ABSTRACT
Inherited thrombocytopenia is a genetically heterogeneous disease characterized by varying degrees of thrombocytopenia and risk of haematological malignancy, and the genetic cause of many cases remains unknown. We performed whole-exome sequencing of a family with thrombocytopenia and myeloid malignancy and identified a novel TUBB1 variant, T149P. Screening of other thrombocytopenia pedigrees identified another TUBB1 variant, R251H. TUBB1 encodes the tubulin ß-1 chain, a major component of microtubules abundant in megakaryocytes. Variant TUBB1 disrupted the normal assembly of microtubules and impaired proplatelet formation in vitro. In addition, DNA damage response was severely attenuated by loss of TUBB1. We found that the nuclear accumulation of p53 (also termed TP53) and the expression of pro-apoptotic genes triggered by genotoxic stress were blocked in TUBB1-deficient cells and, accordingly, apoptosis after DNA damage was diminished by knockdown of TUBB1. Thus, we have demonstrated that microtubule dysfunction confers resistance to apoptosis, even in DNA damage-accumulated cells, which explains genome instability in the affected individuals. These studies will lead us to a better understanding of how microtubule dysfunction can contribute to the accumulation of DNA damage, genetic instability and leukaemogenesis.
Subject(s)
Thrombocytopenia/genetics , Tubulin/genetics , Aged , Amino Acid Sequence , Animals , Apoptosis/physiology , Cell Line, Tumor , Cell Proliferation/physiology , Female , Genomic Instability , Germ-Line Mutation , Humans , Male , Mice , Mice, Inbred C57BL , Middle Aged , Pedigree , Sequence Alignment , Thrombocytopenia/pathology , Tumor Suppressor Protein p53/genetics , Exome SequencingABSTRACT
OBJECTIVE: To assess the effect of azithromycin mass drug administration regimens on spleen rates in children aged 0-5 years. METHODS: Clinical assessment of spleen size was carried out during a cluster-randomised trial of azithromycin mass treatment for trachoma elimination in The Gambia. Twenty-four communities received three annual mass treatments with azithromycin, and 24 communities received treatment at baseline only. RESULTS: At the 30-month follow-up, 3646 children aged 0-5 years had spleen examination and measurement. Palpable splenomegaly was significantly lower in annually treated vs. baseline-only treatment communities and in treated vs. untreated children at 24 months in the annual treatment arm. CONCLUSION: The results suggest an effect of azithromycin on spleen rates at the individual level and are most plausibly due to the antimalarial effects of azithromycin.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Azithromycin/therapeutic use , Spleen/drug effects , Splenomegaly/prevention & control , Trachoma/drug therapy , Anti-Bacterial Agents/pharmacology , Azithromycin/pharmacology , Child, Preschool , Chlamydia trachomatis , Follow-Up Studies , Gambia , Humans , Infant , Spleen/pathology , Trachoma/pathology , Treatment OutcomeABSTRACT
The requirement of antifungal prophylaxis has not been established in the chemotherapies for malignant lymphoma. This study was conducted to explore the incidence of invasive fungal diseases (IFD) and their risk factors in patients receiving salvage therapies for malignant lymphoma. We retrospectively analyzed 177 consecutive patients who received these therapies (705 courses in total) at our institute. IFD were observed in 16 courses and the incidence was 2.3 %. A multivariate analysis showed that the factors associated with IFD were primary refractoriness (adjusted odds ratio (aOR), 4.22; 95 % confidence interval (CI), 1.38-13.0; p value = 0.012), two (aOR, 10.5, 95 % CI, 1.20-91.7; p = 0.033) or more (aOR, 26.2; 95 % CI, 3.27-210; p = 0.002) previous treatment lines, and the minimum neutrophil count during the therapies equal to or less than 500/µL (aOR, 9.69; 95 % CI, 1.25-74.9; p = 0.030). Using these factors, we created the IFD scoring model by assigning one point to each of primary refractoriness, two previous treatment lines and treatment that caused neutropenia (≤500/µL minimal neutrophil count) and two points to three or more previous treatment lines. The IFD incidence of lower risk group (IFD score <3) was 0.19 % and that of higher (IFD score ≥3) was 9.0 %. In conclusion, adequate prophylaxis for IFD might be required for patients with primary refractoriness, repeated therapies, or therapies which cause neutropenia. Furthermore, the IFD scoring model of this study underscores the need to account for disease and host factors in determining administration of adequate prophylaxis in salvage treatments for malignant lymphoma.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Fungemia/epidemiology , Lymphoma/drug therapy , Risk Assessment/methods , Salvage Therapy , Severity of Illness Index , Adult , Aged , Aged, 80 and over , Antifungal Agents/administration & dosage , Antifungal Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chemotherapy-Induced Febrile Neutropenia/complications , Disease Susceptibility , Drug Resistance, Neoplasm , Female , Fluconazole/administration & dosage , Fluconazole/therapeutic use , Fungemia/etiology , Fungemia/prevention & control , Humans , Incidence , Kaplan-Meier Estimate , Leukocyte Count , Lymphoma/complications , Male , Middle Aged , Neutrophils , Opportunistic Infections/epidemiology , Opportunistic Infections/etiology , Opportunistic Infections/prevention & control , Retrospective Studies , Risk Factors , Salvage Therapy/adverse effects , Treatment Outcome , Young AdultABSTRACT
Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant clonal plasma cell disorder characterized by monoclonal immunoglobulins and/or an abnormal free immunoglobulin light chain ratio. MGUS can be associated with immune-mediated neuropathies, including chronic inflammatory demyelinating neuropathy and its variants. Here, we report the case of a 76-year-old male who presented with progressive weakness, initially in the lower extremities and later including the upper extremities. Serum protein electrophoresis and immunofixation identified an IgM kappa monoclonal protein and further testing confirmed high titers of anti-myelin-associated glycoprotein (MAG) antibodies, leading to a diagnosis of anti-MAG-associated demyelinating peripheral neuropathy. The coexistence of MGUS and anti-MAG antibodies requires meticulous diagnosis and management, especially in patients who present with atypical symptoms of the disease.
ABSTRACT
Desmoplastic small round cell tumors (DSRCT) are very rare and aggressive diseases typically present with abdominal or retroperitoneal masses. We present a case of a young female who presented with ST-segment elevation myocardial infarction and cardiac tamponade and who was found to have DSRCT. The patient was coded at the emergency department. Left heart catheterization showed normal coronary arteries, and pericardiocentesis removed 1,260 mL of bloody pericardial effusions. The patient was stabilized, and a positron emission tomography scan revealed left intrahilar, hilar, and cardiophrenic masses with associated hypermetabolic right hilar, left hilar, subcarinal, costophrenic, aortopulmonary, paratracheal, and mediastinal lymphadenopathy. Cardiac magnetic resonance imaging showed multiple masses visualized in the pericardium, one mass anterior to the right ventricular outflow tract/pulmonary artery, and a second mass adjacent to the right ventricular apex. Computed tomography abdomen/pelvis showed no evidence of metastatic malignancy in the abdomen/pelvis. A biopsy of lung mass and lymph nodes showed desmoplastic small round cell tumors with sarcoma fusion gene detected (Ewing sarcoma RNA-binding protein 1-Wilms' tumor 1). We performed cycle 1 of chemotherapy, including doxorubicin, vincristine, and cyclophosphamide, and the patient was transferred to an oncology center for further care. This case suggested that one of the differential diagnoses of lung and pericardium masses at a young age can be desmoplastic small round cell tumors. This case also highlighted that ST-segment elevation myocardial infarction can be secondary to neoplasm, especially at a young age besides myocardial infarction.
ABSTRACT
Evans syndrome (ES) is a rare autoimmune disorder characterised by autoimmune haemolytic anaemia (AIHA), immune thrombocytopenia and autoimmune neutropenia. The precise pathogenesis of ES remains unclear, but it is believed to involve immune-mediated destruction of erythrocytes and platelets. Thrombotic complications, such as stroke, are critical yet largely unrecognised in ES. Here, we present a case of an 80-year-old male with ES who developed multiple strokes, emphasising the complex management challenges associated with this condition. The patient, known for stage IIB lung adenocarcinoma, presented with right-sided weakness and was diagnosed with a stroke of undetermined aetiology. He was started on warfarin for secondary prevention alongside intravenous immunoglobulin (IVIG) and corticosteroids for ES. Stroke in ES is rarely reported, and the optimal management remains inconclusive due to its rarity. The patient's management was guided by existing guidelines for stroke prevention and anticoagulation in the setting of antiphospholipid syndrome. While anticoagulants are recommended for venous thromboembolism prophylaxis in AIHA, there are no clear guidelines for stroke prevention in ES. This case underscores the necessity of individualised treatment approaches and highlights the gaps in evidence regarding stroke management in ES. Future research is essential to determine the optimal management of stroke in this complex clinical scenario. LEARNING POINTS: Evans syndrome is a rare autoimmune disorder characterised by the coexistence of autoimmune haemolytic anaemia and immune thrombocytopenia, which potentially increase venous and arterial thrombotic risk.Managing strokes in Evans syndrome remains challenging due to its rarity and lack of definitive guidelines, necessitating individualised treatment approaches.Future prospective studies are warranted to determine the optimal patient population that needs secondary prevention with anticoagulants following a stroke in the context of Evans syndrome.
