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Indian Journal of Hematology & Blood... Jul 2018
PubMed: 30127574
DOI: 10.1007/s12288-018-0943-z -
Neural Regeneration Research Feb 2024Roof plate secretion of bone morphogenetic proteins (BMPs) directs the cellular fate of sensory neurons during spinal cord development, including the formation of the...
Roof plate secretion of bone morphogenetic proteins (BMPs) directs the cellular fate of sensory neurons during spinal cord development, including the formation of the ascending sensory columns, though their biology is not well understood. Type-II BMP receptor (BMPRII), the cognate receptor, is expressed by neural precursor cells during embryogenesis; however, an in vitro method of enriching BMPRII human neural precursor cells (hNPCs) from the fetal spinal cord is absent. Immunofluorescence was undertaken on intact second-trimester human fetal spinal cord using antibodies to BMPRII and leukemia inhibitory factor (LIF). Regions of highest BMPRII immunofluorescence localized to sensory columns. Parenchymal and meningeal-associated BMPRII vascular cells were identified in both intact fetal spinal cord and cortex by co-positivity with vascular lineage markers, CD34/CD39. LIF immunostaining identified a population of somas concentrated in dorsal and ventral horn interneurons, mirroring the expression of LIF receptor/CD118. A combination of LIF supplementation and high-density culture maintained culture growth beyond 10 passages, while synergistically increasing the proportion of neurospheres with a stratified, cytoarchitecture. These neurospheres were characterized by BMPRII/MAP2ab/βIII-tubulin/nestin/vimentin/GFAP/NeuN surface hNPCs surrounding a heterogeneous core of βIII-tubulin/nestin/vimentin/GFAP/MAP2ab/NeuN multipotent precursors. Dissociated cultures from tripotential neurospheres contained neuronal (βIII-tubulin), astrocytic (GFAP), and oligodendrocytic (O4) lineage cells. Fluorescence-activated cell sorting-sorted BMPRII hNPCs were MAP2ab/βIII-tubulin/GFAP/O4 in culture. This is the first isolation of BMPRII hNPCs identified and characterized in human fetal spinal cords. Our data show that LIF combines synergistically with high-density reaggregate cultures to support the organotypic reorganization of neurospheres, characterized by surface BMPRII hNPCs. Our study has provided a new methodology for an in vitro model capable of amplifying human fetal spinal cord cell numbers for > 10 passages. Investigations of the role BMPRII plays in spinal cord development have primarily relied upon mouse and rat models, with interpolations to human development being derived through inference. Because of significant species differences between murine biology and human, including anatomical dissimilarities in central nervous system (CNS) structure, the findings made in murine models cannot be presumed to apply to human spinal cord development. For these reasons, our human in vitro model offers a novel tool to better understand neurodevelopmental pathways, including BMP signaling, as well as spinal cord injury research and testing drug therapies.
PubMed: 37488910
DOI: 10.4103/1673-5374.373669 -
Haematologica Aug 2020
Topics: Central Nervous System; Drug Resistance, Neoplasm; Humans; Leukemia; Meninges
PubMed: 32739886
DOI: 10.3324/haematol.2020.253609 -
Vaccines Jan 2021Corticosteroids, when given in high dosages, have long been recognized as a risk factor for severe infection with wild-type varicella-zoster virus in both children and... (Review)
Review
Corticosteroids, when given in high dosages, have long been recognized as a risk factor for severe infection with wild-type varicella-zoster virus in both children and adults. The goal of this review is to assess the degree to which both low-dosage and high-dosage corticosteroids contribute to serious adverse events (SAEs) following live varicella vaccination and live zoster vaccination. To this end, we examined multiple published reports of SAEs following varicella vaccination (Varivax) and zoster vaccination (Zostavax). We observed that five of eight viral SAEs following varicella vaccination, including two deaths, occurred in children receiving corticosteroids, while one of three fatal viral SAEs following live zoster vaccination occurred in an adult being treated with low-dosage prednisone. The latter death after live zoster vaccination occurred in a 70 year-old man with rheumatoid arthritis, being treated with prednisone 10 mg daily. Thus, corticosteroids contributed to more severe infectious complications in subjects immunized with each of the two live virus vaccines. Further, when we surveyed the rheumatology literature as well as individual case reports, we documented examples where daily dosages of 7.5-20 mg prednisone were associated with increased rates of severe wild-type varicella-zoster virus infections in children and adults.
PubMed: 33418856
DOI: 10.3390/vaccines9010023 -
BioRxiv : the Preprint Server For... Dec 2023Leptomeningeal disease (LMD) occurs when tumors seed into the leptomeningeal space and cerebrospinal fluid (CSF), leading to severe neurological deterioration and poor...
