CDK8/19 inhibitor enhances arginase-1 expression in macrophages via STAT6 and p38 MAPK activation.

Macrophages polarize into alternatively activated M2 macrophages through interleukin (IL)-4, and they express high levels of arginase-1, which promotes anti-inflammatory responses. Several studies have confirmed the anti-inflammatory effects of cyclin-dependent kinase (CDK) 8/19 inhibition, and hence, numerous CDK8/19 inhibitors, such as BRD6989, have been developed. However, the effects of CDK8/19 inhibitors on arginase-1 expression in macrophages have not yet been elucidated. This study investigated the effects of CDK8/19 inhibitor on arginase-1 expression in IL-4-activated macrophages. The results showed that BRD6989 increased arginase-1 expression transcriptionally in murine peritoneal macrophages and the murine macrophage cell line RAW264.7 in an IL-4-dependent manner. In addition, the results indicated that BRD6989 enhances signal transducer and activator of transcription (STAT) 6 phosphorylation. Meanwhile, BRD6989 exhibited the capability to activate p38 mitogen-activated protein kinase (MAPK） even in the absence of IL-4 stimulation. Moreover, we observed that a p38 MAPK inhibitor suppressed the BRD6989-induced increase in arginase-1 expression. Besides, BRD6989 increased the surface expression of CD206, an M2 macrophage marker. Thus, this study demonstrated for the first time that CDK8/19 inhibition increases arginase-1 expression, suggesting that this mechanism involves the activation of STAT6 and p38 MAPK. This finding implies that CDK8/19 inhibition may facilitate the production of anti-inflammatory M2 macrophages.

Effect of revascularization surgery on cerebral hemodynamics in adult moyamoya disease.

OBJECTIVE: Few studies have reported local hemodynamic changes after revascularization surgery. This study aimed to identify regional hemodynamic changes after combined revascularization surgery for moyamoya disease using single-photon emission computed tomography with N-isopropyl-p-123I-iodoamphetamine. METHODS: A total of 46 adults with moyamoya disease who underwent combined revascularization surgery from August 2009 to July 2021 at our facility were enrolled. The combined bypass procedure comprised a single direct bypass to the motor area and encephalo-duro-arterio-myo-synangiosis. The preoperative and postoperative cerebral blood flow (CBF) and cerebral vascular reserve (CVR) in the genu; precentral, central, parietal, angular, temporal, and posterior regions; splenium; hippocampus; and cerebellum were measured. To modify the examination variability, the cerebral-to-cerebellar activity ratio (CCR) was calculated by dividing the counts in the region by those in the cerebellum (CBF-CCR and CVR-CCR). RESULTS: Postoperatively, asymptomatic cerebral infarction occurred in three (6.5%) patients. The CBF-CCR and CVR-CCR improved in the precentral, parietal, and temporal regions and in the overall middle cerebral artery (MCA) territory. Sub-analysis of anterior cerebral artery (ACA) and posterior cerebral artery (PCA) territory hemodynamics revealed that patients with normal preoperative hemodynamics showed no changes in the CBF-CCR and CVR-CCR postoperatively, whereas patients with preoperative perfusion impairment exhibited improved CVR-CCR in the ACA territory (0.13-0.3, p=0.019) and CBF-CCR in the PCA territory (0.93-0.96, p=0.0039). CONCLUSION: Combined revascularization surgery with single bypass to the motor area improved hemodynamics in the primary targeted MCA territory and in the ACA and PCA territories among patients with preoperative hemodynamic impairment.

Recovery of Oculomotor Nerve Palsy After Surgical and Endovascular Repair of Unruptured Internal Carotid-Posterior Communicating Artery Aneurysms.

