and a rapid-cycling mood disorder. The mood disorder responded to treatment of pseudohypoparathyroidism with a vitamin D analogue.Although endocrine psychic syndrome is not unusual, epileptic psychosis combined with endocrine disease, as in our cases, is confusing as to whether the symptoms mimicked postictal or chronic psychosis. We propose to reconsider the association of psychiatric problems with endocrine disease when we encounter epilepsy patients with psychosis. Single Small Enhancing CT Lesions (SSECTL) in Epilepsy in India.Purpose:Single small enhancing CT lesions (SSECTLs) are extremely common in Indian epilepsy patients seen for the first time with seizures. Various hypotheses exist regarding their etiology, ranging from tuberculomas to neurocysticercosis, on the basis of histology and excisions done in a small percentage of cases. It also has been observed that these lesions disappear spontaneously over a short period after treatment with antiepileptic drugs (AEDs), causing doubts about their etiology and raising questions regarding management. The present study was carried out to observe such patients with SSECTLs with respect to persistence or disappearance of these lesions with AED treatment alone.Methods:All the new patients who attended our neurology clinics, with seizures, generalized or focal, were studied for the purpose of the present study. Apart from historical details and the seizure characteristics, complete neurologic examinations were done and recorded in specified form. Routine blood counts, erythrocyte sedimentation rate, urine examination, blood biochemistry, chest radiograph, and EEG were carried out. Computed tomography (CT) scan was done at the first instance and repeated after≥10–12 weeks of AED wherever possible. All the patients were given AEDs alone.Results:All the patients with first-ever seizures during the study period formed the subjects of this study; 43.5% of the patients had normal scans, whereas in 56.5%, the scans were abnormal. Of the patients, 12.9% had specific abnormalities, which included meningioma (5), gliosis (21), atrophy (21), multiple neurocysticercosis (43), and multiple infarcts (18), among others. 40.4% of patients showed nonspecific abnormalities on their scans such as low attenuation (51), high-attenuation disks (67), high-attenuation rings (241), generalized edema (56), and calcified spots (75). A follow-up scan was possible in 219 cases. Of these, 131 (59.8%) showed complete resolution, whereas 53 (24.2%) had significant resolution, but 35 (16%) remained unresolved.Discussion:The appearing and disappearing CT scan lesions in epilepsy in India have been an enigma. Initially these were thought to be tuberculous granulomas, as tuberculosis is one of the commonest diseases prevalent in this region. Disappearance of these lesions or healing by calcification by antituberculosis therapy (ATT) was taken as evidence for the hypothesis of tuberculosis. When some of these patients had to discontinue ATT because of adverse drug reactions, it was noted that these lesions disappear also without ATT. Subsequently, some histopathologic studies were conducted, with an evidence of neurocysticercosis in some of these patients, which resolved with cysticidal drugs. However, a majority of these patients who neither had ATT nor cysticidal therapy had their lesions resolve spontaneously on follow-up CT scans. Our study also supports the hypothesis. However, a small number of cases were seen in which these lesions either do not resolve or increase on follow-up CT scans. It is probable that these lesions do not represent one single etiology, and they must be managed appropriately.Conclusions:The SSECTL are one of the most common findings on CT in patients of epilepsy in India. These lesions resolve spontaneously without any specific treatment such as ATT or cysticidal therapy in the majority of patients. Therefore, there is an ample justification in treating them initially with AEDs only. A Neuropathological Study on the Limbic System in Dentatorubral-Pallidoluysian Atrophy.Purpose:Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder characterized by progressive myoclonic epilepsy (PME), dementia, and cerebellar ataxia. According to the age at onset, DRPLA is classified into juvenile, early-adult, and late-adult types. In the juvenile type, PME is most frequently observed, whereas seizures or PME sometimes and rarely occurs in early- and late-adult types. In general, glutamate transporters and calcium-binding proteins (parvalbumin and calbindin-D28K) are believed to reflect glutamate neurotoxicity and functions of theγ-aminobutyric acid (GABA)ergic inhibitory interneurons in the limbic system, respectively. To investigate epileptogenesis in DRPLA, we examined the expressions of glutamate transporters and calcium-binding proteins in the limbic system in autopsy cases of DRPLA.Methods:Fourteen autopsy cases of clinicopathologically confirmed DRPLA, comprising nine cases of juvenile type with PME and five cases of late-adult type without PME, as well as 10 age-matched controls, were studied. Immunohistochemistry was performed on serial sections of the temporal lobe including the hippocampus, amygdaloid complex, and entorhinal cortex, by using mouse monoclonal antibodies to parvalbumin and calbindin-D28K (Sigma-Aldrich, St. Louis, MO, U.S.A.) and rabbit polyclonal antibodies to excitatory amino acid transporters 1 (EAAT1), EAAT2, and EAAT3 (Wako Pure Chemicals Industries, Japan). The degree of immunoreactivity was evaluated by semiquantitative visual inspection.Results:The number of interneurons immunoreactive for parvalbumin or calbindin-D28K seemed to be lower in cases of the juvenile type of DRPLA with PME compared with that in cases of late-adult type of DRPLA not manifesting PME. Reduction of calbindin-D28K–immunoreactive neurons appeared to be more prominent than that of parvalbumin-immunoreactive neurons. It is noteworthy that four of five cases of the juvenile type, in which