ABSTRACT
Atypical lymphoplasmacytic and immunoblastic proliferation (ALPIBP) was first reported in 1984 as characteristic histological findings in lymph nodes associated with autoimmune diseases, but it has not been clearly defined to date. To summarize the histological characteristics and clinical diagnoses associated with ALPIBP, we searched MEDLINE and EMBASE for all peer-reviewed articles using keywords including "atypical lymphoplasmacytic and immunoblastic lymphadenopathy" from their inception to December 27, 2023. We also summarized the courses of three cases with a pathological diagnosis of ALPIBP. Nine articles with 52 cases were included. Among the total of 55 cases, including the three from our institution, the median age of the cases was 63.5 years with a female predominance (69.5%). Lymphadenopathy was generalized in 65.6% and regional in 34.4% of cases. RA (24.4%), SLE (24.4%), and autoimmune hemolytic anemia (20.0%), were common clinical diagnoses. A combination of cytotoxic chemotherapy was used in 15.6% of cases due to the suspicion of malignancy. Nodal T-follicular helper cell lymphoma, angioimmunoblastic type, methotrexate-associated lymphoproliferative disorders, and IgG4-related diseases were listed as important diseases that need to be pathologically differentiated from ALPIBP. This review summarizes the current understanding of the characteristics of ALPIBP. Given that underrecognition of ALPIBP could lead to overdiagnosis of hematological malignancy and unnecessary treatment, increased awareness of the condition in pathologists and clinicians is crucial.
Subject(s)
Lymphoproliferative Disorders , Humans , Female , Male , Middle Aged , Lymphoproliferative Disorders/pathology , Lymphoproliferative Disorders/diagnosis , Lymphadenopathy/pathology , Lymphadenopathy/diagnosis , Lymph Nodes/pathology , Autoimmune Diseases/pathology , Autoimmune Diseases/diagnosisABSTRACT
Post-transplant lymphoproliferative disorders (PTLDs) are lymphoproliferative diseases that occur after solid organ transplantation or hematopoietic stem cell transplantation (HSCT). The development of PTLD is often associated with reactivation of Epstein-Barr virus (EBV). A 26-year-old woman with a history of HSCT and total-body irradiation developed spinal cord hemorrhage from a radiation-induced cavernous hemangioma (RICH) shortly after the development of classical Hodgkin lymphoma PTLD with EBV reactivation. Although little is known about the factors leading to hemorrhagic events from spinal cord RICH, we suspect that EBV reactivation may have been a factor contributing to the hemorrhage in the present case.
ABSTRACT
Giant cell arteritis (GCA) mainly involves large-sized arteries, while microscopic polyangiitis (mPA), characterized by pauci-immune necrotizing vasculitis, mainly affects small-sized vessels. We report a very rare concomitant case of GCA diagnosed by temporal artery biopsy and mPA with a high titer of myeloperoxidase antineutrophil cytoplasmic antibody, exacerbation of interstitial pneumonia, and suspected rapidly progressive glomerulonephritis. The patient died by sudden rupture of the gastroepiploic artery (medium-sized vessel), which may have been triggered by GCA and/or mPA.
Subject(s)
Gastroepiploic Artery/pathology , Giant Cell Arteritis/complications , Hemoperitoneum/complications , Microscopic Polyangiitis/complications , Aged, 80 and over , Fatal Outcome , Giant Cell Arteritis/pathology , Hemoperitoneum/pathology , Humans , Male , Microscopic Polyangiitis/pathology , Rupture, Spontaneous/complications , Rupture, Spontaneous/pathologyABSTRACT
It is recommended that a sharp-pointed object, such as a dental crown, in the proximal duodenum be retrieved endoscopically if this can be accomplished safely.