OBJECTIVE: Unruptured posterior communicating artery (Pcom) aneurysms cause oculomotor nerve palsy (ONP). However, the time course of recovery after aneurysm repair remains unclear. We aimed to evaluate the ONP course after clipping and coiling for unruptured Pcom aneurysms. METHODS: We retrospectively reviewed the medical records of 25 consecutive patients with ONP due to unruptured Pcom aneurysms, undergoing aneurysm repair at our institution during 2010-2022. We analyzed the clinical data, angiographic results, and surgical complications. The time to ONP recovery was evaluated using the Kaplan-Meier method. RESULTS: This study included 14 patients undergoing surgical clipping and 11 undergoing endovascular coiling. The two groups exhibited no significant differences in complete or partial ONP percentage or in symptom presentation (ptosis, diplopia, ocular paralysis, pupillary light reflex disorder, or mydriasis). All patients achieved complete or partial recovery during the follow-up period. The median time to partial or complete improvement in ONP was significantly shorter for clipping compared to coiling (2 days vs. 33 days; P = 0.009). Preoperative partial and complete ONP were stratified; clipping improved significantly earlier than coiling in the complete ONP group (P = 0.010). In the early treatment group (based on the median duration of treatment), clipping resulted in earlier improvement than coiling (P = 0.014). In the small aneurysm group (based on the median of the aneurysm maximum diameter), clipping resulted in earlier improvement than coiling (P = 0.005). CONCLUSION: In ONP caused by an unruptured Pcom aneurysm, clipping may provide faster recovery than coiling, particularly in cases of early onset, complete palsy, and small aneurysms.

Clinical Outcomes in Elderly Patients with Chronic Subdural Hematoma: Validation of Irrigation Assignment Based on Hematoma Characteristics.

The number of elderly patients with chronic subdural hematomas (CSDH) is increasing worldwide; however, there is limited data regarding the clinical outcomes in this population. Our therapeutic method using burr hole evacuation for CSDH is based on the hematoma characteristics, using simple drainage for single-layer lesions and drainage with irrigation for multiple-layer lesions. This study aimed to compare the postoperative outcomes of elderly and younger patients, identify the predictors of outcomes in elderly patients, and verify the validity of our therapeutic methods. In total, we included 214 patients who underwent burr hole evacuation between April 2018 and March 2022. Baseline characteristics, hematoma characteristics, recurrence, and clinical outcomes were compared between the elderly and younger patients. Overall, 96 elderly patients (44.9%) were included in the study, and more elderly patients underwent antithrombotic therapy than younger patients (33.3% vs. 19.5%, p = 0.027). Moreover, elderly patients had significantly fewer favorable outcomes than younger patients (70.8% vs. 91.5%; p < 0.001); however, this was not significant after adjusting for the baseline modified Rankin Scale (mRS). Similarly, elderly patients had higher recurrence rates than younger patients (10.4% vs. 2.5%; p = 0.021). However, the baseline mRS score was the only predictor of unfavorable outcomes. In conclusion, although the clinical outcomes of elderly patients were comparable to those of younger patients, the higher rate of preoperative antithrombotic therapy in elderly patients may result in a higher rate of recurrence requiring a long-term follow-up.

QUANTITATIVE EVALUATION OF CONSERVATISM INCLUDED IN PARAMETER SETTINGS FOR CLEARANCE LEVEL CALCULATIONS: A CASE STUDY IN JAPAN.

In the evaluation of radiation safety standards, representative, average or conservative parameter values are set for dose calculation, and it is expected that excessive conservatism may be occasionally included in the standards already established. In this study, we attempted to quantitatively evaluate the 'factor of conservatism' for parameters used in the dose calculations for an actual case of clearance level calculations in Japan. The 'factor of conservatism' was calculated using the selected value for the parameter actually applied in the clearance level calculation and the expected values evaluated from the probability distribution. As a result, it was estimated that the 'factor of conservatism' for the parameters used in the clearance level calculation for the main nuclear facilities in Japan is approximately 1 to 7.

Facet joint thickness and lumbar instability documented on myelo-computed tomography studies in patients with lumbar degenerative disease.