seizure occurred before puberty and the amygdaloid complex could be examined, and one case of the adult type completely lacked the amygdaloid immunoreactivity for parvalbumin or calbindin-D28K. The amygdaloid lesion is likely to be related to PME in DRPLA as either a cause or a result. Conversely, the expression of glutamate transporters seemed to be mildly affected. Three cases of juvenile type and one case of adult type showed a reduced expression of EAAT1 or EAAT2 or both in the entorhinal cortex, hippocampus, or amygdaloid complex. The expression of neuronal glutamate transporter EAAT3 was comparatively preserved in most of the remaining neurons in all subjects.Conclusions:An active debate has continued on the subject of whether the cerebral or subcortical lesions are more involved in the epileptogenesis in DRPLA. Neuropathologically, various brainstem changes, such as atrophy of the brainstem tegmentum, have been delineated. Previously we performed neuropathologic analysis of the brainstem in the same subjects and failed to find any PME-specific lesions. The current study showed that the GABAergic interneurons were altered more definitively in cases of juvenile type manifesting PME, whereas glutamate transport might not be severely disturbed in the limbic system in DRPLA. Recently, neuroradiologic studies have shown the presence of cerebral cortical atrophy in DRPLA. Furthermore, the extensive involvement of cerebral cortical neurons was demonstrated by immunohistochemistry against mutant atrophin-1, a responsible protein for DRPLA, particularly in the juvenile type. Taking these findings together, we speculate that the occurrence of PME in DRPLA may be related to the lesions of the cerebral cortex, including the limbic system. We also believe that further functional analysis of the cerebral cortex is useful to examine treatment for the usually intractable PME in DRPLA. Prevalence and Localizing Value of Emotional Facial Paresis in Medically Refractory Temporal Lobe Epilepsy.Purpose:The selection of patients with medically refractory temporal lobe epilepsy (TLE) for surgery depends on the concordance of data from clinical, electroencephalographic (EEG), radiologic, and neuropsychological evaluation. Although the clinical examination is often normal, contralateral emotional facial paresis (EFP) has been observed in patients with medically refractory mesial TLE (MTLE). Emotional facial paresis refers to unilateral lower facial weakness during emotional expression such as smiling, along with normal voluntary facial movements. We intended to determine the frequency of occurrence of EFP and its lateralizing significance in identifying appropriate candidates for anterior temporal lobectomy (ATL) with amygdalohippocampectomy.Methods:We investigated the prevalence, predictive value, and associations of EFP among 50 consecutive patients who underwent ATL during the period from November 1999 to July 2001 and satisfied the following criteria: (a) magnetic resonance imaging (MRI) findings consistent with mesial temporal sclerosis (MTS) and concordant interictal and ictal EEG data; and (b) seizure free or≥90% seizure reduction for≥6 months after ATL. Fifty age- and sex-matched normal subjects acted as controls. Facial asymmetry was assessed at rest and during volitional movements. EFP was looked for during conversation, by provoking a smile. The whole examination undertaken during the video-EEG monitoring was available for review. To ascertain observer bias, two investigators (A.J. and J.C.) independently examined the first 20 patients for the presence or absence of emotional facial paresis. The interobserver agreement was 80% with a kappa value of 0.63. Subsequently, one investigator (A.J.) assessed all subjects, and controversies were resolved by reexamination along with J.C. or K.R. We used standard deviation to define the dispersion, andttest (two-tailed) and Fisher's exact test to evaluate the significance of the association of different clinical characteristics between patient and control groups, and between patients with and without emotional facial paresis.Results:The patients comprised 27 male and 23 female subjects. The age at ATL ranged from 14 to 55 years, and the mean duration of epilepsy before ATL was 17.8 years. When compared with eight (16%) of 50 control subjects, 36 (72%) of 50 MTLE patients exhibited unilateral EFP; the difference was highly significant (p<0.0001). The presence of contralateral EFP correctly predicted the side of ATL in 86.1% of patients. Patients with EFP had a longer duration of epilepsy compared with those without this sign (19.2± 8.0 vs. 14.4± 6.1 years; p= 0.048). We did not find any significant association between EFP and the following clinical characteristics: age at epilepsy onset, age at ATL, gender, and antecedent history of febrile seizures. Both the patients and the control subjects had EFP more frequently involving the right side of the face. Of the eight control subjects who had EFP, seven had it on the right. Whereas 13 (54.2%) of 24 patients with right MTLE had EFP (on the left side in 11), 23 (88.5%) of 26 with left MTLE had emotional facial paresis (right side in 20; p= 0.011).Conclusions:Our observations confirm that EFP contralateral to the side of MTS is a valuable localizing sign in correctly predicting the epileptogenic temporal lobe. To our knowledge, the significant association we observed between left MTLE and more frequent occurrence of emotional facial paresis has not been previously documented. The value of EFP in localizing the ictal-onset zone in patients with bilateral MTS is uncertain. We hypothesize that the presence of an intact right hemisphere and pathologic changes more extensive than MTS may be required for EFP to be readily manifest. Convulsive Episodes in Patients with Group A Xeroderma Pigmentosum.Purpose:Xeroderma pigmentosum is an autosomal recessive disease characterized by sunlight hypersensitivity, freckles, and skin cancers. In addition to these skin