Leptomeningeal disease (LMD) occurs when tumors seed into the leptomeningeal space and cerebrospinal fluid (CSF), leading to severe neurological deterioration and poor survival outcomes. We utilized comprehensive multi-omics analyses of CSF from patients with lymphoma LMD to demonstrate an immunosuppressive cellular microenvironment and identified dysregulations in proteins and lipids indicating neurodegenerative processes. Strikingly, we found a significant accumulation of toxic branched-chain keto acids (BCKA) in the CSF of patients with LMD. The BCKA accumulation was found to be a pan-cancer occurrence, evident in lymphoma, breast cancer, and melanoma LMD patients. Functionally, BCKA disrupted the viability and function of endogenous T lymphocytes, chimeric antigen receptor (CAR) T cells, neurons, and meningeal cells. Treatment of LMD mice with BCKA-reducing sodium phenylbutyrate significantly improved neurological function, survival outcomes, and efficacy of anti-CD19 CAR T cell therapy. This is the first report of BCKA accumulation in LMD and provides preclinical evidence that targeting these toxic metabolites improves outcomes.
PubMed: 38187773
DOI: 10.1101/2023.12.18.572239 -
Cureus Apr 2023Sarcoidosis is a systemic disease of unknown etiology with multi-system affection. It typically involves the skin, eyes, hilar lymph nodes, and pulmonary parenchyma....
Sarcoidosis is a systemic disease of unknown etiology with multi-system affection. It typically involves the skin, eyes, hilar lymph nodes, and pulmonary parenchyma. However, as any organ system could be involved, one has to be aware of its atypical manifestations. We present three uncommon manifestations of the disease. Our first case presented with fever, arthralgias, and right hilar lymphadenopathy with a history of tuberculosis in the past. He was treated for tuberculosis but had a relapse of symptoms three months after completion of treatment. The second patient presented with a headache for two months. On evaluation, cerebrospinal fluid examination showed evidence of aseptic meningitis, while an MRI of the brain demonstrated enhancement of the basal meninges. The third patient was admitted with a mass on the left side of the neck for one year. On evaluation, he was found to have left cervical lymphadenopathy, with its biopsy showing non-caseating epitheloid granuloma. Immunofluorescence did not show evidence of leukemia or lymphoma. All the patients had negative tuberculin skin tests and elevated serum angiotensin-converting enzyme levels supporting the diagnosis of sarcoidosis. They were treated with steroids with complete resolution of symptoms and no recurrence at follow-up. Sarcoidosis is an underdiagnosed entity in India. Thus, awareness of the atypical clinical features could lead to early recognition of the disease and its treatment.
PubMed: 37159764
DOI: 10.7759/cureus.37208 -
Journal of Neurosurgery. Case Lessons Jun 2021Acute promyelocytic leukemia (APL) has long been associated with coagulation disorders. The proposed mechanism is a combination of fibrinolysis, proteolysis, platelet...
Concomitant central venous sinus thrombosis and subdural hematoma in acute promyelocytic leukemia: middle meningeal artery embolization enables safe anticoagulation. Illustrative case.
BACKGROUND
Acute promyelocytic leukemia (APL) has long been associated with coagulation disorders. The proposed mechanism is a combination of fibrinolysis, proteolysis, platelet dysfunction, thrombocytopenia, and possibly disseminated intravascular coagulation. Hemorrhagic complications are prominent.
OBSERVATIONS
In this case, a 25-year-old female with newly diagnosed APL developed extensive cerebral venous thrombosis (CVT) and was initiated on a protocol with idarubicin and all- retinoic acid. The general recommendation for treating CVT is anticoagulation to stabilize the existing thrombus and prevent propagation. The patient was initiated on a heparin drip, but her clinical course was complicated by subdural hemorrhage (SDH) and epidural hemorrhage in the setting of thrombocytopenia. Anticoagulation was held, and her CVT propagated on follow-up imaging. To restart anticoagulation for CVT with a limited risk of SDH, the authors pursued middle meningeal artery (MMA) embolization. The patient was transitioned to apixaban and discharged to home.
LESSONS
MMA embolization enables safe anticoagulation in patients with concomitant CVT and SDH. The authors report the complex clinical course and effective management of this rare clinical scenario.
PubMed: 36046512
DOI: 10.3171/CASE2080 -
Nature Communications Aug 2017Cranial radiotherapy improves survival of the most common childhood cancers, including brain tumors and leukemia. Unfortunately, long-term survivors are faced with...
