Kikuchi-Fujimoto disease:A comprehensive review

Kikuchi-Fujimoto disease,a rare form of necrotizing lymphadenitis,is an uncommon,benign,self-limiting disorder of obscure etiology.It affects mostly young adults of both genders.Clinically,it presents with fever and lymphadenopathy of a firm to rubbery consistency frequently involving cervical lymph nodes while weight loss,splenomegaly,leucopenia,and elevated erythrocyte sedimentation rate feature in severely affected patients.Cutaneous involvement occurs in about 30%-40%of cases as facial erythema and nonspecific erythematous papules,plaques,acneiform or morbilliform lesions of great histologic heterogeneity.Both Kikuchi-Fujimoto disease and systemic lupus erythematosus share an obscure and complex relationship as systemic lupus erythematosus may occasionally precede,develop subsequently,or sometimes be associated concurrently with Kikuchi-Fujimoto disease.It is often mistaken for non-Hodgkin lymphoma while lupus lymphadenitis,cat-scratch disease,Sweet’s syndrome,Still’s disease,drug eruptions,infectious mononucleosis,and viral or tubercular lymphadenitis are other common differentials.Fine needle aspiration cytology mostly has features of nonspecific reactive lymphadenitis and immunohistochemistry studies usually show variable features of uncertain diagnostic value.Since its diagnosis is exclusively from histopathology,it needs to be evaluated more carefully;an early lymph node biopsy will obviate the need for unnecessary investigations and therapeutic trials.Its treatment with systemic corticosteroids,hydroxychloroquine,or antimicrobial agents mostly remains empirical.The article reviews clinicoepidemiological,diagnostic,and management aspects of KFD from the perspective of practicing clinicians.

Kikuchi-Fujimoto Disease with Hemophagocytic Syndrome and Pleural Effusion in an Elder Man: A Case Report and Literature Review

Background: Kikuchi-Fujimoto disease (KFD), also named Histiocytic necrotizing lymphadenitis (HNL), is a rare and self-limited necrotizing lymphadenitis, most commonly affects young Asian female. KFD is characterized by lymphadenopathy, cytopenia, fever, rashes, and weight loss, however, hemophagocytic syndrome and pleural effusion are rarely reported. Case Presentation: We present the case of a 61-year-old man with clinical features including fever, lymphadenopathy, purpura, arthralgia, pleural effusion and pulmonary infection. He had cervical lymphnodebiopsy and the pathology is consistent with KFD, laboratory tests and clinical manifestations were consistent with hemophagocytic syndrome (HLH). After initial treatment including corticosteroid and anti-infection drugs, the patient showed improvement but soon deteriorated. Conclusion: KFD is a self-limited disease with spontaneous resolution. However, the cases of KFD with HLH may have a fatal course. Early appropriate intensive immunosuppressive therapy and strong anti-infection therapy could be beneficial for the treatment outcome.

Kikuchi-Fujimoto Disease in Patients with Sjogren’s Syndrome

Sjogren’s syndrome is a chronic autoimmune exocrinopathy associated with dry eyes and dry mouth as major clinical manifestations. It is characterized by lymphocytic infiltration of lacrimal and salivary glands and autoantibody production, especially anti-Ro (or SSA) and anti-La (or SSB). Lymphoproliferative disorders are a feature of Sjogren’s syndrome, and can be considered an extraglandular manifestation of the disease. Kikuchi-Fujimoto disease or histiocytic necrotizing lymphadenitis is a rare form of lymphadenitis. It is reported more often in young adult women with localized lymphadenopathy (usually cervical), fever, rashes, and leukopenia. It is a self-limiting disease with resolution within 1 - 4 months in almost all patients. Sjogren’s syndrome has been reported in patients with other systemic diseases including SLE and lymphomas. Here we present a patient with Kikuchi-Fujimoto disease who developed Sjogren’s Syndrome 8 years after her diagnosis of Kikuchi-Fujimoto disease.