lesions, patients with group A xeroderma pigmentosum (A-XP) show progressive and severe neurologic complications of unknown causes. However, few A-XP patients with seizure disorders have been reported in the literature (Mimaki et al., 1988), and no systematic search for seizure disorders in A-XP patients has been performed. We aimed to clarify the incidence of convulsive episodes in patients with A-XP.Methods:We investigated the history of convulsive episodes of 33 A-XP patients in our institute by reviewing the medical charts or conducting interviews with caregivers.Results:Five patients had episodes of convulsions at age 12 years (YoT, male), 13 (MA, female), 14 (HM, female), 16 (YY, female), and 19 and 21 (YaT, male) years. YoT and YY were siblings, and they had another healthy brother who had no history of convulsive episodes. Their parents also had no history of convulsions. Among family members of MA, HM, and YaT, no seizure disorder was identified. YoT, MA, HM, and YY exhibited brief episodes of loss of consciousness with cessation of movement. Valproate acid (VPA) was effective for these episodes. YaT had a brief cessation of respiration at age 19 years, which disappeared after phenobarbital (PB) administration. PB was discontinued by the family after 6 months of treatment, and he (YaT) had a generalized tonic seizure with left upper extremity focality at age 21 years. He has been taking PB again, and no further episode appeared for the past 4 years. A few low-voltage theta rhythms were the dominant background activities of drug-induced sleep EEG recordings of these five patients. Except HM, no apparent epileptic discharge was found on interictal EEG recordings. HM showed periodic high-voltage sharp waves at bilateral frontal regions on drug-induced sleep EEG recording when she was 15 years old. Except MA, no A-XP patient had an episode of febrile seizure. MA had a single febrile seizure when she was 4 years old.Conclusions:Because these five patients exhibited recurrent afebrile seizures, we diagnosed them as having epilepsy. However, we could not identify the precise type of epilepsy, in part because of few EEG findings. A-XP patients exhibit marked diffuse brain atrophy after age 5 years (Ohinata et al., 2002), which makes it difficult to obtain apparent epileptic discharges on routine EEG recordings. From the clinical standpoint, YaT is considered to have symptomatic localization-related epilepsy, showing complex partial seizures at age 19 years with secondary generalization at 21 years. The other four patients might exhibit complex partial seizures (due to localization-related epilepsy) or atypical absence seizures (due to generalized epilepsy), but few typical EEG findings, making it difficult to differentiate the types of epilepsy. Nevertheless, we diagnosed five (15%) of 33 A-XP patients as having symptomatic epilepsy. In contrast, we found only one (3%) patient with a history of febrile seizures. In the general population,∼3% of all people living to age 80 years in the United States will be diagnosed with epilepsy (Westbrook, 2000). The cumulative incidence of febrile seizures in Europe and the United States is 2–5%, and that in Japan is 8–10% (Maeda, 2001). Taking these figures together, in comparison with the general Japanese population, Japanese A-XP patients show a lower incidence of febrile seizures, whereas they exhibit a higher prevalence of epilepsy. Neurohumoral Behavior of Epilepsy with Neurocysticercosis in Nepal.Purpose:Epilepsy due to neurocysticercosis (NC) is common in Nepal. The 120 epilepsy cases with NC confirmed by magnetic resonance imaging (MRI),Diagnostic and Statistical Manual of Mental DisordersIV, and International League Against Epilepsy criteria were subjected to enzyme-linked immunosorbent assay (ELISA) testing for comparative study of serum anti-cysticercus antibody levels between epilepsy with various types of NC before and after treatment with antihelminthic, correlation with therapeutic efficacy of cysticide, and identification of a prognostic indicator. Comparative MRI studies of the brain were done with various types of NC before and after treatment to evaluate drug efficacy, resolution rate of the cerebral lesion, and correlation with antibody titer.Methods:Ninety persons with epilepsy with single benign parenchymal NC and 30 with multiple benign parenchymal NC were subjected to ELISA before and 1 month after the unified treatment regimen with albendazole, 15 mg/kg/body wt daily, for 8 days, and oral cortisone. Comparative studies of serum antibody titers and correlation between mean optical density (OD) and therapeutic efficacy of cysticide before and after treatment were done to evaluate the therapeutic efficacy. Assessment of antibody titer was done to understand the efficacy of treatment and to find an indicator of prognosis. MRI scan of the brain was done before and 8 days after the treatment to assess the resolution of the cerebral lesion and correlation with antibody titer.Results:The sensitivity of ELISA for serum anti-cysticercus antibodies in epilepsy with multiple benign parenchymal NC was 93.3%, showing strong positivity in contrast to epilepsy with single benign parenchymal NC, with a sensitivity of 77.8%. Comparative studies of the sensitivity of ELISA between epilepsy with single and multiple benign parenchymal NC before treatment were significant (F= 15.47; p≤ 0.0001). The mean ODs of epilepsy cases with single benign parenchymal NC before and after treatment were mean, 1.387; SD, 0.433; and m, 0.314 SD, 0.102, respectively (F= 430.31; p= 0.0001). In contrast, the ODs of epilepsy with multiple benign parenchymal NC were m, 1.757; SD, 0.321; and m, 0.482; SD, 0.164, respectively (p= 0.0001). The differences between the OD of epilepsy with single (m, 0.314; SD, 0.102) and multiple benign parenchymal NC (m, 0.482; SD, 0.164) before and after treatment were highly statistically significance (F= 43.93; p= 0.0001). MRI study after treatment for epilepsy with various