O-Linked N-Acetylglucosamine Transferase Ensures Survival of Mouse Fetal Liver Hematopoietic Progenitors Partly by Regulating Bcl-xL and Oxidative Phosphorylation.

O-linked N-acetylglucosamine transferase (OGT) critically regulates wide variety of biological processes such as gene expression, metabolism, stress response, signaling and proteostasis. In adult hematopoiesis, OGT is crucial for differentiation of B and T cells and the maintenance of hematopoietic stem cells (HSCs). However, a role for OGT in fetal liver (FL) hematopoiesis remains unknown. To investigate a role for OGT in FL hematopoiesis, we conditionally disrupted OGT in hematopoietic cells in developing FLs. Hematopoietic specific disruption of OGT resulted in embryonic lethality in late stage of gestation due to severe anemia and growth retardation. OGT loss led to profound reduction of differentiating erythroid cells and erythroid progenitors in FLs due to massive apoptosis. In addition, clonogenic capacity of FL cells was severely impaired by OGT loss. Interestingly, expression of BCL-XL, a well-known inhibitor of apoptosis in FL cells, dramatically decreased, and the levels of reactive oxygen species (ROS) were increased in OGT-deficient FL cells. Overexpression of Bcl-xL and reduction of ROS significantly restored the colony formation of OGT-deficient FL cells. This study revealed a novel role for OGT during embryogenesis, which ensures survival of FL hematopoietic cells partly by regulating Bcl-xL and oxidative phosphorylation.

Pericardial Effusion and Progressive Bilateral Effusion as Rare Presentations of Idiopathic Hypereosinophilic Syndrome.

Hypereosinophilic syndrome (HES) is a rare disease with peripheral blood eosinophils >1500/µL and end-organ damage. We encountered a case of idiopathic HES in a woman in her 60s who presented with dyspnea due to cardiac effusion and bilateral pleural effusions. At first, the patient did not have eosinophilia in the peripheral blood, and the presence of serum pericardial fluid and pleural effusion led to suspicion of carcinomatous pericarditis and pleurisy. One month later after onset, eosinophilia in the peripheral blood was observed, and HES was suspected for the first time. However, inflammatory cell infiltration by eosinophils has been observed in the pleural fluid specimen before eosinophilia in the peripheral blood. Prednisolone was administered, and the pleural effusion and respiratory failure quickly abated. This case provided an educational illustration of a unique manifestation of cardiac tamponade and HES, characterized by the absence of peripheral blood eosinophilia at the initial presentation.

Peripheral Parenteral Nutrition and Activities of Daily Living in Hospitalized Older Frail Patients.

BACKGROUND: Frail older adults require nursing care following hospitalization for acute illnesses. Frailty is reversible, and appropriate nutritional management and rehabilitation during hospitalization are essential. However, optimal nutritional management for patients who are unable to obtain adequate nutrition via oral intake has not been established. We aimed to determine whether peripheral parenteral nutrition (PPN) promotes the recovery of activities of daily living (ADLs) in frail older patients. METHODS: This was a retrospective, observational cohort study conducted at the General Medicine Department of Aomori Prefectural Central Hospital in Aomori, Japan. The primary outcome was recovery of the Barthel index (BI) from the beginning of rehabilitation to discharge, and the secondary outcomes were the proportion of patients transferred for rehabilitation and the nutritional status. RESULTS: In total, 342 patients hospitalized during the period of April 2018 to January 2022 were included, of whom 127 (37.1%) received PPN and 215 (62.9%) did not. Contrary to our expectations, recovery of the BI was lower in the PPN group than that in the non-PPN group (12.2 (95% confidence interval (CI): 8.5-16.0) vs. 22.4 (18.8-23.0); p < 0.01). Multivariable analysis revealed PPN as an independent risk factor for poor BI recovery (mean difference = -7.3 (95% CI = -12.7 to -1.9)). CONCLUSION: Nutritional management through PPN for frail older adults may not improve physical activity. The nutritional management of frail patients with inadequate oral intake remains challenging.

Community-Acquired Severe Clostridium difficile Enteritis Complicated by Metabolic Acidosis and Acute Kidney Injury.

