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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.16.137034v1?rss=1 Authors: Konduru, S. S., Wallace, E. P., Pfammatter, J. A., Rodrigues, P. V., Jones, M., Maganti, R. Abstract: Study objectives: Traumatic brain injury (TBI) results in sequelae that include post-traumatic epilepsy (PTE) and sleep-wake disturbances. Here we sought to determine whether sleep characteristics could predict development of PTE in a model of severe TBI. Methods: Following controlled cortical impact (CCI), sham injury (craniotomy only) or no craniotomy (NC), CD-1 mice were implanted with epidural electroencephalography (EEG) and nuchal electromyography (EMG) electrodes. Acute (1st week) and chronic (months 1, 2 and 3 after injury) 1-week long video-EEG/EMG recordings were examined for epileptiform activity. We analyzed sleep-wake patterns manually and extracted high amplitude interictal events from EEG using an automated method. Sleep spindles and EEG delta power were derived from non-rapid eye movement (NREM) sleep epochs. Brain CTs (computerized tomography) were performed to quantify the extent of brain lesions in cohorts of sham and CCI. Results: Posttraumatic seizures were seen with CCI, whereas interictal epileptiform activity as well as sleep-wake disruptions (shorter wake or NREM bout lengths, shorter duration or lower power for spindles, and increased NREM EEG delta power) were seen in CCI and sham groups. No sleep feature predicted PTE. Follow up brain CTs showed a small lesion in the sham injury group suggesting a milder form of TBI that may account for their interictal activity and sleep changes. Conclusions: In our model, interictal epileptiform activity and sleep disruptions resulted from CCI and sham and thus, sham injury was not an optimal negative control. Further work is necessary to determine the relationship between sleep-wake disturbances and PTE. Copy rights belong to original authors. Visit the link for more info

Background: Gilles de la Tourette Syndrome is a neurodevelopmental disorder that is caused by the interaction of environment with a complex genetic background. The genetic etiology of the disorder remains, so far, elusive, although multiple promising leads have been recently reported. The recent implication of the histamine decarboxylase (HDC) gene, the key enzyme in histamine production, raises the intriguing hypothesis of a possible role of histaminergic dysfunction leading to TS onset. Methods: Following up on the finding of a nonsense mutation in a single family with TS, we investigated variation across the HDC gene for association with TS. As a result of a collaborative international effort, we studied a large sample of 520 nuclear families originating from seven European populations (Greek, Hungarian, Italian, Polish, German, Albanian, Spanish) as well as a sample collected in Canada. Results and Conclusions: Interrogating 12 tagging SNPs (tSNP) across the HDC region, we find strong over-transmission of alleles at two SNPs (rs854150 and rs1894236) in the complete sample, as well as a statistically significant associated haplotypes. Analysis of individual populations also reveals signals of association in the Canadian, German and Italian samples. Our results provide strong support for the histaminergic hypothesis in TS etiology and point to a possible role of histamine pathways in neuronal development.

Background: Extensive sets of data are required to investigate the potential use of a therapeutic drug monitoring with individualization of dosage of the antimycotic compound caspofungin. The goal was to develop an improved liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for this aim. Methods: Following protein precipitation, on-line solid phase extraction was performed for sample preparation. As the internal standard compound the veterinary drug tylosin was used. A standard validation protocol was applied. Results: Good reproducibility and accuracy of the method were observed. On-line solid phase extraction resulted in a convenient work-flow and good robustness of the method. Conclusions: This improved LC-MS/MS method was found reliable and convenient. It can be suggested for further work on the clinical pharmacology of caspofungin in the setting of clinical research laboratories.

Purpose: This study explores whether meningioma expresses epidermal growth factor receptor (EGFR) and determines if there is a correlation between the WHO grade of this tumor and the degree of EGFR expression. Methods: Following institutional review board approval, 113 meningioma specimens from 89 patients were chosen. Of these, 85 were used for final analysis. After a blinded review, immunohistochemical stains for EGFR were performed. Staining intensity (SI) was scored on a scale 0-3 (from no staining to strong staining). Staining percentage of immunoreactive cells (SP) was scored 1-5 (from the least to the maximum percent of the specimen staining). Immunohistochemical score (IHS) was calculated as the product of SI and SP. Results: Eighty-five samples of meningioma were classified in accordance with World Health Organization (WHO) criteria: benign 57/85 (67%), atypical 23/85 (27%), and malignant 5/85 (6%). The majority of samples demonstrated a moderate SI for EGFR. IHS for EGFR demonstrated a significant association between SI and histopathologic subtype. Also, there was a correlation between the SP and histopathologic subtype (p = 0.029). A significant association was determined when the benign and the atypical samples were compared to the malignant with respect to the SP (p = 0.009). While there was a range of the IHS for the benign and the atypical histologic subtypes, malignant tumors exhibited the lowest score and were statistically different from the benign and the atypical specimens (p < 0.001). Conclusions: To our knowledge, this represents the largest series of meningioma samples analyzed for EGFR expression reported in the literature. EGFR expression is greatest in benign meningiomas and may serve a potential target for therapeutic intervention with selective EGFR inhibitors.

Background: In animal models ursodeoxycholic acid (UDCA) showed a chemoprotective effect against colon cancer. To explain this, a reduced proliferation of the colorectal mucosal proliferation was suggested. We, therefore, examined the influence of UDCA on the proliferation of normal colorectal mucosa in humans. Methods: Following endoscopic polypectomy, 20 patients with colorectal adenomas were randomized to receive either UDCA (750 mg/day, n = 10, group A) or placebo (n = 10, group B) for 6 months in a double-blinded way. Colorectal biopsies were sampled before and at the end of the medication by total colonoscopy. Colorectal mucosal proliferation was measured by FACScan analysis of propidium iodine labeling. Serum was sampled, and serum bile acids were analyzed by gas chromatography. Results: The proliferation rates at the end of the study were similar in both groups (median 15.4%; range 12.0-20.9 in group A; median 16.0%, 14.0-20.2 in group B, p = 0.41). Serum lithocholic acid levels at the end of the study were significantly higher in group A (1.3 mumol/l, 0.9-1.8) than in group B (0.7 mumol/l, 0-1.7, p < 0.02), whereas serum deoxycholic acid levels were similar in both groups. Conclusions: In this study, UDCA treatment for 6 months does not seem to induce changes in the proliferative behavior of the colorectal mucosa in patients with adenomas. It seems likely that a putative chemopreventive effect of UDCA in humans is not exerted by a reduction of the colorectal proliferation. Copyright (C) 2003 S. Karger AG, Basel.