Fatality in Kikuchi-Fujimoto disease: A rare phenomenon

Kikuchi-Fujimoto disease(KFD), also known as histiocytic necrotizing lymphadenitis, is an uncommon condition, typically characterized by lymphadenopathy and fevers. It usually has a benign course; however, it may progress to fatality in extremely rare occasions. The diagnosis is made via lymph node biopsy and histopathology. Our patient was a young female who presented with shortness of breath, fever, and malaise. Physical examination revealed significant cervical and axillary lymphadenopathy. Chest X-ray displayed multilobar pneumonia. She required intubation and mechanical ventilation for progressive respiratory distress. Histopathology of lymph nodes demonstrated variable involvement of patchy areas of necrosis within the paracortex composed of karyorrhectic debris with abundant histiocytes consistent with KFD. After initial stabilization, the patient's condition quickly deteriorated with acute anemia, thrombocytopenia and elevated prothrombin time, partial prothrombin time, and D-dimer levels. Disseminated intravascular coagulopathy(DIC) ensued resulting in the patient's fatality. DIC in KFD is not well understood, but it is an important cause of mortality in patients with aggressive disease.

Kikuchi-Fujimoto Disease Mimicking Tuberculosis

A 32-year-old woman presented with a fever and cervical lymphadenopathies. The research for Mycobacterium tuberculosis was negative. Tuberculin skin test was positive. Laboratory investigations showed an elevated erythrocyte sedimentation rate and a normal white blood cell count. Bacteriological and viral investigations were negative. Quantiferon-Tb Gold test was indeterminate. Thraco-abdominal and pelvic computed tomography, FDG-PET and gallium scintigraphy revealed no abnormalities. Histological study of cervical lymph node biopsy found signs in favor of histiocytic necrotizing lymphadenitis. There were no epithelioid cell granulomas. A test tuberculosis treatment was refused by the patient. The evolution was marked by spontaneous clinical and biological resolution in fifty days. The negative Lowenstein-Jensen culture eliminated formally the tuberculosis. KFD was thus the most likely diagnosis.

An atypical presentation of Kikuchi-Fujimoto disease mimicking systemic lupus erythematosus: case report and literature review

Purpose: To report a case of atypical Kikuchi-Fujimoto disease (KFD) that illustrates several overlapping features with systemic lupus erythematosus (SLE). Methods: A case is reported followed by a review of the current literature. Case report: A 16-year-old boy with an unusual manifestation of Kikuchi-Fujimoto disease (KFD) is described. The patient presented with fever, weight loss and severe abdominal pain, due to extensive necrotizing retroperitoneal and mesenteric lymphadenopathy. During the course of his illness, he developed several symptoms suggestive of systemic lupus erythematosus (SLE): a pericardial effusion, cotton wool spots on the retina and antibodies against nuclear antigens (ANA), Smith (Sm) and ribonucleoprotein (RNP) antigens. However, no additional features of SLE were found. The patient subsequently fully recovered within two months, without initiation of immunosuppressive therapy. His autoantibodies became negative five months after initial presentation and he remains well at his 23 month follow up visit. Discussion: We hypothesize that the autoantibodies developed by our patient were secondary to self-antigen induced autoimmunity related to his extensive tissue necrosis. Despite initially having clinical features suggestive of SLE, our patient’s full and spontaneous recovery strongly supports the diagnosis of KFD. This illustrates the need for careful diagnosis, in order to avoid unnecessary and potentially toxic treatment with immunosuppressive agents.

Kikuchi-Fujimoto Disease Associated to the Epstein-Barr Virus. A Type of Rare Necrotizing Lymphadenitis and Its Differential Diagnosis

