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Cureus May 2024The hemophagocytic syndrome (HS) or hemophagocytic lymphohistiocytosis (HLH) is a syndrome with apoptosis deficiency that results in the impairment of a regulatory...
The hemophagocytic syndrome (HS) or hemophagocytic lymphohistiocytosis (HLH) is a syndrome with apoptosis deficiency that results in the impairment of a regulatory pathway with consequent immune and inflammatory responses. Fever, cytopenias, splenomegaly, and hemophagocytosis are cardinal signs. It may be familial or secondary to infection, autoimmunity, or neoplasia. Impaired natural killer (NK)-cell cytotoxicity is the hallmark of HLH. All genetic defects in familial HLH are related to granule-dependent cytotoxicity. The authors present a 50-year-old black female patient with a history of drepanocytosis who attended the emergency department due to fever, asthenia, lethargy, and hypogastric pain. Her laboratory workup on admission revealed severe pancytopenia. She was ultimately diagnosed with HLH due to sepsis of urinary origin, with a fatal outcome. HLH is a rare and life-threatening syndrome. The delay in its diagnosis due to the variability of the clinical and laboratory findings constitutes the main obstacle to a successful prognosis, as illustrated in this case report.
PubMed: 38910771
DOI: 10.7759/cureus.61015 -
Alzheimer's Research & Therapy Jun 2024Aging and sex are major risk factors for developing late-onset Alzheimer's disease. Compared to men, women experience worse neuropathological burden and cognitive...
Age, sex and Alzheimer's disease: a longitudinal study of 3xTg-AD mice reveals sex-specific disease trajectories and inflammatory responses mirrored in postmortem brains from Alzheimer's patients.
BACKGROUND
Aging and sex are major risk factors for developing late-onset Alzheimer's disease. Compared to men, women experience worse neuropathological burden and cognitive decline despite living longer with the disease. Similarly, male 3xTg-AD mice, developed to model Alzheimer's disease, no longer consistently exhibit standard Alzheimer's neuropathology yet experience higher rates of mortality - providing a unique opportunity to further elucidate this dichotomy. We hypothesized that sex differences in the biological aging process yield distinct pathological and molecular Alzheimer's disease signatures in males and females, which could be harnessed for therapeutic and biomarker development.
METHODS
We aged male and female, 3xTg-AD and B6129 control mice across their respective lifespans (n = 3-8 mice per sex, strain, and age group) and longitudinally assessed neuropathological hallmarks of Alzheimer's disease, markers of hepatic inflammation, splenic mass and morphology, as well as plasma cytokine levels. We conducted RNA sequencing analysis on bulk brain tissue and examined differentially expressed genes (DEGs) between 3xTg-AD and B6129 samples and across ages in each sex. We also examined DEGs between clinical Alzheimer's and control parahippocampal gyrus brain tissue samples from the Mount Sinai Brain Bank study in each sex.
RESULTS
3xTg-AD females significantly outlived 3xTg-AD males and exhibited progressive Alzheimer's neuropathology, while 3xTg-AD males demonstrated progressive hepatic inflammation, splenomegaly, circulating inflammatory proteins, and minimal Alzheimer's neuropathological hallmarks. Instead, 3xTg-AD males experienced an accelerated upregulation of immune-related gene expression in the brain relative to females. Our clinical investigations revealed that individuals with Alzheimer's disease develop similar sex-specific alterations in neuronal and immune function. In diseased males of both species, we observed greater upregulation of complement-related gene expression, and lipopolysaccharide was predicted as the top upstream regulator of DEGs.
CONCLUSIONS
Our data demonstrate that chronic inflammation and complement activation are associated with increased mortality, indicating that age-related changes in immune response contribute to sex differences in Alzheimer's disease trajectories. We provide evidence that aging and transgene-driven disease progression trigger a widespread inflammatory response in 3xTg-AD males, which mimics the impact of lipopolysaccharide stimulation despite the absence of infection.
Topics: Alzheimer Disease; Animals; Female; Male; Mice, Transgenic; Mice; Brain; Humans; Longitudinal Studies; Aging; Disease Models, Animal; Sex Characteristics; Inflammation; Sex Factors; Age Factors; Cytokines
PubMed: 38909241
DOI: 10.1186/s13195-024-01492-x -
Neurobiology of Disease Jun 2024Arketamine, the (R)-enantiomer of ketamine, exhibits antidepressant-like effects in mice, though the precise molecular mechanisms remain elusive. It has been shown to...