types of NC revealed that of 90 epilepsy cases with single benign parenchymal NC, 94.4% resolved completely, 2.2% resolved partially, and 3.3% showed no change, whereas, of 30 epilepsy cases with multiple benign parenchymal NC, 40% resolved completely, 30% resolved partially, and 30% showed no change. The comparative therapeutic responses to albendazole in epilepsy cases with single benign parenchymal NC and multiple benign parenchymal NC revealed that the former responded better than the latter (i.e., the cure and resolution rate was 94.4% vs. 40% for epilepsy with single benign parenchymal NC vs. multiple benign parenchymal NC). Epilepsy with single benign parenchymal NC having low serum OD showed better response to treatment, in contrast to epilepsy with multiple benign parenchymal NC having higher serum OD.Conclusions:Epilepsy with NC is the biologic marker of poverty and poor sanitation in the community of an undeveloped country. The low serum OD in epilepsy with single benign parenchymal NC showed a better response to the treatment in contrast to epilepsy with multiple benign parenchymal NC having higher serum OD. These results indicate that low serum antibody titer of epilepsy with NC predicts good prognosis and better therapeutic efficacy of antihelminthic treatment. The evaluation of the serum antibody titer of epilepsy with NC may be used for the diagnosis, assessment of therapeutic efficacy of antihelminthic treatment, and prediction of prognosis. Probable Molecular Dysfunction by Autoantibodies Against NMDA-Receptor GluRℇ2 in Epilepsies After Acute Encephalitis.Purpose:Glutamate receptors (GluRs) in the central nervous system play an important role in the excitatory synapse and have been implicated in neurodegenerative diseases and symptomatic epilepsy. After Rogers et al. reported that autoantibodies against GluR3 were involved in some cases of Rasmussen encephalitis, studies focused on other neurologic diseases with a possible causal relation to autoantibodies against GluRs. In 1999, we found autoantibodies against theN-methyl-d-aspartate (NMDA) GluRℇ2 subunit in sera and CSF from patients with chronic progressive epilepsia partialis continua, Rasmussen encephalitis, and other diseases. To elucidate the pathophysiologic mechanisms of intractable epilepsy after acute encephalitis or encephalopathies, we studied the autoantibodies in sera and CSF from such patients.Methods:With the tetracycline-induction system, we established stable NIH3T3 transformant cell lines expressing the NMDA-type GluRℇ2 subunit. Cell extracts of the transformants were transferred to nitrocellulose membranes to detect the presence of antibodies against GluRℇ2. The membrane was exposed to sera from patients and was stained by second antibodies coupled to alkaline phosphatase. Four peptides (an N-terminal, and three C-terminal fragments) were synthesized from GluRℇ2 cDNA by using bacterial fusion protein vectors. Homogenates of the transformants and bacteria were transferred to nitrocellulose membranes, and the membranes were incubated with the patients' sera or CSF, and stained by second antibodies coupled to alkaline phosphatase. Fifteen patients with epilepsies after acute encephalitis (influenza virus; two patients, herpes simplex virus; two, varicella zoster virus; one, others) and three after acute encephalopathies (influenza vaccination, others) were studied. Ages at onset were from 2 to 36 years (0–5 years, eight patients; 6–10 years, four; 11–15 years, three; older than 16 years, three). Cerebral palsy was found in eight patients, and mental retardation (IQ<70) in 11 of 18 patients. Seizure outcome ranged from seizure free (five patients), monthly (four), weekly (five), to daily (three).Results:Immunoglobulin G (IgG) and IgM autoantibodies against the NMDA GluRℇ2 subunit were positive in 13 and 12, respectively, of 18 patients. IgM autoantibodies disappeared in two patients, and IgG autoantibodies changed from absence to presence in three patients evolutionally. Two patients continued to have the autoantibodies even several years after acute encephalitis. Production of autoantibodies against GluRℇ2 was related significantly to episodes of convulsive status epilepticus in the acute stage of encephalitis (p= 0.19; Spearman's correlation coefficient by rank test) and insignificantly to cell counts and protein levels in CSF, duration of unconsciousness, and the latency of first convulsion from onset. Comparing neuropsychological outcomes between patients with and without the autoantibodies, the autoantibodies were causally related to mental retardation (p<0.03, Mann–WhitneyUtest), motor impairment (p<0.03,χ2 for independent test), and seizure frequencies (p<0.03, Spearman's correlation coefficient by rank test). The epitopes of the autoantibodies existed mainly in the c-terminal of GluRℇ2 molecules. In five patients (broader type), both n- and c-terminals were epitopes of the autoantibodies; in eight (narrow type), only c-terminals were epitopes. Comparing the relations between broadness of epitopes and clinical factors, no significant correlation was found for age at onset (p= 0.11, Spearman's correlation coefficient by rank test), concentration of proteins in CSF (p= 0.07, Spearman's test), and latency of convulsion from the onset of illness (p= 0.09, Spearman's test). The broadness of epitopes was not related to neuropsychological outcomes but was related to lower cell counts in CSF. The spectra of epitopes were broader in CSF than in sera.Conclusions:Production of the autoantibodies might be related to destruction of brain tissue by a convulsive status and might contribute to severe neuropsychological outcomes. Relationship Between Clinical Characteristics and Magnetoencephalographic Findings in Typical and Atypical Benign Childhood Epilepsy with Centrotemporal Spikes.Purpose:Benign childhood epilepsy with centrotemporal spikes (BECT) is an electroclinical syndrome characterized by partial sensorimotor seizures (sylvian seizures: SSs) with centrotemporal spikes (rolandic discharges: RDs). Typically the prognosis is excellent with remission before age 16 years. However, some patients with BECT initially seem to evolve into atypical or complicated types, one of which has been called atypical benign partial epilepsy of childhood (ABPC) by Aicardi. Recently, the search for the predictor of evolution into atypical or complicated types was attempted. In this article, we use the termcomplicated BECT(CECT) to include atypical or complicated types. We report the detailed analysis of the generator of RDs in BECT and CECT by using magnetoencephalography (MEG).Methods:Sixteen children with BECT undertook MEG examination; seven were excluded because of insufficient numbers of RDs for analysis, leaving nine patients. All three patients with CECT were characterized as having frequent atonic seizures (negative myoclonus) or hemifacial or hand twitching, with continuous spike–waves during slow wave sleep in EEG, and also mental deterioration. MEG activity was recorded during sleep by using a whole-head 204-channel neuro-magnetometer (Neuromag-204) with simultaneous EEG recordings. Locations and directions of estimated dipoles of high-amplitude MEG sharp waves were displayed on magnetic resonance images. The data were sampled at 300 Hz with a 160-Hz low-pass filter and analyzed under 45-Hz low-pass filter and 1- to 3-Hz high-pass filter. Analysis of three types of MEG spikes was performed: current dipoles of the first of the highest or lowest peak. Therefore, a uniform pattern of MEG spikes was analyzed individually.Results:In nine (56.3%) of 16 patients with BECT and all three (100%) patients with CECT, sufficient numbers of MEG spikes (>30 spikes in several sampling sequences for about several minutes each) were detected for analysis. Five typical BECT patients had only SSs during sleep, typical unilateral RDs, and over a 2-year seizure-free period, except one patient. These patients had typical MEG spikes characterized by current dipoles showing relatively limited localization and regular directions. The remaining four patients with BECT had clinical characteristics other than SSs, such as refractory SSs, perioral twitching during wakefulness, febrile convulsions after epilepsy onset, and fewer RDs on EEG while remaining significant in number on MEG. These patients showed less concentrated MEG spikes and moderately irregular dipole directions. In all three patients with CECT, current dipoles were scattered widely around rolandic areas, showing more irregular directions.Conclusions:Although we have not developed sequential MEG data of individual patients, our MEG findings may suggest an intermediate type of BECT as a continuum between typical BECT and CECT. Scattering of epileptic foci from the restricted rolandic areas may be due to some immaturity of neuronal systems. Multifocal activated cortical areas, including excessively inhibitory or excitatory neuronal generators, may induce CECT evolution and neuropsychological dysfunction. This kind of mechanism may play a role in the formation of secondary bilateral synchrony, which is considered to cause generalized spike–waves in some cases of BECT. If sequential MEG data in the very early stages of BECT onset are obtainable individually, evolution to complicated BECT may be predictable. Our MEG findings suggest an intermediate type of BECT as a continuum between typical BECT and CECT or ABPC. If current dipoles are scattered and showing more irregular directions, even in the early stage of CECT, MEG study may be a quick predictor of complications. MEG may be able to explain the mechanism of evolution of typical BECT to complicated BECT. Safe Pregnancy in Epilepsy: Registry of Epilepsy and Pregnancy Initiative in India.Background:Care for women with epilepsy (WWE) is suboptimal in most countries. The Government of India has recently eased the legal constraints to marriage for WWE. The proportion of married among WWE is comparable to that in the community, according to a survey in Kerala State. WWE in developing countries face several difficulties. Health services are sparse and expensive. Many of them have malnutrition, anemia, or intercurrent infections. Social stigma is another major handicap.Objective:Indian Registry of Epilepsy and Pregnancy (IREP) is established to monitor reproductive functions in WWE and facilitate their optimal care under prevailing conditions.Methods:The first registry in India was started at Trivandrum (TVM) in 1998. A consensus protocol was developed in a workshop held in Trivandrum in 1998. Preconception management focuses on diagnosis, antiepileptic drug (AED) therapy, if required, and initiation of folate supplementation. We use a higher dose of folate (5 mg daily) to obviate any nutritional deficiency. The early antenatal care includes estimation of serumα-fetoprotein (16 weeks) and malformation-targeted ultrasonography (18 weeks). The couple is provided extensive counseling on the diverse aspects of epilepsy and pregnancy. It is often necessary to counsel close relatives also, as many couples live in joint families. Two intramuscular injections of vitamin K (10 mg) are recommended in the last 6 weeks of pregnancy, as oral vitamin K preparations are not widely available. Three months after delivery, babies are screened for malformations by physical examination, echocardiography and abdominal ultrasonography. We assess development and language at 1 and 3 years, respectively. Similar registries were set up on the east coast (Vishakhapattanam-VZG, 1999) and North India (Ludhiana-LDH, 2000). These registries are following a unified protocol and joined together to form IREP. Three new centers are being established in other parts of India. IREP is now pooling data with the European Registry of Epilepsy and Pregnancy.Results:As of January 2002, 547 WWE (mean age, 24 years) were enrolled (TVM, 386; VZG, 125; LDH, 36), and 320 had completed pregnancies (TVM, 224; VZG, 66; LDH, 30). AEDs included