Cranial radiotherapy improves survival of the most common childhood cancers, including brain tumors and leukemia. Unfortunately, long-term survivors are faced with consequences of secondary neoplasia, including radiation-induced meningiomas (RIMs). We characterized 31 RIMs with exome/NF2 intronic sequencing, RNA sequencing and methylation profiling, and found NF2 gene rearrangements in 12/31 of RIMs, an observation previously unreported in sporadic meningioma (SM). Additionally, known recurrent mutations characteristic of SM, including AKT1, KLF4, TRAF7 and SMO, were not observed in RIMs. Combined losses of chromosomes 1p and 22q were common in RIMs (16/18 cases) and overall, chromosomal aberrations were more complex than that observed in SM. Patterns of DNA methylation profiling supported similar cell of origin between RIMs and SMs. The findings indicate that the mutational landscape of RIMs is distinct from SMs, and have significant therapeutic implications for survivors of childhood cranial radiation and the elucidation of the molecular pathogenesis of meningiomas.Radiation-induced meningiomas are often more aggressive than sporadic ones. In this study, the authors perform an exome, methylation and RNA-seq analysis of 31 cases of radiation-induced meningioma and show NF2 rearrangement, an observation previously unreported in the sporadic tumors.
Topics: Adult; Aged; Cancer Survivors; Case-Control Studies; Cerebellar Neoplasms; Cranial Irradiation; DNA Methylation; Female; Gene Rearrangement; Genes, Neurofibromatosis 2; Humans; Kruppel-Like Factor 4; Leukemia; Male; Medulloblastoma; Meningeal Neoplasms; Meningioma; Middle Aged; Mutation; Neoplasms, Radiation-Induced; Sequence Analysis, DNA; Sequence Analysis, RNA; Young Adult
PubMed: 28775249
DOI: 10.1038/s41467-017-00174-7 -
Journal of Hematology Apr 2024Intracerebral hemorrhage is a potentially fatal complication in patients with acute leukemia and contributing factors include thrombocytopenia and coagulopathy. Patients...
Intracerebral hemorrhage is a potentially fatal complication in patients with acute leukemia and contributing factors include thrombocytopenia and coagulopathy. Patients with acute leukemia may develop subdural hematoma (SDH) spontaneously or secondary to trauma. In patients with acute leukemia and SDH, the surgical evacuation of the hematoma causes significant morbidity and mortality. New approaches and strategies to reduce the need for surgical evacuation are needed to improve outcomes in patients with acute leukemia and intracerebral hemorrhage. We report two cases of acute SDH in patients with acute leukemia successfully treated with middle meningeal artery embolization, a minimally invasive interventional radiology technique, obviating the need for a surgical intervention. The first patient with acute promyelocytic leukemia (APL) presented with coagulopathy and developed an acute SDH after a fall. The second patient with acute myeloid leukemia presented with gum bleeding and also sustained an acute SDH after a fall. Both patients underwent middle meningeal artery embolization for treating their SDHs while actively receiving induction chemotherapy for acute leukemia. Both patients had resolution of their acute SDH and are in remission from their acute leukemia. Middle meningeal artery embolization is a very effective, and within the context of this setting, a novel, minimally invasive technique for management of SDH in acute leukemia patients, which can prevent the need for surgical interventions with its associated comorbidities and high risk of fatal outcomes in patients with acute leukemia and acute SDH.
PubMed: 38644984
DOI: 10.14740/jh1215 -
Journal of Cytology 2018Neoplastic involvement of cerebrospinal fluid (CSF) secondary to known or unknown primaries elsewhere is a poor prognostic factor and is equivalent to stage IV disease.
INTRODUCTION
Neoplastic involvement of cerebrospinal fluid (CSF) secondary to known or unknown primaries elsewhere is a poor prognostic factor and is equivalent to stage IV disease.
AIM
The aim of the study is to analyse the cytological features of neoplastic meningitis in a tertiary care center.
MATERIALS AND METHODS
A retrospective study of 400 consecutive CSF samples was done in the cytology laboratory of our hospital. The fluid obtained by spinal tap was sent for microbiological, biochemical and cytological evaluation. Smears that showed the presence of malignant cells were included in this study.
RESULTS
Out of 400 cases, 36 (9%) showed neoplastic meningitis. Of which, 13 cases (36%) revealed leukemic infiltration, 2 (6%) lymphomatous infiltration and 21 (58%) carcinomatous meningitis. The leukemia cases included seven cases of acute lymphoblastic leukemia and six cases of acute myeloid leukemia. Among the carcinomatous meningitis cases, eight were metastasis from carcinoma breast, six from lung carcinoma and one each from malignancies of gallbladder, stomach and retinoblastoma. Four cases were metastatic adenocarcinoma from unknown primary. Pleocytosis was a significant finding seen in 58% cases ( = 21). Elevated protein and hypoglychorrhachia was noted in 68% cases ( = 18).
CONCLUSION
A combined diagnostic approach including biochemical, microbiological and pathological evaluation was useful in eliminating infectious meningitis and confirming neoplastic meningitis in these cases. Cytology should be performed on cerebrospinal specimens from all patients with known or suspected malignancy with meningismus. Detection of malignant cells on cytological examination of CSF is the diagnostic gold standard for neoplastic meningitis.
PubMed: 30498301
DOI: 10.4103/JOC.JOC_167_17