SYNCRIP controls miR-137 and striatal learning in animal models of methamphetamine abstinence

Abstinence from prolonged psychostimulant use prompts stimulant withdrawal syndrome. Molecular adaptations within the dorsal striatum have been considered the main hallmark of stimulant abstinence. Here we explored striatal miRNA–target interaction and its impact on circulating miRNA marker as well as behavioral dysfunctions in methamphetamine (MA) abstinence. We conducted miRNA sequencing and profiling in the nonhuman primate model of MA abstinence, followed by miRNA qPCR, LC–MS/MS proteomics, immunoassays, and behavior tests in mice. In nonhuman primates, MA abstinence triggered a lasting upregulation of miR-137 in the dorsal striatum but a simultaneous downregulation of circulating miR-137. In mice, aberrant increase in striatal miR-137-dependent inhibition of SYNCRIP essentially mediated the MA abstinence-induced reduction of circulating miR-137. Pathway modeling through experimental deduction illustrated that the MA abstinence-mediated downregulation of circulating miR-137 was caused by reduction of SYNCRIP-dependent miRNA sorting into the exosomes in the dorsal striatum. Furthermore, diminished SYNCRIP in the dorsal striatum was necessary for MA abstinence-induced behavioral bias towards egocentric spatial learning. Taken together, our data revealed circulating miR-137 as a potential blood-based marker that could reflect MA abstinence-dependent changes in striatal miR-137/SYNCRIP axis, and striatal SYNCRIP as a potential therapeutic target for striatum-associated cognitive dysfunction by MA withdrawal syndrome.     

Clinical Outcomes Associated with Degree of Hypernatremia in Neurocritically Ill Patients

ObjectiveHypernatremia is a common complication encountered during the treatment of neurocritically ill patients. However, it is unclear whether clinical outcomes correlate with the severity of hypernatremia in such patients. Therefore, we investigated the impact of hypernatremia on mortality of these patients, depending on the degree of hypernatremia. MethodsAmong neurosurgical patients admitted to the intensive care unit (ICU) in a tertiary hospital from January 2013 to December 2019, patients who were hospitalized in the ICU for more than 5 days and whose serum sodium levels were obtained during ICU admission were included. Hypernatremia was defined as the highest serum sodium level exceeding 150 mEq/L observed. We classified the patients into four subgroups according to the severity of hypernatremia and performed propensity score matching analysis. ResultsAmong 1146 patients, 353 patients (30.8%) showed hypernatremia. Based on propensity score matching, 290 pairs were included in the analysis. The hypernatremia group had higher rates of in-hospital mortality and 28-day mortality in both overall and matched population (both p<0.001 and p=0.001, respectively). In multivariable analysis of propensity score-matched population, moderate and severe hypernatremia were significantly associated with in-hospital mortality (adjusted odds ratio [OR], 4.58; 95% confidence interval [CI], 2.15–9.75 and adjusted OR, 6.93; 95% CI, 3.46–13.90, respectively) and 28-day mortality (adjusted OR, 3.51; 95% CI, 1.54–7.98 and adjusted OR, 10.60; 95% CI, 5.10–21.90, respectively) compared with the absence of hypernatremia. However, clinical outcomes, including in-hospital mortality and 28-day mortality, were not significantly different between the group without hypernatremia and the group with mild hypernatremia (p=0.720 and p=0.690, respectively). The mortality rates of patients with moderate and severe hypernatremia were significantly higher in both overall and matched population. Interestingly, the mild hypernatremia group of matched population showed the best survival rate. ConclusionModerate and severe hypernatremia were associated with poor clinical outcomes in neurocritically ill patients. However, the prognosis of patients with mild hypernatremia was similar with that of patients without hypernatremia. Therefore, mild hypernatremia may be allowed during treatment of intracranial hypertension using hyperosmolar therapy.     