Introduction: Kikuchi-Fujimoto disease (KFD), also known as histiocytic necrotizing lymphadenitis, is a specific and self-limited disease;its etiology is unknown. Some causal microorganisms have been proposed. The objective of the present article is to emphasize the clinicopathological characteristics of this disease that has been associated to the Epstein-Barr virus and to compare the histological changes with other types of necrotizing lymphadenopathies. Material and Methods: We studied 32 patients of the Surgical Pathology Service with necrotizing lymphadenitis, diagnosed in the years from 2004 to 2012 to found more cases of this rare disease in our Institution. Patients were 18 women and 14 men with an average age of 37 years. Results: The lymph nodes were cervical and axillary ones, some were associated to autoimmune diseases and no cause was identified in others. One of the cases, was diagnosed as KFD, presented morphological changes characteristic of this disease, such as subcapsular lymphoid follicles, zones with cell debris, epithelioid macrophages, clear-cytoplasm histiocytes, and immunoblast-reactive lymphocytes. Immunohistochemical markers were determined, such as CD20, CD2, CD4, CD8, CD68, lysozyme, CD56, granzyme B and EBER, which demonstrated the presence of B, T lymphocytes, histiocytes and cells positive to EBER. Histological changes in KFD occurred in three stages: proliferative stage, necrotizing, and xanthomatous. It is important to identify the histological stages of the disease because a differential diagnosis must be performed in regard to lymphadenopathies with necrosis and diverse types of lymphomas. Conclusion: We present a case of necrotizing lymphadenitis (KFD) associated to the Epstein-Barr virus and in some cases it is not possible to render a specific diagnosis based on morphologic findings, alone, and a diagnosis of necrotizing lymphadenitis may be used.

The role of exosomes in adult neurogenesis:implications for neurodegenerative diseases

Exosomes are cup-shaped extracellular vesicles with a lipid bilayer that is approximately 30 to 200 nm in thickness.Exosomes are widely distributed in a range of body fluids,including urine,blood,milk,and saliva.Exosomes exert biological function by transporting factors between different cells and by regulating biological pathways in recipient cells.As an important form of intercellular communication,exosomes are increasingly being investigated due to their ability to transfer bioactive molecules such as lipids,proteins,mRNAs,and microRNAs between cells,and because they can regulate physiological and pathological processes in the central nervous system.Adult neurogenesis is a multistage process by which new neurons are generated and migrate to be integrated into existing neuronal circuits.In the adult brain,neurogenesis is mainly localized in two specialized niches:the subventricular zone adjacent to the lateral ventricles and the subgranular zone of the dentate gyrus.An increasing body of evidence indicates that adult neurogenesis is tightly controlled by environmental conditions with the niches.In recent studies,exosomes released from different sources of cells were shown to play an active role in regulating neurogenesis both in vitro and in vivo,thereby participating in the progression of neurodegenerative disorders in patients and in various disease models.Here,we provide a state-of-the-art synopsis of existing research that aimed to identify the diverse components of exosome cargoes and elucidate the therapeutic potential of exosomal contents in the regulation of neurogenesis in several neurodegenerative diseases.We emphasize that exosomal cargoes could serve as a potential biomarker to monitor functional neurogenesis in adults.In addition,exosomes can also be considered as a novel therapeutic approach to treat various neurodegenerative disorders by improving endogenous neurogenesis to mitigate neuronal loss in the central nervous system.

Antisense therapy:a potential breakthrough in the treatment of neurodegenerative diseases

Neurodegenerative diseases are a group of disorders characterized by the progressive degeneration of neurons in the central or peripheral nervous system.Currently,there is no cure for neurodegenerative diseases and this means a heavy burden for patients and the health system worldwide.Therefore,it is necessary to find new therapeutic approaches,and antisense therapies offer this possibility,having the great advantage of not modifying cellular genome and potentially being safer.Many preclinical and clinical studies aim to test the safety and effectiveness of antisense therapies in the treatment of neurodegenerative diseases.The objective of this review is to summarize the recent advances in the development of these new technologies to treat the most common neurodegenerative diseases,with a focus on those antisense therapies that have already received the approval of the U.S.Food and Drug Administration.

ATP-binding cassette transporters as possible targets for the intervention of neurodegenerative diseases

ATP-binding cassette(ABC)transporters are ubiquitous membrane-bound proteins that are responsible for the translocation of a broad spectrum of substrates across cellular membranes,including lipids,amino acids,nucleosides,sugars,and xenobiotics.Interestingly,ABC transporters are highly expressed in the brain.While their functions in the brain still need to be elucidated,several members are implicated in the pathogenesis of neurodegenerative diseases,including Alzheimer’s disease(AD),Parkinson’s disease(PD),and frontotemporal dementia.In this perspective,we will review current knowledge of ABC transporters in the central nervous system in terms of physiological functions and pathology in neurodegeneration.Furthermore,we will explore the possibilities of ABC transporters as potential targets in the development of therapeutics for neurodegenerative diseases.

