Melatonin Attenuates Memory Impairment Induced by Klotho Gene Deficiency Via Interactive Signaling Between MT2 Receptor,ERK, and Nrf2-Related Antioxidant Potential

Background:

We demonstrated that oxidative stress plays a crucial role in cognitive impairment in klotho mutant mice, a genetic model of aging. Since down-regulation of melatonin due to aging is well documented, we used this genetic model to determine whether the antioxidant property of melatonin affects memory impairment.

Methods:

First, we examined the effects of melatonin on hippocampal oxidative parameters and the glutathione/oxidized glutathione (GSH/GSSG) ratio and memory dysfunction of klotho mutant mice. Second, we investigated whether a specific melatonin receptor is involved in the melatonin-mediated pharmacological response by application with melatonin receptor antagonists. Third, we examined phospho-extracellular-signal-regulated kinase (ERK) expression, nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation, Nrf2 DNA binding activity, and glutamate-cysteine ligase (GCL) mRNA expression. Finally, we examined effects of the ERK inhibitor SL327 in response to antioxidant efficacy and memory enhancement mediated by melatonin.

Results:

Treatment with melatonin resulted in significant attenuations of oxidative damage, a decrease in the GSH/GSSG ratio, and a significant amelioration of memory impairment in this aging model. These effects of melatonin were significantly counteracted by the selective MT2 receptor antagonist 4-P-PDOT. Importantly, 4-P-PDOT or SL327 also counteracted melatonin-mediated attenuation in response to the decreases in phospho-ERK expression, Nrf2 nuclear translocation, Nrf2 DNA-binding activity, and GCL mRNA expression in the hippocampi of klotho mutant mice. SL327 also counteracted the up-regulation of the GSH/GSSG ratio and the memory enhancement mediated by melatonin in klotho mutant mice.

Conclusions:

Melatonin attenuates oxidative stress and the associated memory impairment induced by klotho deficiency via signaling interaction between the MT2 receptor and ERK- and Nrf2-related antioxidant potential.     

Successful defibrotide treatment of a patient with veno-occlusive disease after living-donor liver transplantation: A case report

Rationale:Veno-occlusive disease (VOD) is characterized by painful hepatomegaly, ascites, weight gain, and jaundice with nonthrombotic, fibrous obliteration of the centrilobular hepatic veins. VOD after liver transplantation is a rare complication, with an incidence of approximately 2%; however, it can be life-threatening in severe cases. The precise etiology and mechanism of VOD after liver transplantation remains unclear. Acute cellular rejection, antibody-mediated rejection, and treatment with tacrolimus or azathioprine may be associated with the development of VOD after liver transplantation. Additionally, the optimal treatment of VOD after liver transplantation has not yet been established and focuses on supportive care. Defibrotide is an anti-ischemic and antithrombotic drug with no systemic anticoagulant effects. Moreover, only a few reports have investigated the use of defibrotide for VOD after liver transplantation, which has shown promising results.Patient concerns:A 39-year-old woman with primary biliary cholangitis underwent living-donor liver transplantation at our center. She experienced right upper quadrant pain with increased ascites, pleural effusion, and weight gain on postoperative day 14.Diagnoses:Imaging and pathological tests showed no evidence of rejection or vessel complications. VOD was diagnosed clinically based on the findings of weight gain, ascites, jaundice, and pathological biopsy.Interventions:Defibrotid, 25 mg/kg/day, was administered intravenously for 21 days.Outcomes:She showed complete clinical resolution of the VOD.Lessons:Herein, we report a case of successful defibrotide treatment of VOD after living-donor liver transplantation.     

Clinical significance of performing Sonazoid-based contrast-enhanced ultrasonography before ablation of uterine fibroids by high-intensity focused ultrasound: A preliminary cohort study