Role of adjuvant chemoradiotherapy and chemotherapy in patients with resected gallbladder carcinoma: a multi-institutional analysis (KROG 19-04)

Objective:The effectiveness of adjuvant treatments for resected gallbladder carcinoma (GBC) has remained unclear due to lack of randomized controlled trials; thus, the aim of present study was to evaluate the role of adjuvant treatments, including chemoradiotherapy (CRT) and/or chemotherapy (CTx), in patients with resected GBC.Methods:A total of 733 GBC patients who received curative-intent surgical resection were identified in a multi-institutional database. Of 733 patients, 372 (50.8%) did not receive adjuvant treatment, whereas 215 (29.3%) and 146 (19.9%) received adjuvant CTx and CRT, respectively. The locoregional recurrence-free survival (LRFS), recurrence-free survival (RFS), and overall survival (OS) of the adjuvant treatment groups were compared according to tumor stage (stage II vs. stage III–IV).Results:In stage II disease (n = 381), the 5-year LRFS, RFS, and OS were not significantly different among the no-adjuvant therapy, CTx, and CRT groups, and positive resection margin, presence of perineural invasion, and Nx classification were consistently associated with worse LRFS, RFS, and OS in the multivariate analysis (P < 0.05). For stage III–IV (n = 352), the CRT group had significantly higher 5-year LRFS, RFS, and OS than the no-adjuvant therapy and CTx groups (67.8%, 45.2%, and 56.9%; 37.9%, 28.8%, and 35.4%; and 45.0%, 30.0%, and 45.7%, respectively) (P < 0.05).Conclusions:CRT has value as adjuvant treatment for resected GBC with stage III–IV disease. Further study is needed for stage II disease with high-risk features.     

Die Luftembolie bei kriminellem Abort

Ohne Zusammenfassung     

Improved treatment outcome of pembrolizumab in patients with nonsmall cell lung cancer and chronic obstructive pulmonary disease

Emerging immune profiling data suggest a higher sensitivity to immune checkpoint inhibitors (ICIs) in nonsmall cell lung cancer (NSCLC) patients with chronic obstructive pulmonary disease (COPD), compared to those without COPD. This study aimed to investigate the clinical impact of COPD on the treatment response to ICIs in a large number of patients with NSCLC. In total, 133 patients with spirometry test results were retrospectively identified among those who received palliative pembrolizumab for NSCLC. COPD was defined as pre-bronchodilator forced expiratory volume in 1 s/forced vital capacity <0.7. Overall survival (OS), progression-free survival (PFS), and objective response rate were analyzed according to the presence of COPD. Spirometry-based COPD was present in 59 (44%) patients. Patients with COPD had better OS (hazard ratio [HR] for death, 0.45; 95% confidence interval [CI], 0.26–0.78) and PFS (HR for disease progression or death, 0.50; 95% CI, 0.31–0.79) than those without COPD. These associations persisted after adjusting for potential confounders including smoking history. The response rate was also higher in patients with COPD than in those without COPD (38.2% vs. 20.5%, p = 0.028). Spirometry-defined COPD was associated with a significantly longer OS and PFS in patients with NSCLC treated with palliative pembrolizumab. Identifying coexisting COPD could predict favorable treatment outcomes in patients with NSCLC treated with pembrolizumab.     

Children in the Blind Spot of Social Medical Concerns: Supporting Children with Mentally Ill Parents in Korea

Community Mental Health Journal - Children whose parents have mental disorders are more likely to be vulnerable and exposed to an environment where they may not be cared for by parents or guardians...     

Study of cobalt doping control via various routes in thoroughbred horses

Cobalt is a substance that has been abused for athletic performance enhancement and has thus been prohibited by human and animal sports doping control authorities. However, because cobalt is present in humans and animals as a trace element, a certain level of cobalt is naturally present in their excretions. In the racing industry, cobalt is a controlled substance with a threshold concentration specified by the International Agreement on Breeding, Racing and Wagering (IABRW) for international harmonization. Due to environmental and feed consumption differences among countries, regional cobalt concentration trends should be evaluated before cobalt testing is introduced. In this study, we conducted a preliminary evaluation of the urinary concentration of cobalt among a population of racehorses in Korea using inductively coupled plasma mass spectrometry (ICP-MS) analysis, followed by analysis of the urinary release of cobalt after the administration of cobalt chloride in various situations. The normal distribution for the Korea-based racehorses was used to determine a urine concentration limit (96.5 ng/ml, risk factor of 1 in 10,000). After the intravenous (IV) administration of CoCl₂, the initial elimination of cobalt was rapid. A high concentration (over 2,000 ng/ml) and a slow excretion pattern were observed during the final 2 weeks of the 3-week observation period. When CoCl₂ was administered orally, maximum concentration (C_max, 92–992 ng/ml) was observed at 6–8 h.