Causal associations between gastroesophageal reflux disease and essential hypertension: A bidirectional Mendelian randomization study

BACKGROUND Clinical studies have reported that patients with gastroesophageal reflux disease(GERD)have a higher prevalence of hypertension.AIM To performed a bidirectional Mendelian randomization(MR)analysis to investi-gate the causal link between GERD and essential hypertension.METHODS Eligible single nucleotide polymorphisms(SNPs)were selected,and weighted median,inverse variance weighted(IVW)as well as MR egger(MR-Egger)re-gression were used to examine the potential causal association between GERD and hypertension.The MR-Pleiotropy RESidual Sum and Outlier analysis was used to detect and attempt to reduce horizontal pleiotropy by removing outliers SNPs.The MR-Egger intercept test,Cochran’s Q test and“leave-one-out”sen-sitivity analysis were performed to evaluate the horizontal pleiotropy,heterogen-eities,and stability of single instrumental variable.RESULTS IVW analysis exhibited an increased risk of hypertension(OR=1.46,95%CI:1.33-1.59,P=2.14E-16)in GERD patients.And the same result was obtained in replication practice(OR=1.002,95%CI:1.0008-1.003,P=0.000498).Meanwhile,the IVW analysis showed an increased risk of systolic blood pressure(β=0.78,95%CI:0.11-1.44,P=0.021)and hypertensive heart disease(OR=1.68,95%CI:1.36-2.08,P=0.0000016)in GERD patients.Moreover,we found an decreased risk of Barrett's esophagus(OR=0.91,95%CI:0.83-0.99,P=0.043)in essential hypertension patients.CONCLUSION We found that GERD would increase the risk of essential hypertension,which provided a novel prevent and therapeutic perspectives of essential hypertension.

The History of Controlling and Treating Infectious Diseases in Ancient China

Infectious diseases are the common enemies of mankind.In the course of historical development,they persistently threaten human health and safety.Even today,despite the developments in medical science,we cannot escape the fear and suffering caused by infectious diseases.Whether in ancient or modern times,the source of infection,route of transmission,and a susceptible population are the three key conditions for the prevalence and spread of infectious diseases.All factors closely related to these three conditions can affect the prevalence of infectious diseases.China is one of the cradles of world civilization.The ancient people accumulated a great deal of experience and lessons in the long struggle against infectious diseases.In the face of the current threat posed by widespread infectious disease,it is imperative to review and summarize ancient Chinese ideas and health policies on epidemic prevention and control to inspire contemporary efforts in the prevention and control of infectious disease.The combination of prevention-oriented epidemic prevention ideology and traditional medicine provides valuable insights,especially for impoverished and medically underserved regions.

Correlation between the gut microbiome and neurodegenerative diseases:a review of metagenomics evidence

A growing body of evidence suggests that the gut microbiota contributes to the development of neurodegenerative diseases via the microbiota-gut-brain axis.As a contributing factor,microbiota dysbiosis always occurs in pathological changes of neurodegenerative diseases,such as Alzheimer’s disease,Parkinson’s disease,and amyotrophic lateral sclerosis.High-throughput sequencing technology has helped to reveal that the bidirectional communication between the central nervous system and the enteric nervous system is facilitated by the microbiota’s diverse microorganisms,and for both neuroimmune and neuroendocrine systems.Here,we summarize the bioinformatics analysis and wet-biology validation for the gut metagenomics in neurodegenerative diseases,with an emphasis on multi-omics studies and the gut virome.The pathogen-associated signaling biomarkers for identifying brain disorders and potential therapeutic targets are also elucidated.Finally,we discuss the role of diet,prebiotics,probiotics,postbiotics and exercise interventions in remodeling the microbiome and reducing the symptoms of neurodegenerative diseases.