ABSTRACT
OBJECTIVES: The hallmark of sickle cell disease (SCD) is acute and chronic pain, and the pain dominates the clinical characteristics of SCD patients. Although pharmacological treatments of SCD targeting the disease mechanisms have been improved, many SCD patients suffer from pain. To overcome the pain of the disease, there have been renewed requirements to understand the novel molecular mechanisms of the pain in SCD. METHODS: We concisely summarized the molecular mechanisms of SCD-related acute and chronic pain, focusing on potential drug targets to treat pain. RESULTS: Acute pain of SCD is caused by vaso-occulusive crisis (VOC), impaired oxygen supply or infarction-reperfusion tissue injuries. In VOC, inflammatory cytokines include tryptase activate nociceptors and transient receptor potential vanilloid type 1. In tissue injury, the secondary inflammatory response is triggered and causes further tissue injuries. Tissue injury generates cytokines and pain mediators including bradykinin, and they activate nociceptive afferent nerves and trigger pain. The main causes of chronic pain are from extended hyperalgesia after a VOC and central sensitization. Neuropathic pain could be due to central or peripheral nerve injury, and protein kinase C might be associated with the pain. In central sensitization, neuroplasticity in the brain and the activation of glial cells may be related with the pain. DISCUSSION: In this review, we summarized the molecular mechanisms of SCD-related acute and chronic pain. The novel treatments targeting the disease mechanisms would interrupt complications of SCD and reduce the pain of the SCD patients.
ABSTRACT
This is the first case of concurrent Mycobacterium genavense lymphadenitis and Epstein-Barr virus (EBV)-positive lymphoproliferative disorder (LPD) in the same lymph node with no immunocompromised history. M. genavense infection is a rare opportunistic infection mainly for human immunodeficiency virus (HIV)-infected patients. Although no immunodeficiency was detected in our patient, our case indicates that the immunodeficiency in the background of EBV latency type III and the immunosuppression by malignant lymphoma itself might induce the M. genavense lymphadenitis. This case highly alerts clinicians to the immunosuppressive state of EBV-positive LPD with latency type III even if any immunodeficient serological factors are not detected.
ABSTRACT
Although several pedigrees of familial myelodysplastic syndromes/acute myeloid leukemia (fMDS/AML) have been reported, the epidemiology and clinical features has been poorly understood. To explore the epidemiology of this entity, we performed a retrospective nationwide epidemiological survey in Japan using questionnaire sheets. The questionnaire was sent to 561 institutions or hospitals certified by Japanese Society of Hematology, unearthing the existence of 41 pedigrees of fMDS/AML. Among them, we obtained the clinical information of 31 patients in 20 pedigrees. The median age of the initial diagnosis was 51 years (range 9-88 years) and the WHO classification 2008 ranged from refractory anemia (RA) to AML. Focusing on the familial MDS patients, refractory anemia with excess blasts (RAEB)-2 was the largest group (27.3%). The median overall survival (OS) of fMDS and fAML in this study were 71.6 and 12.4 months, and the five-year OS were 61.3 and 50%, respectively.
Subject(s)
Leukemia, Myeloid, Acute , Myelodysplastic Syndromes , Adolescent , Adult , Aged , Aged, 80 and over , Child , Humans , Japan/epidemiology , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/epidemiology , Leukemia, Myeloid, Acute/genetics , Middle Aged , Myelodysplastic Syndromes/diagnosis , Myelodysplastic Syndromes/epidemiology , Myelodysplastic Syndromes/genetics , Retrospective Studies , Surveys and Questionnaires , Young AdultABSTRACT
Although several causal genes of familial myelodysplastic syndromes (MDS) have been identified, the genetic landscape and the molecular pathogenesis are not totally understood. To explore novel driver genes and their pathogenetic significance, we performed whole-exome sequence analysis of four individuals from a familial MDS pedigree and 10 candidate single-nucleotide variants (C9orf43, CYP7B1, EFHB, ENTPD7, FAM160B2, HELZ2, HLTF, INPP5J, ITPKB, and RYK) were identified. Knockdown screening revealed that Hltf downregulation enhanced colony-forming capacity of primary murine bone marrow (BM) stem/progenitor cells. γH2AX immunofluorescent staining assay revealed increased DNA damage in a human acute myeloid leukemia (AML) cell line ectopically expressing HLTF E259K, which was not observed in cells expressing wild-type HLTF. Silencing of HLTF in human AML cells also led to DNA damage, indicating that HLTF E259K is a loss-of-function mutation. Molecularly, we found that an E259K mutation reduced the binding capacity of HLTF with ubiquitin-conjugating enzymes, methanesulfonate sensitive 2 and ubiquitin-conjugating enzyme E2N, resulting in impaired polyubiquitination of proliferating cell nuclear antigen (PCNA) in HLTF E259K-transduced cells. In summary, our results indicate that a familial MDS-associated HLTF E259K germline mutation induces accumulation of DNA double-strand breaks, possibly through impaired PCNA polyubiquitination.