Background: Various indicators of vertebral instability in patients with lumbar degenerative disease can be identified in myelo-computed tomography (CT) studies. Methods: Of 120 patients, 45 with lumbar degenerative spondylolisthesis (LDS; 53 lumbar lesions) and 75 with lumbar spinal stenosis alone (LSS; 105 lesions) (2015-2019) myelo-CT studies and surgery confirmed the presence of lumbar instability. Myelo-CT findings indicative of instability included facet joint thickness (FJT), fluid in the facet joint, facet tropism, and air in the facet and/or disc. Results: For the 120 study patients, FJT was significantly elevated in both the LDS and LSS groups. Conclusion: FJT on myelo-CT is more specific for lumbar instability than other imaging parameters when evaluating LDS. An increase in FJT suggests vertebral instability likely warranting fusion.

Study of certain easily available biochemical markers in prognostication in severe traumatic brain injury requiring surgery.

Background: This study aimed to identify easily available prognostic factors in severe traumatic brain injury (TBI) patients undergoing craniotomy. Methods: We retrospectively analyzed the clinical characteristics (age, sex, Glasgow coma scale score, cause of TBI, and oral antithrombotic drug use), laboratory parameters (hemoglobin, sodium, C-reactive protein, D-dimer, activated partial thromboplastin time, prothrombin time-international normalized ratio, and glucose-potassium [GP] ratio), and neuroradiological findings of 132 patients who underwent craniotomy for severe TBI in our hospital between January 2015 and December 2021. The patients were divided into two groups: Those with fatal clinical outcomes and those with non-fatal clinical outcomes, and compared between the two groups. Results: The patients comprised 79 (59.8%) male and 53 (40.2%) female patients. Their mean age was 67 ± 17 years (range, 16-94 years). Computed tomography revealed acute subdural hematoma in 108 (81.8%) patients, acute epidural hematoma in 31 (23.5%), traumatic brain contusion in 39 (29.5%), and traumatic subarachnoid hemorrhage in 62 (47.0%). All 132 patients underwent craniotomy, and 41 eventually died. There were significant differences in the D-dimer, GP ratio, and optic nerve sheath diameter between the groups (all P < 0.01). Multivariate logistic regression analysis showed elevated GP ratio and D-dimer were associated with the death group (P < 0.01, P < 0.01, respectively). A GP ratio of >42 was the optimal cutoff value for the prediction of a fatal outcome of TBI (sensitivity, 85.4%; specificity, 51.1%). Conclusion: The GP ratio and D-dimer were significantly associated with poor outcomes of TBI. A GP ratio of >42 could be a predictor of a fatal outcome of TBI.

Estimation of the mortality rate of workers in Japan.

BACKGROUND: Risk-based decision-making is used to identify risk factors for which threshold points have not been identified. The occupational mortality rate was referred to as a reference risk. This study aimed to analyze recent trends in worker mortality using three data sources. METHODS: The Reports of Worker Casualties (RWC), the Annual Statistics Report of the Industrial Accident Compensation Insurance Council (ASR), and the Annual Business Report of the Industrial Accident Compensation Insurance Council (ABR) were used. Mortality rates were estimated by age group and industry category (overall, and manufacturing and construction industries) from 1991 to 2019. The mortality rates were compared with those estimated in Western countries. RESULTS: The mortality rates for the three industry categories in the RWC and ASR decreased, whereas those for the manufacturing and construction industries in the ABR did not. In 2019, the mortality rates in the ABR were 3.1, 4.8, and 3.1 times higher than those in the RWC overall and in the manufacturing and construction industries, respectively. The differences decreased when deaths after long-term medical treatment were considered. The mortality rate trends in Japan were similar to those in Western countries. The upper mortality rate among Japan and Western countries was at least five to 15 times higher than the lowest. CONCLUSION: When occupational mortality rates are used as a reference risk, it is important to consider any changes with time, the data sources used, and the differences between countries.