Sorl1 knockout inhibits expression of brain-derived neurotrophic factor:involvement in the development of late-onset Alzheimer's disease

Sortilin-related receptor 1(SORL1)is a critical gene associated with late-onset Alzheimer’s disease.SORL1 contributes to the development and progression of this neurodegenerative condition by affecting the transport and metabolism of intracellularβ-amyloid precursor protein.To better understand the underlying mechanisms of SORL1 in the pathogenesis of late-onset Alzheimer s disease,in this study,we established a mouse model of SorI1 gene knockout using cluste red regularly inters paced short palindro mic repeats-associated protein 9 technology.We found that Sorl1-knocko ut mice displayed deficits in learning and memory.Furthermore,the expression of brain-derived neurotrophic factor was significantly downregulated in the hippocampus and co rtex,and amyloidβ-protein deposits were observed in the brains of 5orl1-knockout mice.In vitro,hippocampal neuronal cell synapses from homozygous Sorl1-knockout mice were impaired.The expression of synaptic proteins,including Drebrin and NR2B,was significantly reduced,and also their colocalization.Additionally,by knocking out the Sorl1 gene in N2a cells,we found that expression of the N-methyl-D-aspartate receptor,NR2B,and cyclic adenosine monophosphate-response element binding protein was also inhibited.These findings suggest that SORL1 participates in the pathogenesis of late-onset Alzheimer s disease by regulating the N-methyl-D-aspartate receptor NR2B/cyclic adenosine monophosphate-response element binding protein signaling axis.

Large animal models for Huntington's disease research

Huntington'sdisease(HD)isahereditary neurodegenerative disorder for which there is currently no effectivetreatmentavailable.Consequently,the development of appropriate disease models is critical to thoroughly investigate disease progression.The genetic basis of HD involves the abnormal expansion of CAG repeats in the huntingtin(HTT)gene,leading to the expansion of a polyglutamine repeat in the HTT protein.Mutant HTT carrying the expanded polyglutamine repeat undergoes misfolding and forms aggregates in the brain,which precipitate selective neuronal loss in specific brain regions.Animal models play an important role in elucidating the pathogenesis of neurodegenerative disorders such as HD and in identifying potential therapeutic targets.Due to the marked species differences between rodents and larger animals,substantial efforts have been directed toward establishing large animal models for HD research.These models are pivotal for advancing the discovery of novel therapeutic targets,enhancing effective drug delivery methods,and improving treatment outcomes.We have explored the advantages of utilizing large animal models,particularly pigs,in previous reviews.Since then,however,significant progress has been made in developing more sophisticated animal models that faithfully replicate the typical pathology of HD.In the current review,we provide a comprehensive overview of large animal models of HD,incorporating recent findings regarding the establishment of HD knock-in(KI)pigs and their genetic therapy.We also explore the utilization of large animal models in HD research,with a focus on sheep,non-human primates(NHPs),and pigs.Our objective is to provide valuable insights into the application of these large animal models for the investigation and treatment of neurodegenerative disorders.

Biomaterials-based anti-inflammatory treatment strategies for Alzheimer's disease

The current therapeutic drugs for Alzheimer's disease only improve symptoms,they do not delay disease progression.Therefo re,there is an urgent need for new effective drugs.The underlying pathogenic factors of Alzheimer's disease are not clear,but neuroinflammation can link various hypotheses of Alzheimer's disease;hence,targeting neuroinflammation may be a new hope for Alzheimer's disease treatment.Inhibiting inflammation can restore neuronal function,promote neuro regeneration,reduce the pathological burden of Alzheimer's disease,and improve or even reverse symptoms of Alzheimer's disease.This review focuses on the relationship between inflammation and various pathological hypotheses of Alzheimer's disease;reports the mechanisms and characteristics of small-molecule drugs(e.g.,nonsteroidal anti-inflammatory drugs,neurosteroids,and plant extracts);macromolecule drugs(e.g.,peptides,proteins,and gene therapeutics);and nanocarriers(e.g.,lipid-based nanoparticles,polymeric nanoparticles,nanoemulsions,and inorganic nanoparticles)in the treatment of Alzheimer's disease.The review also makes recommendations for the prospective development of anti-inflammatory strategies based on nanocarriers for the treatment of Alzheimer's disease.