High-intensity focused ultrasound (HIFU) is effective for the ablation of uterine fibroids. However, no research has indicated whether HIFU ablation of uterine fibroids might be improved by application of contrast-enhanced ultrasonography (CEUS) with Sonazoid as a contrast agent. This study aimed to assess the clinical significance of Sonazoid-based CEUS 30 minute before HIFU ablation of uterine fibroids.This retrospective cohort study included Asian patients with solitary uterine fibroids who were treated with HIFU at Seoul HICARE Clinic (South Korea; n = 34) and the Second Affiliated Hospital of Chongqing Medical University (China; n = 30) between August 1, 2017, and October 31, 2017. The patients in Seoul underwent Sonazoid-based CEUS 30 minute before HIFU. All the patients received contrast-enhanced magnetic resonance imaging to diagnose uterine fibroids. The ablation results were evaluated 1 day after HIFU by contrast-enhanced magnetic resonance imaging or Sonazoid-based CEUS.All the patients were successfully treated with HIFU. The CEUS+HIFU group had lower values for sonication power, treatment time, sonication time, total energy applied, and energy efficiency factor compared with HIFU alone group (P < .001). There were no major adverse events after ablation therapy in either group. The incidence of post-procedure sacrococcygeal pain was lower in the CEUS+HIFU group than that in the HIFU alone group (P = .045), while the incidences of all other intraoperative and postoperative adverse events were similar between the 2 groups.Our findings suggest that Sonazoid-based CEUS before HIFU may enhance the ablation of uterine fibroids.     

Metformin use in cancer survivors with diabetes reduces all-cause mortality,based on the Korean National Health Insurance Service between 2002 and 2015

Malignant neoplasms are the leading cause of death in Korea. We aimed to examine if metformin use in cancer survivors reduces all-cause mortality. This study was retrospectively designed based on data from the Korean National Health Insurance Service-National Health Screening Cohort (HEALS) between 2002 and 2015. The Kaplan–Meier estimator and log-rank test was performed to estimate the survival function according to metformin usage (3721 metformin non-users with diabetes, 5580 metformin users with diabetes, and 24,483 non-diabetic individuals). Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause mortality were calculated using Cox proportional hazards regression models.The median follow-up duration was 4.2 years. The HRs (95% CIs) for all-cause mortality of metformin users and the non-diabetic group were 0.762 (0.683–0.850) and 1.055 (0.966–1.152) in men and 0.805 (0.649–0.999), and 1.049 (0.873–1.260) in women, respectively, compared with metformin non-users among diabetic cancer survivors, in a fully adjusted model. After stratifying metformin users into pre- and post-diagnosis of cancers, adjusted HRs (95% CIs) of pre- and post-diagnosis metformin users for all-cause mortality were 0.948 (0.839–1.071) and 0.530 (0.452–0.621) in men and 1.163 (0.921–1.469) and 0.439 (0.323–0.596) in women, respectively.Metformin use in cancer survivors with diabetes reduced overall mortality rates. In particular, metformin use after cancer diagnosis, not before cancer diagnosis, was inversely associated with overall mortality.Active treatment with metformin for diabetic cancer survivors after cancer diagnosis can improve their survival rates.     

Tumor microenvironment immune subtypes for classification of novel clear cell renal cell carcinoma profiles with prognostic and therapeutic implications

Currently, no effective prognostic model of clear cell renal cell carcinoma (ccRCC) based on immune cell infiltration has been developed. Recent studies have identified 6 immune groups (IS) in 33 solid tumors. We aimed to characterize the expression pattern of IS in ccRCC and evaluate the potential in predicting patient prognosis. The clinical information, immune subgroup, somatic mutation, copy number variation, and methylation score of patients with TCGA ccRCC cohort were downloaded from UCSC Xena for further analysis. The most dominant IS in ccRCC was the inflammatory subgroup (immune C3) (86.5%), regardless of different pathological stages, pathological grades, and genders. In the C3 subgroup, stage IV (69.1%) and grade 4 (69.9%) were the least presented. Survival analysis showed that the IS could effectively predict the overall survival (OS) (P < .0001) and disease-specific survival (DSS) (P < .0001) of ccRCC alone, of which group C3 (OS, HR = 2.3, P < .001; DSS, HR = 2.84, P < .001) exhibited the best prognosis. Among the most frequently mutated ccRCC genes, only VHL and PBRM1 were found to be common in the C3 group. The homologous recombination deficiency score was also lower. High heterogeneity was observed in immune cells and immunoregulatory genes of IS. Notably, CD4+ memory resting T cells were highly infiltrating, regulatory T cells (Treg) showed low infiltration, and most immunoregulatory genes (such as CX3CL1, IFNA2, TLR4, SELP, HMGB1, and TNFRSF14) were highly expressed in the C3 subgroup than in other subgroups. Enrichment analysis showed that adipogenesis, apical junction, hypoxia, IL2 STAT5 signaling, TGF-beta signaling, and UV response DN were activated, whereas E2F targets, G2M checkpoint, and MYC targets V2 were downregulated in the C3 group. Immune classification can more accurately classify ccRCC patients and predict OS and DSS. Thus, IS-based classification may be a valuable tool that enables individualized treatment of patients with ccRCC.     