Effect of bacterial siderophore on cesium dissolution from biotite.

In this study, the adsorption of cesium (Cs) on biotite and dissolution of Cs from Cs-bearing biotite using a siderophore were investigated aiming to contribute to the elucidation of radiocesium migration mechanisms in the soil environment. Thus, a siderophore was extracted and purified from the culture medium of Pseudomonas sp., and the purified siderophore was used in five consecutive dissolution experiments of biotite samples. Prior to the dissolution experiments, Cs was adsorbed on a hardly weathered biotite powder sample. The major components of the biotite (Al, Fe, and Mg) were dissolved almost stoichiometrically, strongly suggesting that the siderophore selectively dissolves the broken edges of the biotite. The amount of the dissolved Cs decreased by increasing the repetition times of the dissolution experiment. Therefore, the Cs adsorbed on the broken edges was dissolved rapidly as the siderophore dissolved the broken edges, and then, the Cs adsorbed on the outer planar surface of the biotite particles was slowly dissolved because the siderophore did not directly dissolve the outer planar surface of the biotite but dissolved the surface edge.

Clinical Characteristics of Ruptured Intracranial Aneurysm in Patients with Multiple Intracranial Aneurysms.

OBJECTIVE: It is difficult to correctly identify the ruptured aneurysm in patients with multiple intracranial aneurysms. Here, we investigated the clinical characteristics of ruptured intracranial aneurysms in such patients. METHODS: We retrospectively analyzed 361 patients who underwent microsurgical clipping of ruptured intracranial aneurysms at our institution from 2012 to 2018. Patients' age, sex, Fisher group, World Federation of Neurosurgical Societies grade, size (neck width, depth, maximum diameter), location, and shape of intracranial aneurysm, and hemorrhage pattern on admission were reviewed. RESULTS: In total, 266 patients (74%) had single intracranial aneurysms and 95 (26%) had multiple intracranial aneurysms. Eighty-nine of the 95 multiple intracranial aneurysms (94%) had irregular shape (P < 0.01). The median aspect ratios of ruptured and unruptured intracranial aneurysms were 2.2 ± 1.1 and 1.0 ± 0.4, respectively (P < 0.01). Twelve of 95 patients (13%) had ruptured intracranial aneurysms that were smaller than unruptured intracranial aneurysms. Among the 12 patients, the aspect ratios of ruptured intracranial aneurysms were greater than those of unruptured intracranial aneurysms (P < 0.01). Regarding morphologic characteristics, aspect ratio, maximum size, and irregular shape could be the useful predictive factors, but the greatest aspect ratio among patients with multiple aneurysms was the most predictive of an intracranial aneurysm rupture, after adjustment for aneurysmal size (adjusted odds ratio 217.82; 95% confidence interval 56.41-841.08). CONCLUSIONS: The results of this study indicate that the aspect ratio is the most predictive factor of a ruptured intracranial aneurysm in patients with multiple intracranial aneurysms.

Identification of Prognostic Factors in Surgically Treated Patients with Acute Epidural Hematoma.

CONTEXT: Only few comprehensive studies have investigated acute epidural hematoma (AEDH), and a low incidence of the lesion has been observed in comparison with other types of traumatic brain injuries such as subdural hematoma, traumatic subarachnoid hemorrhage, and contusion. AIM: This study aims to identify the prognostic factors of surgically treated AEDH. SETTINGS AND DESIGN: The medical records of 58 consecutive patients with surgically treated AEDH between September 2011 and 2018 were retrospectively reviewed. SUBJECTS AND METHODS: All patients were diagnosed with AEDHs using 5-mm-slice computed tomography (CT). Information regarding the following demographic and clinical characteristics was collected: age, sex, antithrombotic drug use, mechanisms of injury, time from onset to operation, neurological examination, vital signs, blood examination, and CT findings. STATISTICAL ANALYSIS USED: We analyzed prognostic factors in patients with AEDH using univariate and multivariate regression analyses. RESULTS: Univariate and multivariate regression analyses revealed that age (P < 0.01) and the Glasgow Coma Scale (GCS; P < 0.01) were independent predictive factors for good prognosis. In addition, receiver operating characteristics (ROC) analysis showed that an age of <55 years and a GCS score of >12 were optimal cutoff values for predicting good prognoses, with the areas under the ROC curve of 0.827 and 0.810, respectively. CONCLUSIONS: Age and GCS are useful predictors of prognosis in patients with surgically treated AEDH. These findings are appropriate prognostic indicators for urgent surgery performed to treat AEDH and intended to help clinicians make a prompt diagnosis.