carbamazepine,141; phenytoin, 98; phenobarbitone, 83; valproate, 63; clobazam, 12; clonazepam, seven; and lamotrigine, seven. Preconception or first trimester folate supplementation was high in TVM (83%) but low in VZG (33%) and LDH (17%). There were 38 (11.9%) cases with malformations (including two terminations). Nervous system malformations included spina bifida and meningomyelocele (three). There were 20 cases of cardiac defects, including tetrology of Fallot, coarctation of the aorta, patent ductus, septal defects, and patent foramen ovale; some of latter had closed subsequently. Other malformations involved the skeleton (seven), genitourinary system (four), and anterior abdominal wall (three). Babies from one center (TVM) showed mild delay in motor and mental development at age 1 year, when compared with matched normal babies.Conclusions:The spectrum and prevalence of birth defects observed in this study are comparable to those in reports from elsewhere. Ultrasonography and echocardiography has enabled us to detect malformations like hydronephrosis, cyst in liver, and small septal defects. It is debatable whether patent foramen ovale should be recognized as an anomaly or otherwise, as several of them closed subsequently. This initiative has sensitized the medical fraternity to the special needs of WWE and has contributed to improving the standards of care for them. Wada Test and Interictal[ 18F]FDG-PET in Unilateral Temporal Lobe Epilepsy.Purpose:To investigate the association between regional glucose metabolism obtained with interictal[18F]fluorodeoxyglucose positron emission tomography (18FDG-PET) and material-specific memory measured with the Wada test in patients with unilateral temporal lobe epilepsy.Methods:We investigated 47 consecutive patients with intractable, unilateral temporal lobe epilepsy (26 left and 21 right) who underwent presurgical evaluation including interictal18FDG-PET and the Wada test. Nine patients had non-left dominance for language (one right and eight mixed); the remainder were left dominant. To obtain regional glucose metabolism, we worked with 14 groups of regions of interest (ROIs) in either hemisphere. We calculated the PET asymmetry index (PET-AI) for each group of ROIs by using the formula: (L− R)/(L+ R)× 200, where L or R represents averaged glucose metabolism in each ROI on the left or right hemisphere. In addition, we created a“general asymmetry factor,” which is the mean of all the 14 PET-AIs, to diminish general effects of unilateral hemispheric hypometabolism that are commonly seen in patients with unilateral temporal lobe epilepsy. To estimate unilateral memory, we used recognition memory paradigms in the Wada test based on words, faces, and pictures and obtained three material-specific memory scores for each hemisphere. The memory asymmetry index (memory-AI) for each material was calculated by using the formula: (L− R)/6× 100, where L or R represents material-specific memory scores performed on the left or right hemisphere. In our statistical analysis, we created a linear regression model to predict the memory-AI for each material by combining the PET-AI for each ROI with the general asymmetry factor. The model was compared between subgroups according to the side of focus or the language dominance.Results:The associations between the PET-AI and the memory-AI did not significantly differ between patients with left and right foci. In four combinations of PET-AI and memory-AI, the associations were significantly different between the subgroups according to language dominance. Only patients with non-left language dominance showed positive correlation of PET-AI with memory-AI: PET-AI for the lateral frontal region with memory-AI for words (t=−3.39; p= 0.002) or for pictures (t=−2.29; p= 0.027); PET-AI for the anterior inferior temporal region and memory-AI for faces (t=−2.48; p= 0.017); and memory-AI for words and PET-AI for the anterior superior temporal regions (t=−1.99; p= 0.053).Conclusions:When we analysed the subgroups according to the side of focus, we found no significant associations between the PET-AI in any brain area and the memory-AI for any material. In contrast, when we analyzed the subgroups according to language dominance, we found four significant associations between hypometabolism in certain areas and material-specific memory deficits, and this was observed only in patients with non-left language dominance. Our results suggest that in patients with unilateral, drug-resistant temporal lobe epilepsy, functional anatomy of memory also is influenced by language dominance. Muscle Activity During Non-REM Sleep in Patients with Infantile Spasms.Purpose:Under physiologic conditions, muscle activity is abolished during rapid-eye-movement (REM) sleep but is sustained in non-REM sleep. We found a disturbance of muscle activity during REM sleep in patients with infantile spasms (ISs) (Kohyama et al., 2000). In the current study, we examined muscle activity during non-REM sleep in patients with ISs.Methods:Twelve IS patients (ages, 53–83 postconceptional weeks; mean, 64.1), who had not previously been treated, were enrolled in the study. Nine of 12 patients had a good prognosis on convulsions. One all-night polysomnography was performed for each patient, and the percentage of chin muscle atonia during non-REM sleep (%ATNR) was calculated. Seven neurologically unaffected infants (ages, 55–81 postconceptional weeks; mean, 70.4 weeks) served as age-matched controls.Results:%ATNR in IS patients ranged from 5.5 to 33.4 (mean, 19.0). The mean value was higher than that in the controls (13.8; range, 3.4–29.4), although no significant difference was obtained (p= 0.27).Conclusions:Petre-Quadens (1972) reported the normal %ATNR value in 10 children aged three months to 5 years as 14.7%. In comparison with this value, Fukuyama et al. (1979) reported elevation of %ATNR in IS patients. They also reported that the mean %ATNR value in three patients who showed unfavorable response to