Arketamine, the (R)-enantiomer of ketamine, exhibits antidepressant-like effects in mice, though the precise molecular mechanisms remain elusive. It has been shown to reduce splenomegaly and depression-like behaviors in the chronic social defeat stress (CSDS) model of depression. This study investigated whether the spleen contributes to the antidepressant-like effects of arketamine in the CSDS model. We found that splenectomy significantly inhibited arketamine's antidepressant-like effects in CSDS-susceptible mice. RNA-sequencing analysis identified the oxidative phosphorylation (OXPHOS) pathway in the prefrontal cortex (PFC) as a key mediator of splenectomy's impact on arketamine's effects. Furthermore, oligomycin A, an inhibitor of the OXPHOS pathway, reversed the suppressive effects of splenectomy on arketamine's antidepressant-like effects. Specific genes within the OXPHOS pathways, such as COX11, UQCR11 and ATP5e, may contribute to these inhibitory effects. Notably, transforming growth factor (TGF)-β1, along with COX11, appears to modulate the suppressive effects of splenectomy and contribute to arketamine's antidepressant-like effects. Additionally, SRI-01138, an agonist of the TGF-β1 receptor, alleviated the inhibitory effects of splenectomy on arketamine's antidepressant-like effects. Subdiaphragmatic vagotomy also counteracted the inhibitory effects of splenectomy on arketamine's antidepressant-like effects in CSDS-susceptible mice. These findings suggest that the OXPHOS pathway and TGF-β1 in the PFC play significant roles in the antidepressant-like effects of arketamine, mediated through the spleen-brain axis via the vagus nerve.
PubMed: 38901783
DOI: 10.1016/j.nbd.2024.106573 -
World Journal of Clinical Cases Jun 2024Angioimmunoblastic T-cell lymphoma (AITL) is a common subtype of peripheral T-cell lymphoma. Approximately half of patients with AITL may concurrently present with...
BACKGROUND
Angioimmunoblastic T-cell lymphoma (AITL) is a common subtype of peripheral T-cell lymphoma. Approximately half of patients with AITL may concurrently present with hypergammaglobulinemia. Increased numbers of plasma cells in the bone marrow are commonly observed at diagnosis. These tumors mimic plasma cell myelomas, hindering a conundrum of clinical diagnoses and potentially delaying appropriate treatment.
CASE SUMMARY
A 78-year-old woman experienced poor appetite, weight loss of 5 kg, fatigue 2 months before presentation, and shortness of breath 2 d before presentation, but no fever or night sweats. Physical examination revealed splenomegaly and many palpable masses over the bilateral axillary regions, approximately > 2 cm in size, with rubbery consistency and no tenderness. Blood tests revealed anemia and thrombocytopenia, lactate dehydrogenase level of 153 U/L, total protein level of 10.9 g/dL, albumin to globulin ratio of 0.2, and immunoglobulin G level more than the upper limit of 3000 mg/dL. The free kappa and lambda light chain concentrations were 451 and 614 mg/L, respectively. A pathological examination confirmed the diagnosis of AITL. The initial treatment was the cyclophosphamide, epirubicin, vincristine, and prednisolone regimen. Following this treatment, pleural effusion was controlled, and the patient was discharged in a stable condition and followed up in our outpatient department.
CONCLUSION
This report highlights the importance of differentiating reactive plasmacytosis from plasma cell myeloma in patients with hypergammaglobulinemia. A precise diagnosis of AITL requires a comprehensive evaluation, involving clinical, immunophenotypic, and histological findings conducted by a multidisciplinary team to ensure appropriate treatment.
PubMed: 38898855
DOI: 10.12998/wjcc.v12.i17.3226 -
Frontiers in Veterinary Science 2024This study marks the first occasion that has been isolated, identified, and characterized as the causative pathogen in spotted sea bass (). Infected fish exhibited a...
This study marks the first occasion that has been isolated, identified, and characterized as the causative pathogen in spotted sea bass (). Infected fish exhibited a range of external symptoms, including scale loss, bleeding from the jaw, anus, and tail, among other signs, as well as internal manifestations such as congested liver, splenomegaly, branchial anemia, yellow fat syndrome, and intestinal edema. Notably, exophthalmia and meningoencephalitis-typical symptoms associated with previous infections-were not observed. A predominant bacterial isolate (designated 10S01) was recovered from the pure culture of spleen of a diseased spotted sea bass in Zhuhai, China. The strain was then subjected to Gram staining, biochemical profiling, and molecular confirmation through 16S rRNA and gene, corroborating its identity as . Pathogenicity was assessed by intraperitoneal injection challenge in spotted sea bass weighing approximately 13 g/fish, revealing a LD50 of 74 cfu/g-fish. The 10S01 strain demonstrated the ability to colonize various organs, including the spleen, liver, kidney, and brain, with a relatively higher affinity for the spleen. Furthermore, antimicrobial susceptibility testing indicated that the 10S01 strain was sensitive to 14 tested antibiotics, particularly chloramphenicol, ciprofloxacin, clarithromycin, florfenicol, ofloxacin, rifampicin, and trimethoprim/sulfamethoxazole, highlighting these as preferred treatments for infections in spotted sea bass. These findings contribute significantly to our understanding of pathogenesis and inform the prompt and appropriate antibiotic treatment of infections.