Clinical Features of Neurogenic Pulmonary Edema in Patients with Subarachnoid Hemorrhage.

OBJECTIVE: Neurogenic pulmonary edema (NPE) is a clinical syndrome characterized by acute onset after central nervous system injury. Here, we investigated the clinical features of NPE in patients with subarachnoid hemorrhage (SAH). METHODS: We retrospectively analyzed a total of 350 patients with SAH who were treated at our hospital from April 2014 to September 2017. Patient demographics, aneurysm size and location, clinical characteristics, and patient outcomes were reviewed and compared between an NPE and a non-NPE group. RESULTS: Sixteen patients (4.6%) presented with NPE at admission. Ten of these (62.5%) recovered from NPE immediately, and ventilatory support was withdrawn within 2 days from onset. A univariate analysis showed that patients with NPE were younger (P = 0.04), had a higher rate of vertebral artery dissection (P < 0.01), more severe World Federation of Neurosurgical Societies (WFNS) grades (P = 0.01), and lower systolic blood pressure on admission (P = 0.01). A multivariate analysis revealed significant differences in the frequency of vertebral artery dissection (odds ratio 4.83, 95% confidence interval 1.50-15.56, P < 0.01) and in WFNS grades (odds ratio 3.73, 95% confidence interval 1.02-13.66, P = 0.04) between the groups. No significant group differences were found in other factors including heart rate, radiographic sign (Fisher grade), aneurysm size and location, blood sample tests on admission, and neurologic outcomes. CONCLUSIONS: Vertebral artery dissection and severe WFNS grade on admission were confirmed as significant risk factors for NPE. However, neurologic outcomes at discharge did not differ between groups, suggesting that poor outcomes due to NPE could be reduced by appropriate diagnosis and treatment.

Factors associated with early seizures after surgery of unruptured intracranial aneurysms.

OBJECTIVE: The aim of the study was to better define the incidence of and risk factors for early seizures after repair of unruptured intracranial aneurysms in modern microsurgical techniques. PATIENTS AND METHODS: The medical records of 414 consecutive patients who underwent neck clipping of unruptured intracranial aneurysms in our institution over a 5-year period were retrospectively reviewed. Clinical and neuroimaging variables were analyzed to investigate putative predictors of perioperative seizures using multivariate logistic regression analysis. RESULTS: Overall, 24 patients (5.8%) developed seizures within 14 days of surgery without routine prophylactic use of anticonvulsants. Eleven patients experienced partial seizures, while 13 experienced secondary generalized seizures. The interval between surgery and seizure onset was less than 6 h in 8 patients, 6-24 h in 3, and 1-14 days in 11. History of dialysis (odds ratio [OR] = 77.6, 95% confidence interval [CI] 7.5-1783.4, P < 0.001), and presence of cerebral contusion (OR = 5.1, 95% CI 1.3-16.9, P = 0.02) or infarction (OR = 13.9, 95% CI 3.9-48.5, P < 0.001) detected by postoperative computed tomography were independent and significant risk factors. No patients with early seizures went on to develop refractory epilepsy. CONCLUSIONS: Dialysis and iatrogenic brain damage were associated with a higher risk of early seizures after aneurysm surgery. Our data support the selective use of anticonvulsants during the perioperative period of elective aneurysm surgery.