Plasma DNA Profile Associated with DNASE1L3 Gene Mutations: Clinical Observations, Relationships to Nuclease Substrate Preference, and In Vivo Correction.

Plasma DNA fragmentomics is an emerging area in cell-free DNA diagnostics and research. In murine models, it has been shown that the extracellular DNase, DNASE1L3, plays a role in the fragmentation of plasma DNA. In humans, DNASE1L3 deficiency causes familial monogenic systemic lupus erythematosus with childhood onset and anti-dsDNA reactivity. In this study, we found that human patients with DNASE1L3 disease-associated gene variations showed aberrations in size and a reduction of a "CC" end motif of plasma DNA. Furthermore, we demonstrated that DNA from DNASE1L3-digested cell nuclei showed a median length of 153 bp with CC motif frequencies resembling plasma DNA from healthy individuals. Adeno-associated virus-based transduction of Dnase1l3 into Dnase1l3-deficient mice restored the end motif profiles to those seen in the plasma DNA of wild-type mice. Our findings demonstrate that DNASE1L3 is an important player in the fragmentation of plasma DNA, which appears to act in a cell-extrinsic manner to regulate plasma DNA size and motif frequency.

Neuropsychiatric disturbance after aneurysmal subarachnoid hemorrhage.

Although aneurysmal subarachnoid hemorrhage (aSAH) accounts for only 3-5% of all strokes, a high degree of morbidity has been reported in this relatively young subset of patients. Neuropsychiatric disturbance has often been neglected in these reports. We aimed to investigate the pattern and pathological factors of chronic neuropsychiatric disturbance in aSAH patients. This cross-sectional observational four-center study was carried out in Hong Kong. Neuropsychiatric outcome (Neuropsychiatric Inventory Chinese Version [CNPI]) assessments were conducted cross-sectionally 1-4 years after ictus. Pathological factors considered were early brain injury as assessed by admission World Federation of Neurosurgical Societies grade, aneurysm treatment (clipping versus coiling), delayed cerebral infarction, and chronic hydrocephalus. One hundred and three aSAH patients' spouses or caregivers completed the CNPI. Forty-two (41%) patients were reported to have one or more domain(s) of neuropsychiatric disturbance. Common neuropsychiatric disturbance domains included agitation/aggression, depression, apathy/indifference, irritability/lability, and appetite/eating disturbance. Chronic neuropsychiatric disturbance was associated with presence of chronic hydrocephalus. A subscore consisting of the five commonly affected domains seems to be a suitable tool for aSAH patients and should be further validated and replicated in future studies.

Up-regulated pancreatic tissue microRNA-375 associates with human type 2 diabetes through beta-cell deficit and islet amyloid deposition.

OBJECTIVES: The aim of this study was to examine correlations of the islet-specific microRNA-375 expression to islet amyloid formation and pancreatic islet damage in human type 2 diabetes. METHODS: Autopsy pancreas samples from 40 type 2 diabetic and 15 nondiabetic patients were used to detect microRNA-375 expression using real-time quantitative polymerase chain reaction. Serial paraffin sections of the corresponding type 2 diabetic and nondiabetic cases were stained by immunofluorescence to evaluate for amylin expression, amyloid formation, and proportions of alpha and beta cells. RESULTS: Pancreatic microRNA-375 expression was increased in type 2 diabetic patients comparing with the nondiabetic patients (median, 4.02 for the diabetic patients vs 0.92 for the nondiabetic patients; P = 0.0001). The median was 6.14 for the diabetic patients with islet amyloid and 3.51 for islet amyloid-free diabetic patients. The expression level of microRNA-375 correlated positively with the frequency and the severity of islet amyloid formation and negatively with proportions of islet beta-cells and amylin-positive area, and islet mitochondria density. CONCLUSIONS: Up-regulated microRNA-375 is associated with type 2 diabetes and pancreatic islet amyloid formation and beta-cell deficit. microRNA-375 may serve as a biomarker for known and novel pathways in the pathogenesis of type 2 diabetes related to islet amyloid deposition and beta-cell dysfunction.