Genome-edited rabbits:Unleashing the potential of a promising experimental animal model across diverse diseases

Animal models are extensively used in all aspects of biomedical research,with substantial contributions to our understanding of diseases,the development of pharmaceuticals,and the exploration of gene functions.The field of genome modification in rabbits has progressed slowly.However,recent advancements,particularly in CRISPR/Cas9-related technologies,have catalyzed the successful development of various genome-edited rabbit models to mimic diverse diseases,including cardiovascular disorders,immunodeficiencies,agingrelated ailments,neurological diseases,and ophthalmic pathologies.These models hold great promise in advancing biomedical research due to their closer physiological and biochemical resemblance to humans compared to mice.This review aims to summarize the novel gene-editing approaches currently available for rabbits and present the applications and prospects of such models in biomedicine,underscoring their impact and future potential in translational medicine.

Metabolic disease and the liver: A review

Metabolic dysfunction-associated steatotic liver disease(MASLD)is the most common liver disease worldwide,with an estimated prevalence of 31%in Latin America.The presence of metabolic comorbidities coexisting with liver disease varies substantially among populations.It is acknowledged that obesity is boosting the type 2 diabetes mellitus“epidemic,”and both conditions are significant contributors to the increasing number of patients with MASLD.Nonalcoholic steatohepatitis represents a condition of chronic liver inflammation and is considered the most severe form of MASLD.MASLD diagnosis is based on the presence of steatosis,noninvasive scores and altered liver tests.Noninvasive scores of liver fibrosis,such as serum biomarkers,which should be used in primary care to rule out advanced fibrosis,are simple,inexpensive,and widely available.Currently,guidelines from international hepatology societies recommend using noninvasive strategies to simplify case finding and management of high-risk patients with MASLD in clinical practice.Unfortunately,there is no definite pharmacological treatment for the condition.Creating public health policies to treat patients with risk factors for MASLD prevention is essential.

Role of CD36 in central nervous system diseases

CD36 is a highly glycosylated integral membrane protein that belongs to the scavenger receptor class B family and regulates the pathological progress of metabolic diseases.CD36 was recently found to be widely expressed in various cell types in the nervous system,including endothelial cells,pericytes,astrocytes,and microglia.CD36 mediates a number of regulatory processes,such as endothelial dysfunction,oxidative stress,mitochondrial dysfunction,and inflammatory responses,which are involved in many central nervous system diseases,such as stroke,Alzheimer’s disease,Parkinson’s disease,and spinal cord injury.CD36 antagonists can suppress CD36 expression or prevent CD36 binding to its ligand,thereby achieving inhibition of CD36-mediated pathways or functions.Here,we reviewed the mechanisms of action of CD36 antagonists,such as Salvianolic acid B,tanshinone IIA,curcumin,sulfosuccinimidyl oleate,antioxidants,and small-molecule compounds.Moreover,we predicted the structures of binding sites between CD36 and antagonists.These sites can provide targets for more efficient and safer CD36 antagonists for the treatment of central nervous system diseases.

Toward understanding the role of genomic repeat elements in neurodegenerative diseases

Neurodegenerative diseases cause great medical and economic burdens for both patients and society;however, the complex molecular mechanisms thereof are not yet well understood. With the development of high-coverage sequencing technology, researchers have started to notice that genomic repeat regions, previously neglected in search of disease culprits, are active contributors to multiple neurodegenerative diseases. In this review, we describe the association between repeat element variants and multiple degenerative diseases through genome-wide association studies and targeted sequencing. We discuss the identification of disease-relevant repeat element variants, further powered by the advancement of long-read sequencing technologies and their related tools, and summarize recent findings in the molecular mechanisms of repeat element variants in brain degeneration, such as those causing transcriptional silencing or RNA-mediated gain of toxic function. Furthermore, we describe how in silico predictions using innovative computational models, such as deep learning language models, could enhance and accelerate our understanding of the functional impact of repeat element variants. Finally, we discuss future directions to advance current findings for a better understanding of neurodegenerative diseases and the clinical applications of genomic repeat elements.