adrenocorticotropic hormone (ACTH; 45.3; range, 32.0–63.8) was higher than that in five IS patients with a favorable response to ACTH therapy (37.6; range, 17.7–55.1). Interestingly, Petre-Quadens (1972) also reported elevation of a similar index in children with mental retardation. Brain insults may result in the elevation of %ATNR. In the current study, however, we failed to demonstrate a significant difference in %ATNR between IS patients and age-matched controls. Petre-Quadens (1972) also observed the average %ATNR in young adults (aged 15–25 years) to be 2.4% and hypothesized that this index declines with age progression. However, based on a study with healthy young children, we found no age-related decrease of %ATNR (Furushima et al., 2002). The cited works including the current study were based on visual inspection of muscle activity, and so far, no consistent results have been obtained on %ATNR. Recently, Werth et al. (2002) analyzed chin muscle activity during non-REM sleep by using computer analysis, and found that chin muscle atonia during non-REM sleep appeared at a constant rate of 10–15% throughout the night in healthy young adults. They also examined %ATNR in patients with narcolepsy and observed that the latency to chin muscle atonia during non-REM sleep was shorter in narcoleptics (0.7± 1.1 min) than in normal controls (48.8± 28.9 min). They speculated that atonia during non-REM represents a measurement of REM propensity. The brainstem cholinergic and monoaminergic systems are involved in the state-dependent muscle activity control. Cholinergic agents microinjected into the brainstem elicit muscle-tone suppression, and the disfacilitation of serotonergic system is considered to be involved in the decrease of excitability of the hypoglossal motoneuron. %ATNR is easily measured on routine EEG recordings, with the only addition of the measurement of chin muscle tone. %ATNR is a potentially useful index reflecting the balance between the brainstem cholinergic and monoaminergic activities. Broad clinical application of %ATNR with the development of a computerized analyzing system is expected to provide new insights into the assessment of cholino-monoaminergic activities in the brainstem. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to review papers that assessed the vitamin D intake of children living in Norway, as research has suggested that it has remained below the recommended daily allowance of 10 μg/day. Methods: This mini review examined the vitamin D status of Norwegian children aged 0–18 years by systematically searching the PubMed, Google Scholar and Scopus databases from 1 January 2009 to 1 July 2020. Results: The review comprised six studies published in English between 2009 and 2020 on native‐born and non‐Western immigrant children. Most studies defined satisfactory vitamin D status as a plasma 25‐hydroxyvitamin D (25(OH)D) concentration of 50 nmol/L, with 25–50 nmol/L being classified as insufficient and below 25 nmol/L being classified as deficient. A study of healthy children found that 21% had insufficient levels and a further 1% were deficient, but this second finding was only among adolescents. Other studies showed that 47% of Norwegian children with a non‐Western immigrant background were deficient, and so were 19% of overweight children, mainly adolescents. Conclusion: Vitamin D concentrations were often insufficient among children living in Norway, particularly adolescents and those with a non‐Western immigrant background. Higher recommended supplements may be needed. [ABSTRACT FROM AUTHOR]

Eosinophils are a type of granulocyte key to immune system modulation seen in a number of disease processes. Nearly every major organ system can be connected to peripheral eosinophilia through a number of different disease processes, ranging from benign conditions to malignancy. In this paper, we review both common and rare causes of peripheral eosinophilia, their symptoms, and a framework for the workup of peripheral eosinophilia of unknown etiology. [ABSTRACT FROM AUTHOR]

Tattoo-associated cutaneous reactions have become quite frequent given the increasing percentage of tattooed subjects globally and also in Italy. On the other hand, the increasing use of target therapy is showing the ability of these drugs to affect the immune system and also cause adverse tattoo-related reactions. In this paper, we report a case of a 42-year-old patient with stage-IIID melanoma undergoing treatment with Dabrafenib and Trametinib. The patient reported erythema, oedema and scaling in areas of the body containing a black tattoo, and, conversely, no signs and/or symptoms in areas with tattoos of a different color. Histopathological and immunohistochemical features indicated a lympho-histiocytic reaction with a granulomatous morphology, mainly distributed around the vessels and hair adnexa. By discussing the cases reported in the literature prior to ours, we concluded and provided the possible indications of the pathogenesis. [ABSTRACT FROM AUTHOR]

Although not as well studied as the bacterial component of the human microbiota, the commensal fungi or mycobiota play important roles in maintaining our health by augmenting our immune system. This mycobiota is also associated with various fatal diseases like opportunistic mycoses, and even cancer, with different cancers having respective type-specific mycobiota. The different fungal species which comprise these different intratumoral mycobiota play important roles in cancer progression. The aim of this review paper is to decipher the association between mycobiota and cancer, and shed light on new avenues in cancer diagnosis, and the development of new anti-cancer therapeutics. [ABSTRACT FROM AUTHOR]