Subject(s)
DNA Damage , DNA-Binding Proteins/genetics , Germ-Line Mutation , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/pathology , Polyubiquitin/metabolism , Proliferating Cell Nuclear Antigen/metabolism , Transcription Factors/genetics , Ubiquitination , Aged , Aged, 80 and over , Biomarkers, Tumor/genetics , DNA Repair , Female , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Myelodysplastic Syndromes/metabolism , Pedigree , Prognosis , Proliferating Cell Nuclear Antigen/geneticsABSTRACT
BACKGROUND: Few studies have investigated incidence rate and risk factors for giardiasis and strongyloidiasis in returning UK travellers. The clinical presentations of these two diseases are often similar and difficult to distinguish. This study was conducted to investigate the incidence rate and the risk factors for symptomatic giardiasis and strongyloidiasis in returned tropical travellers. METHODS: We retrospectively analysed 3306 consecutive attendances presenting to the emergency clinic at the Hospital for Tropical Diseases in London, the UK from September 2008 to May 2010. Odds ratios between the diagnoses and patient variables were analysed by logistic regression. RESULTS: Giardiasis was diagnosed in 92/3306 cases (2.8%, proportionate morbidity), and the incidence rate per 1000 person-months was 12.5. Multivariate analysis with logistic regression revealed that Caucasian ethnicity (adjusted odds ratio (aOR): 2.37, 95% confidence interval (CI): 1.12-5.03, P value = 0.025), travel length ≥32 days (aOR: 2.63, 95%CI: 1.43-4.83, P = 0.002), travelling to South or South East Asia (aOR: 4.90, 95%CI: 2.03-11.8, P < 0.001, aOR: 3.36, 95%CI: 1.43-7.93, P = 0.006), afebrile presentation (aOR: 2.14, 95%CI: 1.14-4.03, P = 0.018), and presenting with gastro-intestinal symptoms (aOR: 14.6, 95%CI: 6.08-35.0, P < 0.001) were all associated with giardiasis. In contrast, strongyloidiasis was found only in 0.94% (proportionate morbidity) of the cases (31/3306), and the incidence rate per 1000 person-months was 3.1. Multivariate analysis revealed that male sex (aOR: 3.05, 95%CI: 1.36-6.85, P = 0.007), and non-Caucasian ethnicity (aOR: 2.69, 95%CI: 1.32-5.49, P = 0.007) were associated with strongyloidiasis. CONCLUSIONS: The incidence rate and risk factors for both infectious diseases were identified. The results of this study might guide clinicians to make more accurate and timely diagnoses in returned tropical travellers.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Communicable Diseases/epidemiology , Giardiasis/epidemiology , Strongyloidiasis/epidemiology , Travel/statistics & numerical data , Communicable Diseases/diagnosis , Communicable Diseases/drug therapy , Female , Giardiasis/diagnosis , Giardiasis/drug therapy , Humans , Incidence , Logistic Models , Male , Odds Ratio , Retrospective Studies , Risk Factors , Sex Distribution , Strongyloidiasis/diagnosis , Strongyloidiasis/drug therapy , Tropical Medicine , United KingdomABSTRACT
Recently, 5-azacitidine has been reported to improve the survival of patients with high-risk myelodysplastic syndrome (MDS) and was approved for the treatment of MDS in Japan. We herein report a case of high-risk MDS in which the patient exhibited a hematological improvement three months after the first cycle of 5-azacitidine therapy. The second cycle of 5-azacitidine was not administered due to a severe pulmonary infection. Bone marrow aspiration revealed a decrease in the level of blast cells from 7.0% to 0.7%, and the subclassification of MDS improved from refractory anemia with excess blasts (RAEB)-1 to refractory cytopenia with unilineage dysplasia. This case demonstrates a possible late effect of 5-azacitidine treatment.