Novel Injury Scoring Tool for Assessing Brain Injury following Neonatal Hypoxia-Ischemia in Mice.

The variability of severity in hypoxia-ischemia (HI)-induced brain injury among research subjects is a major challenge in developmental brain injury research. Our laboratory developed a novel injury scoring tool based on our gross pathological observations during hippocampal extraction. The hippocampi received scores of 0-6 with 0 being no injury and 6 being severe injury post-HI. The hippocampi exposed to sham surgery were grouped as having no injury. We have validated the injury scoring tool with T2-weighted MRI analysis of percent hippocampal/hemispheric tissue loss and cell survival/death markers after exposing the neonatal mice to Vannucci's rodent model of neonatal HI. In addition, we have isolated hippocampal nuclei and quantified the percent good quality nuclei to provide an example of utilization of our novel injury scoring tool. Our novel injury scores correlated significantly with percent hippocampal and hemispheric tissue loss, cell survival/death markers, and percent good quality nuclei. Caspase-3 and Poly (ADP-ribose) polymerase-1 (PARP1) have been implicated in different cell death pathways in response to neonatal HI. Another gene, sirtuin1 (SIRT1), has been demonstrated to have neuroprotective and anti-apoptotic properties. To assess the correlation between the severity of injury and genes involved in cell survival/death, we analyzed caspase-3, PARP1, and SIRT1 mRNA expressions in hippocampi 3 days post-HI and sham surgery, using quantitative reverse transcription polymerase chain reaction. The ipsilateral (IL) hippocampal caspase-3 and SIRT1 mRNA expressions post-HI were significantly higher than sham IL hippocampi and positively correlated with the novel injury scores in both males and females. We detected a statistically significant sex difference in IL hippocampal caspase-3 mRNA expression with comparable injury scores between males and females with higher expression in females.

Psychiatric comorbidity and quality of life in patients with drug hypersensitivity.

Background: Compared with advances in a drug hypersensitivity diagnosis and management, little is known about the mental health status of patients with drug hypersensitivity and the impact of this psychological distress on their quality of life (QoL). Objective: The objectives were to evaluate anxiety, depression, and QoL levels in patients with drug hypersensitivity, assess how some related factors may affect them, and determine the impact of disease on their QoL. Methods: A total of 203 patients with drug hypersensitivity and 80 healthy controls were evaluated with the Beck Anxiety (BAI) and the Depression Inventory (BDI), and the short version of the World Health Organization Quality of Life (WHOQOL-BREF) scale. Results: The mean ± standard deviation (SD) BAI scores of the patients and the controls were 13.46 ± 11.78 and 1.94 ± 1.93, respectively (p < 0.0001). The mean ± SD BDI scores were higher in the patient group (9.23 ± 6.36) than in the control group (2.18 ± 2.02) (p < 0.0001). The patients had significantly increased risk of anxiety versus the controls (48.8% versus 7.5%) (odds ratio [OR] 11.74 [95% confidence {CI}, 4.88-28.20]; p < 0.0001) and depression versus the controls (31.5% versus 6.2%) (OR 6.90 [95% CI, 2.66-17.90]; p = 0.0001). The comparison of patients' BAI and BDI scores showed that those with more severe reactions had higher scores than those with moderate and mild reactions. A negative correlation was found among all WHOQOL-BREF scale domain scores and the BAI and BDI scores. Conclusion: Anxiety and depressive symptoms have a high prevalence in patients with confirmed drug hypersensitivity, which leads to a notable decrease in QoL. Self-administered psychological questionnaires were shown to be useful in the psychological examination and management of patients with drug hypersensitivity. Therefore, we found that psychological support is critical to reducing the negative outcomes of hypersensitivity reactions in patients.

Loss of skeletal muscle area and fat-free mass during dabrafenib/trametinib and vemurafenib/cobimetinib treatments in patients with BRAF-mutant metastatic malignant melanoma.

This study aimed to assess whether dabrafenib/trametinib and vemurafenib/cobimetinib treatments are associated with a change in skeletal muscle area (SMA) and total fat-free mass (FFM) assessed by computed tomography (CT), and to compare the efficacy and safety profile of these treatments in patients with metastatic melanoma. Thirty-one patients treated with B-Raf proto-oncogene, serine/threonine kinase/MAPK extracellular receptor kinase inhibitors were included between 2016 and 2019. Eighteen patients received dabrafenib/trametinib and remaining patients received vemurafenib/cobimetinib. CT scans were performed at baseline and at 4-6 months of follow-up to measure cross-sectional areas of SMA. FFM and skeletal muscle index (SMI) values were calculated. Of the patients, including 18 treated with dabrafenib/trametinib (58.1%) and 13 with vemurafenib/cobimetinib (41.9%); 58.1% were male, 41.9% were female and median age was 52 years. A significant decrease in SMA was observed after dabrafenib/trametinib and vemurafenib/cobimetinib treatments (P = 0.003 and P = 0.002, respectively). A significant decrease in FFM values was observed after dabrafenib/trametinib and vemurafenib/cobimetinib treatments (P = 0.003 and P = 0.002, respectively). Dose-limiting toxicity (DLT) was observed in 35.9% of the patients with sarcopenia. No significant difference was seen between the dabrafenib/trametinib and vemurafenib/cobimetinib groups in median progression-free survival (PFS) (11.9 vs. 7.3 months, respectively, P = 0.28) and in median overall survival (OS) (25.46 vs. 13.7 months, respectively, P = 0.41). Baseline sarcopenia was not significantly associated with PFS or OS (P = 0.172 and P = 0.326, respectively). We found a significant decrease in SMI values determined at 4-6 months compared to the values before treatment both in dabrafenib/trametinib and vemurafenib/cobimetinib groups. DLT was similar with both treatments. Baseline sarcopenia was not significantly associated with PFS or OS.