A novel assessment of abdominal pseudohernia after thoracolumbar vertebral compression fractures using surface electromyography and ultrasonography: A case report

Rationale:An abdominal pseudohernia is a protrusion of the abdominal wall that there is no actual muscular disruption. This report presents a case in which abdominal muscle activities were accurately and quantitatively measured using ultrasonography (US) and surface electromyography in a patient with abdominal pseudohernia.Patient concerns:A 62-year-old man presented with a marked protrusion on the left abdomen with increasing abdominal pressure.Diagnoses:First, the thickness of the abdominal muscle was measured with US while the patient constantly blew the positive expiratory pressure device. When the force was applied to the abdomen, the mean thickness of the muscle layer on the lesion site was found to be thinner. Second, the activities of the abdominal muscles were measured using surface electromyography by attaching electrodes to 8 channels at the same time. When the same pressure was applied on both sides of the abdomen, more recruitment occurred to compensate for muscle weakness at the lesion site. Through the previous 2 tests, the decrease in muscle activity in the lesion area could be quantitatively evaluated. Third, the denervation of the muscle was confirmed using US-guided needle electromyography.Interventions:The patient in this case was wearing an abdominal binder. In addition, he had been training his abdominal muscles through McGill exercise and breathing exercises such as with a positive expiratory pressure device.Outcomes:The patient was able to understand his symptoms. A follow-up test will be performed to see if there is any improvement.Lessons:By using these outstanding assessment methods, proper diagnosis and rehabilitation treatment strategies can be developed.     

Collapsing focal segmental glomerulosclerosis in a patient with oral cavity cancer: A case report

Rationale:Focal segmental glomerulosclerosis (FSGS) is one of the most common glomerular diseases, leading to end-stage renal disease. Among the 5 variants of FSGS, the collapsing variant is rare and has the worst prognosis. Solid and hematologic malignancies are associated with glomerular diseases, such as membranous nephropathy, minimal change disease, and FSGS. However, squamous cell carcinoma of the oral cavity is rarely associated with nephrotic syndrome, especially FSGS.Patient concerns:A 55-year-old woman diagnosed with oral cavity cancer presented with generalized edema with heavy proteinuria and renal dysfunction after neoadjuvant chemotherapy and wide surgical excision.Diagnosis:Renal biopsy shows segmental or global collapse of glomerular capillaries with marked hyperplasia and swelling of overlying epithelial cells, suggesting a collapsing variant of FSGS.Interventions:After the renal biopsy, we prescribed oral prednisolone at a dose of 1 mg/kg/day. Despite immunosuppressive treatment, renal function deteriorated, and hemodialysis was started.Outcomes:After 23 sessions of hemodialysis and high-dose oral glucocorticoid treatment, renal function gradually improved, and oral glucocorticoid therapy was discontinued after 8 months. Currently, this patient is in a cancer-free state and has normal renal function without proteinuria.Lessons:Unusual collapsing FSGS might be associated with neoadjuvant chemotherapy and wide surgical excision in patients with oral cavity cancer. Proper diagnostic workup, such as renal biopsy and high-dose glucocorticoid therapy, might have helped recover from nephrotic syndrome and acute renal injury in cancer patients.     

Sarcomatoid carcinoma associated with chronic empyema and early lung and pleural metastases: A case report