Artificial immune systems (AIS), as nature-inspired algorithms, have been developed to solve various types of problems, ranging from machine learning to optimization. This paper proposes a novel hybrid model of AIS that incorporates cellular automata (CA), known as the cellular automata-based artificial immune system (CaAIS), specifically designed for dynamic optimization problems where the environment changes over time. In the proposed model, antibodies, representing nominal solutions, are distributed across a cellular grid that corresponds to the search space. These antibodies generate hyper-mutation clones at different times by interacting with neighboring cells in parallel, thereby producing different solutions. Through local interactions between neighboring cells, near-best parameters and near-optimal solutions are propagated throughout the search space. Iteratively, in each cell and in parallel, the most effective antibodies are retained as memory. In contrast, weak antibodies are removed and replaced with new antibodies until stopping criteria are met. The CaAIS combines cellular automata computational power with AIS optimization capability. To evaluate the CaAIS performance, several experiments have been conducted on the Moving Peaks Benchmark. These experiments consider different configurations such as neighborhood size and re-randomization of antibodies. The simulation results statistically demonstrate the superiority of the CaAIS over other artificial immune system algorithms in most cases, particularly in dynamic environments. [ABSTRACT FROM AUTHOR]

Purpose: The immune system is influenced by many factors, including female sex hormones. The extent of this influence, however, is not completely understood so far. This systematic literature review aims at giving an overview of the existing concepts on how endogenous progesterone influences the female immune system along the menstrual cycle. Methods: The inclusion criteria were healthy female subjects in their reproductive age with a regular menstrual cycle. The exclusion criteria were exogenous progesterone, animal models, nonhealthy study populations and pregnancy. This led to 18 papers covered in this review. The search was performed using the databases EMBASE, Ovid MEDLINE and Epub, and the last search was conducted on September 18, 2020. Our findings were analyzed in four categories: cellular immune defense, humoral immune defense, objective and subjective clinical parameters. Results: We demonstrated that progesterone acts in an immunosuppressive way, favoring a Th-2-like cytokine profile. Further, we showed that progesterone inhibits mast cell degranulation and relaxes smooth muscle cells. Furthermore, we found supporting evidence for a so-called window of vulnerability after ovulation, where immune functions are lowered and mediated through progesterone. Conclusion: The clinical relevance of these findings is not completely understood yet. As the sample sizes of included studies were rather small and the content of them was broad, further investigations are needed to define to which extent the described changes actually clinically meaningful, whether they are capable of influencing the female health and how these findings can be used to increase well-being. [ABSTRACT FROM AUTHOR]

Cancer has evolved into a substantial public health concern as the second-leading cause of mortality globally. Radiotherapy and chemotherapy have been the two most widely used cancer therapies in recent years; however, both have drawbacks. Therefore, the focus has shifted to the creation of herbal medicines, the extraction of active ingredients, replacement therapy, and the adverse effects of these medications. Ginsenoside Rh2, which is extracted from ginseng, has been identified in many cancer cells. The immune system of the body is strengthened by ginsenoside Rh2, which can also cause the proliferation, death, and differentiation of tumor cells through various pathways. For instance, it inhibits the expression of the NF- κ B signaling pathway and induces cell apoptosis, affects the expression levels of mitochondrial apoptosis proteins Bcl-2 and Bax, and cooperates with the PD-1 blockade to reactivate T cells to promote an antitumor immune response. Furthermore, ginsenosides Rh2 has the effect of reversing the toxic effect of chemotherapy drugs on normal cells, reducing myocardial damage, and relieving bone marrow function suppression. For clinical applications, it is mainly used as an adjuvant drug for preoperative neoadjuvant chemotherapy, postoperative adjuvant chemotherapy, and rescue treatment of advanced cancer. This paper summarizes the pharmacological action and mechanism of ginsenosides Rh2 in all kinds of cancer and looks forward to its future development and application. [ABSTRACT FROM AUTHOR]

Invasive aspergillosis (IA) is a leading cause of mortality in haematological patients. Appropriate activation of the innate immune system is crucial for the successful clearance of IA. Therefore, we studied the Aspergillus fumigatus-mediated activation of human granulocytes and monocyte-derived immature dendritic cells (DCs), as well as murine bone marrow-derived DCs (BMDCs) from wild type, toll-like receptor (TLR)4-deficient, TLR2 knockout, and TLR2/TLR4 double deficient mice. Aspergillus fumigatus antigens induced the activation and maturation of immature DCs as characterized by CD83 expression, upregulation of major histocompatibility complex and co-stimulatory molecules. Moreover, fungal antigens enhanced the phagocytosis and production of interleukin (IL)-8 in granulocytes. The release of IL-12 by BMDCs in response to A. fumigatus antigens was dependent on the expression of TLR2, whereas the release of IL-6 was dependent on the expression of functional TLR4 molecules. The protein precipitate of A. fumigatus supernatant provided strong stimulation of DCs and granulocytes, indicating that a factor secreted by A. fumigatus might activate innate immune cells. In conclusion, A. fumigatus antigens induced the activation of DCs and granulocytes. Our results indicated that this activation was mediated via TLR2 and TLR4. Future studies are needed to assess the clinical impact of these findings in patients at high risk for IA. [ABSTRACT FROM AUTHOR]