Clostridium difficile (CD) is known to be pathogenic when the balance of intestinal microbiota is disrupted by the administration of broad-spectrum antimicrobial agents. Therefore, CD enteritis is often suspected in cases of hospital-onset diarrhea. There has been a rise in the incidence of community-acquired CD enteritis in recent years in the United States. In this report, we present a case of a 57 year-old-man who was admitted to the emergency department with abdominal distension and dyspnea. The patient suffered from acute renal failure and metabolic acidosis from enteritis. He required mechanical ventilation and continuous renal replacement therapy (CRRT) in the ICU. Analysis of the patient's stool sample on admission revealed the presence of CD antigens, and the prompt administration of metronidazole led to swift improvement. No studies have investigated the actual incidence of community-acquired CD enteritis infection in Japan. Since 20% of community-acquired CD enteritis cases have been reported as severe, all cases of community-acquired enteritis should raise concerns for CD enteritis. CD antigen/toxin in the stool should then be determined promptly before administering antibiotics.

Aortic dissection diagnosed with the aortic dissection detection risk score of 2 without D-dimer elevation.

Acute aortic dissection can be fatal if overlooked, and the absence of D-dimer elevation can be used to exclude acute aortic dissection. However, we report a case of acute aortic dissection without D-dimer elevation. A man in his 70s presented to the emergency department with lumbar back pain. D-dimer was <1.0 µg/mL; however, acute aortic dissection was strongly suspected because of the sudden onset of lumbar back pain with a shifting location. Because of a difference in systolic blood pressure in both upper extremities, we performed a thorough examination using contrast-enhanced CT, leading to a diagnosis of acute aortic dissection. The patient was immediately referred to cardiovascular surgery and treated conservatively with antihypertensive management. The aortic dissection detection risk score (ADD-RS) classified the patient as high risk. This suggests the importance of using the D-dimer with the ADD-RS rather than solely relying on the D-dimer results to diagnose acute aortic dissection.

Multiple Myeloma With a Rare Presentation at Preserved Uninvolved Immunoglobulins.

Multiple myeloma is a neoplastic disease of plasma cells that produces monoclonal immunoglobulins, known as monoclonal proteins, causing hypercalcemia, anemia, renal insufficiency, bone lesion, and other organ damage. In most multiple myeloma, the amount of monoclonal protein correlates with the tumor burden and reflects its prognosis. Uninvolved immunoglobulins are often suppressed as monoclonal protein levels increase as a result of the increasing percentage of myeloma cells in the bone marrow. Detection of monoclonal protein by protein electrophoresis, immunofixation, and serum-free light chain assay is a highly sensitive analysis and is not suitable as a screening test because it is positive in a few percent of healthy elderly people, the majority of whom are classified as benign monoclonal gammopathy of undetermined significance. Therefore, it is widely used in practice to measure quantitation of immunoglobulins by nephelometer, and only when uninvolved immunoglobulins are decreasing in the values for each subtype, monoclonal protein identification by immunofixation, serum-free light chain assay, and bone marrow examination must be additionally performed for proactively diagnosing multiple myeloma. However, we experienced symptomatic multiple myeloma in which uninvolved immunoglobulins were not suppressed and there were no significant changes in immunoglobulin levels despite the relatively rapid progression. It would suggest that if you suspect symptomatic myeloma, you should not rule out the possibility of multiple myeloma because of preserved uninvolved immunoglobulins in laboratory findings.

OGT Regulates Hematopoietic Stem Cell Maintenance via PINK1-Dependent Mitophagy.

O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) is a unique enzyme introducing O-GlcNAc moiety on target proteins, and it critically regulates various cellular processes in diverse cell types. However, its roles in hematopoietic stem and progenitor cells (HSPCs) remain elusive. Here, using Ogt conditional knockout mice, we show that OGT is essential for HSPCs. Ogt is highly expressed in HSPCs, and its disruption induces rapid loss of HSPCs with increased reactive oxygen species and apoptosis. In particular, Ogt-deficient hematopoietic stem cells (HSCs) lose quiescence, cannot be maintained in vivo, and become vulnerable to regenerative and competitive stress. Interestingly, Ogt-deficient HSCs accumulate defective mitochondria due to impaired mitophagy with decreased key mitophagy regulator, Pink1, through dysregulation of H3K4me3. Furthermore, overexpression of PINK1 restores mitophagy and the number of Ogt-deficient HSCs. Collectively, our results reveal that OGT critically regulates maintenance and stress response of HSCs by ensuring mitochondrial quality through PINK1-dependent mitophagy.