Hypoparathyroidism, Sensorineural Deafness, and Renal Disease Syndrome Presenting With Febrile Seizures and Hypocalcemia.

HDR syndrome is a rare genetic disorder caused by mutations in the GATA3 gene and characterized by hypoparathyroidism, sensorineural deafness, and renal disease. Here, we report case of a 9-month-old male with history of hydronephrosis and sensorineural deafness who presented with febrile seizures. He was found to have hypocalcemia and inappropriately normal parathyroid hormone. His neurologic and infectious workup were negative. Genetic testing revealed a nonsense mutation in the GATA3 gene, consistent with HDR syndrome. Hypocalcemia was responsive to calcium carbonate and calcitriol treatment. This case highlights hypocalcemia caused by hypoparathyroidism as a potential etiology of seizures. When hypoparathyroidism is detected with either hearing loss or renal disease, HDR syndrome should be considered, and other features of the syndrome should be investigated.

Aberrant AZIN2 and polyamine metabolism precipitates tau neuropathology.

Tauopathies display a spectrum of phenotypes from cognitive to affective behavioral impairments; however, mechanisms promoting tau pathology and how tau elicits behavioral impairment remain unclear. We report a unique interaction between polyamine metabolism, behavioral impairment, and tau fate. Polyamines are ubiquitous aliphatic molecules that support neuronal function, axonal integrity, and cognitive processing. Transient increases in polyamine metabolism hallmark the cell's response to various insults, known as the polyamine stress response (PSR). Dysregulation of gene transcripts associated with polyamine metabolism in Alzheimer's disease (AD) brains were observed, and we found that ornithine decarboxylase antizyme inhibitor 2 (AZIN2) increased to the greatest extent. We showed that sustained AZIN2 overexpression elicited a maladaptive PSR in mice with underlying tauopathy (MAPT P301S; PS19). AZIN2 also increased acetylpolyamines, augmented tau deposition, and promoted cognitive and affective behavioral impairments. Higher-order polyamines displaced microtubule-associated tau to facilitate polymerization but also decreased tau seeding and oligomerization. Conversely, acetylpolyamines promoted tau seeding and oligomers. These data suggest that tauopathies launch an altered enzymatic signature that endorses a feed-forward cycle of disease progression. Taken together, the tau-induced PSR affects behavior and disease continuance, but may also position the polyamine pathway as a potential entry point for plausible targets and treatments of tauopathy, including AD.

Validation of the Khorana score in acute myeloid leukemia patients: a single-institution experience.

BACKGROUND: Although patients with acute myeloid leukemia (AML) were shown to have an increased risk of thrombosis, no thrombosis risk assessment scoring system has been developed for AML patients. The Khorana Risk Score (KRS), which has been widely used for thrombosis risk assessment in the clinical setting, was developed on the basis of solid tumor data and has not been validated among AML patients. This study aims to validate the use of the KRS as a thrombosis risk-scoring system among patients with AML. METHODS: Using data from H. Lee Moffitt Cancer Center and Research Institution's Total Cancer Care Research Study, we retrospectively identified patients who were histologically confirmed with AML from 2000 to 2018. Clinical and laboratory variables at the time of AML diagnosis were characterized and analyzed. The thrombotic event rate was estimated with the Kaplan-Meier method and compared using the log-rank test. RESULTS: A total of 867 AML patients were included in the analysis. The median age at AML diagnosis was 75 years (range, 51-96), and the majority were male (65%, n = 565). A total of 22% (n = 191), 51% (n = 445), 24% (n = 207), and 3% (n = 24) of patients had a KRS of 0, 1, 2, and 3, respectively. A total of 42 thrombotic events (3% [n = 6/191] with a KRS of 1; 5% [n = 23/445] with a KRS of 2; 6.3% [n = 13/207] with a KRS of 3) were observed, with a median follow-up of 3 months (range, 0.1-307). There was no statistical difference in the risk of thrombosis between these groups (P = .1949). CONCLUSIONS: Although there was an increased risk of thrombosis associated with a higher KRS among AML patients with a KRS of 1 to 3, the difference was not statistically significant. Furthermore, only a few patients were found to have a KRS > 3, and this was largely due to pancytopenia, which is commonly associated with AML. These results indicate the need for a better thrombotic risk-scoring system for AML patients.

Sustained Arginase 1 Expression Modulates Pathological Tau Deposits in a Mouse Model of Tauopathy.

Tau accumulation remains one of the closest correlates of neuronal loss in Alzheimer's disease. In addition, tau associates with several other neurodegenerative diseases, collectively known as tauopathies, in which clinical phenotypes manifest as cognitive impairment, behavioral disturbances, and motor impairment. Polyamines act as bivalent regulators of cellular function and are involved in numerous biological processes. The regulation of the polyamines system can become dysfunctional during disease states. Arginase 1 (Arg1) and nitric oxide synthases compete for l-arginine to produce either polyamines or nitric oxide, respectively. Herein, we show that overexpression of Arg1 using adeno-associated virus (AAV) in the CNS of rTg4510 tau transgenic mice significantly reduced phospho-tau species and tangle pathology. Sustained Arg1 overexpression decreased several kinases capable of phosphorylating tau, decreased inflammation, and modulated changes in the mammalian target of rapamycin and related proteins, suggesting activation of autophagy. Arg1 overexpression also mitigated hippocampal atrophy in tau transgenic mice. Conversely, conditional deletion of Arg1 in myeloid cells resulted in increased tau accumulation relative to Arg1-sufficient mice after transduction with a recombinant AAV-tau construct. These data suggest that Arg1 and the polyamine pathway may offer novel therapeutic targets for tauopathies.