No abstract

No abstract

Schizophrenia is a common, severe and debilitating psychiatric disorder. Despite extensive research there is as yet no biological marker that can aid in its diagnosis and course prediction. This precludes early detection and intervention. Imaging studies suggest brain volume loss around the onset and over the first few years of schizophrenia, and apoptosis has been proposed as the underlying mechanism. Cell-free DNA fragments (cfDNA) are released into the bloodstream following cell death. Tissue-specific methylation patterns allow the identification of the tissue origins of cfDNA. We developed a cocktail of brain specific DNA methylation markers, and used it to assess the presence of brain-derived cfDNA in the plasma of patients with a first psychotic episode. We detected significantly elevated neuron- (p=0.0013), astrocyte- (p=0.0016), oligodendrocyte- (p=0.0129) and whole brain-derived (p=0.0012) cfDNA in the plasma of patients during their first psychotic episode (n=29), compared with healthy controls (n=31). Increased cfDNA levels were not correlated with psychotropic medications use. Area Under the Curve (AUC) was 0.77, with 65% sensitivity at 90% specificity in patients with a psychotic episode. Potential interpretations of these findings include increased brain cell death, disruption of the blood-brain barrier or a defect in clearance of material from dying brain cells. Brain-specific cfDNA methylation markers can potentially assist early detection and monitoring of schizophrenia and thus allow early intervention and adequate therapy.

Radiotherapy has an important role in the treatment of brain metastases (BrM) but carries risk of short and/or long-term toxicity, termed radiation-induced neurotoxicity (RIN). As the diagnosis of RIN is crucial for correct pa-tient management, there is an unmet need for reliable biomarkers for RIN. The aim of this proof-of concept study was to determine the utility of brain-derived circulating free DNA (BncfDNA), identified by specific methylation patterns for neurons, astrocytes, and oligodendrocytes, as RIN biomarkers. Twenty-four patients with BrM were monitored clinically and radiologically before, during and after brain radiotherapy, and blood for BncfDNA analysis (98 samples) was concurrently collected. Sixteen patients were treated with whole brain radiotherapy and eight patients with stereotactic radiosurgery. During follow-up nine RIN events were detected, and all correlated with significant increase in BncfDNA levels compared to baseline. Additionally, resolution of RIN correlated with de-crease in BncfDNA. Changes in BncfDNA were independent of tumor response. Elevated BncfDNA levels reflects brain cell injury incurred by radiotherapy, further research is needed to establish BncfDNA as a novel plasma-based biomarker for RIN.

No abstract

Background: Circulating cell-free DNA (cfDNA) is a novel type of biomarker with a broad utility in diagnostic medicine, based on the release of DNA fragments from dying cells to the circulation. We developed an approach for identifying the tissue origins of cfDNA, using cell-type-specific DNA methylation patterns, based on a massive reference atlas of the genome-wide methylomes of multiple human tissues and cell types. Cancer inflicts damage to surrounding normal tissues, which can culminate in fatal organ failure. We demonstrated that brain cell death in CNS cancer can be detected by tissue-specific methylation patterns of circulating cfDNA. Methods: We developed a cocktail of brain-specific DNA methylation markers, and used it to assess the presence of brain-derived-cfDNA in the plasma of patients with brain metastasis. Results: We identified significantly elevated neuron-, oligodendrocyte-, and astrocyte-derived cfDNA (p<0.0001) in patients with brain metastases (n=29) compared with cancer patients without brain metastasis (n=113). Conclusions: We show a new set of biomarkers to identify brain damage with high specificity and resolution. We detected brain (neurons, oligodendrocytes, astrocytes) cfDNA in the plasma of patients with brain metastasis. Cell-type-specific cfDNA methylation markers allow the identification of collateral tissue damage, reveals the presence of metastases, and potentially assist in early cancer detection.

Background: Schizophrenia is a common, severe and debilitating psychiatric disorder. Despite extensive research there is as yet no biological marker that can aid in its diagnosis and course prediction. This precludes early detection and intervention. Imaging studies suggest brain volume loss around the onset and over the first few years of schizophrenia, and apoptosis has been proposed as the underlying mechanism. Cell free DNA fragments (cfDNA) are released into the bloodstream following cell death. Tissue-specific methylation patterns allow the identification of the tissue origins of cfDNA. Methods: We developed a cocktail of brain specific DNA methylation markers, and used it to assess the presence of brain-derived cfDNA in the plasma of patients with a first psychotic episode. Results: We detected significantly elevated neuron- (p=0.0013), astrocyte- (p=0.0016), oligodendrocyte- (p=0.0129) and whole brain-derived (p=0.0012) cfDNA in the plasma of patients during their first psychotic episode (n=29), compared with healthy controls (n=31). Increased cfDNA levels were not correlated with psychotropic medications use. Area Under the Curve (AUC) was 0.77, with 65% sensitivity at 90% specificity in patients with a psychotic episode. Conclusions: Potential interpretations of these findings include increased brain cell death, disruption of the blood brain barrier or a defect in clearance of material from dying brain cells. Brain-specific cfDNA methylation markers can potentially assist early detection and monitoring of schizophrenia and thus allow early intervention and adequate therapy.

We report 2 cases of dens osteomyelitis. These cases emphasize the need to consider C1-C2 osteomyelitis in the differential diagnosis of neck stiffness and torticollis.