Introduction:The relationship between chronic empyema and malignant tumors, most of which are lymphoma, has been recognized for many decades. Sarcomatoid carcinoma associated with chronic empyema is extremely rare, may metastasize to other organs in the early stage, and rapidly progresses to death. As far as we know, this was the first case report on sarcomatoid carcinoma associated chronic empyema.The patient''s main concerns and important clinical findings:A 59-year-old man presented to our hospital with a 9-year history of chronic empyema and a chief complaint of left chest wall pain for 5 months. The diagnostic contrast-enhanced computed tomography (CT) showed a large irregular soft tissue mass located on the left lower hemithorax at the margin of the empyema cavity extending to the adjacent chest wall and lung parenchyma. In addition, CT revealed pleural and pulmonary metastases surrounded by ground glass opacity.The main diagnosis, therapeutics interventions, and outcomes:The patient underwent CT guided percutaneous core needle biopsy (PCNB). The histopathological evaluation showed carcinomatous proliferation of pleomorphic spindle cells with extensive necrosis. Immunohistochemically, tumor cells were positive for cytokeratin and vimentin. The final histopathological diagnosis was sarcomatoid carcinoma underlying chronic empyema. The tumors showed rapid progression on serial simple radiography. Palliative treatments were performed, but the patient still developed severe dyspnea and died shortly after on day 16.Conclusion:Sarcomatoid carcinoma can occur very rarely as a complication of chronic empyema, and is more aggressive than usual. Early detection of developing malignancy during the follow-up of chronic empyema is an important factor for patient prognosis.     

Effects of preoperative,scheduled administration of antiemetics in reducing postoperative nausea and vomiting in patients undergoing total knee arthroplasty

There is no established protocol regarding the timing of administration of antiemetics in patients undergoing total knee arthroplasty (TKA). The purpose of this study was to determine whether preoperative, rather than postoperative administration of an antiemetic could reduce postoperative nausea and vomiting (PONV) in patients undergoing TKA, and whether there was a difference in postoperative pain, patient satisfaction and complications after TKA between the 2 different administration times.The included patients (N = 101) either received intravenous administration of the ramosetron 1 hour before surgery (N = 50) or at the end of surgery (N = 51) consecutively order. The incidence of PONV and the frequency of rescue medicine use were recorded until 48 hours postoperatively. The severity of postoperative pain and patient satisfaction were assessed using the visual analogue scale. The incidence of complications associated with use of antiemetic was assessed.Preoperative administration of ramosetron did not decrease PONV during the first 48 hours. There was no significant difference in the incidence of nausea and vomiting, use of rescue antiemetics, and the severity of nausea (P > .05). Postoperative pain, satisfaction scores, and the incidence of complications were not different between the 2 groups (P > .05).Preoperative administration of ramosetron did not show clinical advantage in reducing POVN, postoperative pain and improving patient satisfaction. However, the outcomes of complications were not inferior to those of postoperative administration. Therefore, under the current protocol of multimodal therapies, timing of administration of pre-emptive antiemetic did not have significant effect on PONV.     

Factors associated with differential T cell responses to antigens ESAT-6 and CFP-10 in pulmonary tuberculosis patients

The T-SPOT.TB assay detects cellular immune responses to 2 core Mycobacterium tuberculosis antigens, early secreted antigenic target of 6-kDa protein (ESAT-6) and culture filtrate protein-10 (CFP-10). T-SPOT.TB has been recently used for auxiliary diagnosis of active pulmonary tuberculosis (PTB). However, testing can produce inconsistent results due to differential PTB patient immune responses to these antigens, prompting us to identify factors underlying inconsistent results.Data were retrospectively analyzed from 1225 confirmed PTB patients who underwent T-SPOT.TB testing at 5 specialized tuberculosis hospitals in China between December 2012 and November 2015. Numbers of spot-forming cells (SFCs) reflecting T cell responses to ESAT-6 and CFP-10 antigens were recorded then analyzed via multivariable logistic regression to reveal factors underlying discordant T cell responses to these antigens.The agreement rate of 84.98% (82.85%–86.94%) between PTB patient ESAT-6 and CFP-10 responses demonstrated high concordance. Additionally, positivity rates were higher for ESAT-6 than for CFP-10 (84.8% vs 80.7%, P < .001), with ESAT-6 and CFP-10 microwell SFC numbers for each single positive group not differing significantly (P > .99), while spot numbers of the single positive group were lower than numbers for the double positive group (P < .001). Elderly patients (aged ≥66 years) and patients receiving retreatment were most likely to have discordance results.ESAT-6 promoted significantly more positive T-SPOT.TB results than did CFP-10 in PTB patients. Advanced age and retreatment status were correlated with discordant ESAT-6 and CFP-10 results. Assessment of factors underlying discordance may lead to improved PTB diagnosis using T-SPOT.TB.