PubMed: 38895715
DOI: 10.3389/fvets.2024.1404054 -
Cureus May 2024Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the immune system erroneously attacking healthy tissues and organs. SLE has a wide variety...
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the immune system erroneously attacking healthy tissues and organs. SLE has a wide variety of clinical presentations. The signs and symptoms of SLE are very well-known, though rare presentations could occur that require early clinical attention. Macrophage activation syndrome (MAS) is a severe and life-threatening condition in which the immune system becomes overactive, leading to the excessive stimulation and proliferation of immune cells. MAS can occur as a primary immune disorder, which is not very common. It can also happen secondary to a wide variety of pathological conditions, which include infections, malignancies, autoimmune, and rheumatologic disorders. In rare cases, SLE can present with overlapping features of MAS, further complicating the clinical picture, and may require specialized management. Early recognition and intervention of this overlap are essential for improving outcomes, as delayed diagnosis and treatment can lead to significant morbidity and mortality. Here, we present a case of a young adult female who was diagnosed with SLE with the initial presentation of MAS in the form of fever, splenomegaly, cytopenia, and hemophagocytosis.
PubMed: 38894758
DOI: 10.7759/cureus.60567 -
Diagnostics (Basel, Switzerland) May 2024Shear wave elastography (SWE) has become popular in clinical practice for many diseases. However, there is not adequate research on spleen-related diseases. This study...
Shear wave elastography (SWE) has become popular in clinical practice for many diseases. However, there is not adequate research on spleen-related diseases. This study aimed to investigate the potential of quantitative values obtained through SWE in evaluating spleen pathologies in the pediatric population and to demonstrate its performance to differentiate splenomegaly-related diseases. The research group retrospectively included children with pathological diagnoses related to the spleen from November 2016 to April 2021, and they were categorized into three groups, including portal hypertension (PH), benign lymphoid hyperplasia (BLH), and malignant infiltration (MI). Spleen sizes and parenchymal stiffness were also calculated for each group. Subsequently, mean spleen stiffness in each group was compared with normal values within the same age group. In total, 2781 children (1379 children for the study group; 1402 children for the control group) were enrolled in the study. The highest stiffness was observed in the PH group, which is statistically higher than others ( < 0.05). Although the mean spleen stiffness in the group with BLH was higher than the control and MI group, the difference was not statistically significant ( = 0.08). The mean stiffness in the group with MI was significantly lower than both the control group ( = 0.005) and PH ( = 0.01). In conclusion, using SWE in the differential diagnosis of etiologies causing splenomegaly could make an important contribution.
PubMed: 38893668
DOI: 10.3390/diagnostics14111142 -
International Journal of Molecular... May 2024Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterized by the uncontrolled activation of cytotoxic T lymphocytes, NK cells, and... (Review)
Review
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterized by the uncontrolled activation of cytotoxic T lymphocytes, NK cells, and macrophages, resulting in an overproduction of pro-inflammatory cytokines. A primary and a secondary form are distinguished depending on whether or not it is associated with hematologic, infectious, or immune-mediated disease. Clinical manifestations include fever, splenomegaly, neurological changes, coagulopathy, hepatic dysfunction, cytopenia, hypertriglyceridemia, hyperferritinemia, and hemophagocytosis. In adults, therapy, although aggressive, is often unsuccessful. We report the case of a 41-year-old man with no apparent history of previous disease and an acute onset characterized by fever, fatigue, and weight loss. The man was from Burkina Faso and had made trips to his home country in the previous five months. On admission, leukopenia, thrombocytopenia, increased creatinine and transaminases, LDH, and CRP with a normal ESR were found. The patient also presented with hypertriglyceridemia and hyperferritinemia. An infectious or autoimmune etiology was ruled out. A total body CT scan showed bilateral pleural effusion and hilar mesenterial, abdominal, and paratracheal lymphadenopathy. Lymphoproliferative disease with HLH complication was therefore suspected. High doses of glucocorticoids were then administered. A cytologic analysis of the pleural effusion showed anaplastic lymphoma cells and bone marrow aspirate showed hemophagocytosis. An Epstein-Barr Virus (EBV) DNA load of more than 90000 copies/mL was found. Bone marrow biopsy showed a marrow localization of peripheral T lymphoma. The course was rapidly progressive until the patient died. HLH is a rare but usually fatal complication in adults of hematologic, autoimmune, and malignant diseases. Very early diagnosis and treatment are critical but not always sufficient to save patients.
Topics: Humans; Lymphohistiocytosis, Hemophagocytic; Male; Adult; Macrophage Activation Syndrome
PubMed: 38892108
DOI: 10.3390/ijms25115921 -
Frontiers in Immunology 2024This study aims to discuss the clinical manifestations and treatment of Familial hemophagocytic lymphohistiocytosis (FHL) caused by a mutation in the UNC13D gene. (Review)
Review
OBJECTIVES
This study aims to discuss the clinical manifestations and treatment of Familial hemophagocytic lymphohistiocytosis (FHL) caused by a mutation in the UNC13D gene.
METHODS
A 6-year-old female child presented with unexplained febricity, splenomegaly, pancytopenia, hemophagocytic lymphohistiocytosis in bone marrow, decreased NK cell activity, soluble CD25 levels > 44000ng/ml. Genetic sequencing revealed a mutation in the UNC13D gene. Additionally, the patient experienced intermittent fever with seizures characterized by involuntary twitching of the left upper limb. Head magnetic resonance imaging (MRI) showed white matter lesions.
RESULTS
According to the HLH-2004 diagnostic criteria revised by the International Society of Histiocytosis the patient was diagnosed with FHL. Despite receiving HLH-2004 treatment, the disease relapsed. However, after a salvage allogeneic Hematopoietic Stem Cell Transplant (HSCT), febricity, abnormal blood cells, and neurological symptoms significantly improved.
CONCLUSIONS
Prompt performance of allogeneic HSCT is crucial upon diagnosis of FHL, especially when neurological involvement is present.
Topics: Humans; Lymphohistiocytosis, Hemophagocytic; Hematopoietic Stem Cell Transplantation; Female; Child; Transplantation, Homologous; Mutation; Membrane Proteins; Treatment Outcome
PubMed: 38887297
DOI: 10.3389/fimmu.2024.1391074 -
BMC Medical Genomics Jun 2024Haemochromatosis is a genetic disease characterized by the excessive deposition of iron in various tissues and organs, eventually results in organ damage including... (Review)
Review
BACKGROUND
Haemochromatosis is a genetic disease characterized by the excessive deposition of iron in various tissues and organs, eventually results in organ damage including cirrhosis, diabetes, cardiomyopathy, etc. SLC40A1-related haemochromatosis is associated with gain-of-function mutations in the SLC40A1 gene, which encodes ferroportin. While sporadic reports of this condition exist in mainland China, the understanding of the phenotype and genetic pattern associated with the SLC40A1 p.Y333H mutation remains incomplete.
CASE PRESENTATION
We report a pedigree with heterozygous p.Y333H mutation in Chinese Han population. The proband is a 64-year-old man complaining of persistent abnormality of liver enzyme levels for 1 year, with a history of knee joint pain, diabetes and skin pigmentation. He displayed markedly elevated serum ferritin level and transferrin saturation. Magnetic resonance imaging showed iron deposition in the liver, spleen, and pancreas, along with cirrhosis and splenomegaly. Whole exome sequencing identified a heterozygous allelic variant c.997T > C (p.Y333H). Genetic screening of family members identified four first-degree relatives and three second-degree relatives having the same mutation. Additional cases with this mutation from two published studies were included. Among the probands and screened relatives, all eight males aged over 30 y had ferritin level > 1000 µg/L, transferrin saturation > 90%. Four patients with organ damage in the present study received therapeutic phlebotomy, alleviating clinical symptoms and improving in transferrin saturation and serum ferritin.
CONCLUSIONS
This study reports the largest pedigree with heterozygous SLC40A1 p.Y333H mutation in the Chinese population to date. In Chinese families, males over 30 years old with hemochromatosis due to SLC40A1 p.Y333H mutation exhibit severe iron overload phenotypes.
Topics: Humans; Hemochromatosis; Male; Pedigree; Middle Aged; China; Cation Transport Proteins; Mutation; Female
PubMed: 38886778
DOI: 10.1186/s12920-024-01929-0