Exercise accelerates recruitment of CD8+ T cell to promotes anti-tumor immunity in lung cancer via epinephrine.

BACKGROUND AND PURPOSE: In recent years, there has been extensive research on the role of exercise as an adjunctive therapy for cancer. However, the potential mechanisms underlying the anti-tumor therapy of exercise in lung cancer remain to be fully elucidated. As such, our study aims to confirm whether exercise-induced elevation of epinephrine can accelerate CD8+ T cell recruitment through modulation of chemokines and thus ultimately inhibit tumor progression. METHOD: C57BL/6 mice were subcutaneously inoculated with Lewis lung cancer cells (LLCs) to establish a subcutaneous tumor model. The tumor mice were randomly divided into different groups to performed a moderate-intensity exercise program on a treadmill for 5 consecutive days a week, 45 min a day. The blood samples and tumor tissues were collected after exercise for IHC, RT-qPCR, ELISA and Western blot. In addition, another group of mice received daily epinephrine treatment for two weeks (0.05 mg/mL, 200 µL i.p.) (EPI, n = 8) to replicate the effects of exercise on tumors in vivo. Lewis lung cancer cells were treated with different concentrations of epinephrine (0, 5, 10, 20 µM) to detect the effect of epinephrine on chemokine levels via ELISA and RT-qPCR. RESULTS: This study reveals that both pre- and post-cancer exercise effectively impede the tumor progression. Exercise led to an increase in EPI levels and the infiltration of CD8+ T cell into the lung tumor. Exercise-induced elevation of EPI is involved in the regulation of Ccl5 and Cxcl10 levels further leading to enhanced CD8+ T cell infiltration and ultimately inhibiting tumor progression. CONCLUSION: Exercise training enhance the anti-tumor immunity of lung cancer individuals. These findings will provide valuable insights for the future application of exercise therapy in clinical practice.

Incomplete Recovery from the Radiocontrast-Induced Dysregulated Cell Cycle, Adhesion, and Fibrogenesis in Renal Tubular Cells after Radiocontrast (Iohexol) Removal.

Contrast-induced nephropathy (CIN) is one of the most common causes of acute kidney injury (AKI). However, management is still limited, and the cellular response to radiocontrast removal for CIN remains unclear. This study aimed to explore the latent effects of iohexol in cultured renal tubular cells with or without the removal of iohexol by medium replacement. HK2 renal tubular cells were subcultured 24 h before use in CIN experiments. Three treatment groups were established: the control, a radiocontrast (iohexol)-only group at 75 mg I/mL (I-75), and iohexol exposure for 24 h with culture medium replacement (I-75/M). Cell cycle arrest, fibrogenic mediator assays, cell viability, cell function, and cell-cycle-related protein expression were compared between groups. Iohexol induced numerous changes in HK2 renal tubular cells, such as enlarged cell shape, cell cycle arrest, increased apoptosis, and polyploidy. Iohexol inhibited the expression of cyclins, CDKs, ZO-1, and E-cadherin but conversely enhanced the expression of p21 and fibrosis-related genes, including TGF-ß1, CTGF, collagen I, collagen III, and HIF-1α within 60 hr after the exposure. Except for the recovery from cell cycle arrest and cell cycle gene expression, notably, the removal of iohexol by medium replacement could not fully recover the renal tubular cells from the formation of polyploid cells, the adhesion or spreading, or the expression of fibrosis-related genes. The present study demonstrates, for the first time, that iohexol exerts latent cytotoxic effects on cultured renal tubular cells after its removal, suggesting that these irreversible cell changes may cause the insufficiency of radiocontrast reduction in CIN, which is worth investigating further.

NOTCH2NLC GGC Repeat Expansion in Patients With Vascular Leukoencephalopathy.

BACKGROUND: Neuronal intranuclear inclusion disease (NIID), caused by GGC (guanine-guanine-cytosine) repeat expansion in NOTCH2NLC, has several clinical and radiological features akin to cerebral small vessel disease (cSVD). The present study tested the hypothesis that NOTCH2NLC GGC expansion may contribute to cSVD. METHODS: One hundred and ninety-seven unrelated patients with genetically unsolved vascular leukoencephalopathy without NOTCH3, HTRA1, and mitochondrial m.3243A>G mutations and 730 healthy individuals were screened for NOTCH2NLC GGC repeat expansion using repeat-primed polymerase chain reaction, fragment analysis, Southern blot analysis, or nanopore sequencing with Cas9 (CRISPR associated protein 9)-mediated enrichment. The clinical and neuroimaging features of the patients were compared between individuals with and without NOTCH2NLC GGC repeat expansion. RESULTS: Six of the 197 (3.0%) patients with unsolved vascular leukoencephalopathy and none of the controls carried the GGC repeat expansion (P=0.00009). Skin biopsy of 1 patient revealed eosinophilic, ubiquitin-positive, and p62-positive intranuclear inclusions in the cells of sweat gland and capillary, providing pathologic evidence for the involvement of small vessels in NIID. For the 6 patients, gait disturbance and cognitive decline were common manifestations with a median onset age of 65 (59-69) years. They all had multiple neuroimaging features suggestive of cSVD, including diffuse white matter hyperintensities, lacunes, and enlarged perivascular space in all 6 patients, cerebral microbleeds in 5, and old intracerebral hemorrhage in 4. Four patients had linear hyperintensity in the corticomedullary junction on diffusion-weighted imaging-the characteristic neuroimaging feature of NIID. There was no difference in the severity of cSVD imaging features between the patients with and without the GGC expansion but more pronounced brain atrophy in the patients with the GGC expansion. CONCLUSIONS: NOTCH2NLC GGC repeat expansion accounted for 3% of genetically unsolved Taiwanese vascular leukoencephalopathy cases after excluding participants with cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), and mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS). NIID should be considered in patients manifesting cSVD, especially in those with characteristic neuroimaging feature of NIID.

Nationwide Prevalence and Outcomes of Long-Term Nasogastric Tube Placement in Adults.

Tube feeding (TF) is commonly used for patients with severe swallowing disturbance, and patients with chronic dysphagia are often provided with a long-term nasogastric tube (NGT). However, nationwide epidemiological data on long-term NGT placement are limited. The present study identified the prevalence and outcomes of patients with long-term NGT placement in Taiwan. Data were obtained from the Longitudinal Health Insurance Database. Patients with NGT placement for more than 3 months between 2000 and 2012 were enrolled in this cohort study. An NGT cohort of 2754 patients was compared with 11,016 controls matched for age, sex, residential area, and comorbidities. The prevalence rate of long-term NGT reached 0.063% in 2005 and then remained stable at 0.05-0.06%. The major causes of NGT placement were stroke (44%), cancer (16%), head injury (14%), and dementia (12%). Men (63%) were more likely to have long-term NGT placement than women (37%). The adjusted hazard ratios were 28.1 (95% CI = 26.0, 30.3) for acute and chronic respiratory infections; 26.8 (95% CI = 24.1, 29.8) for pneumonia, 8.84 (95% CI = 7.87, 9.93) for diseases of the esophagus, stomach, and duodenum; and 7.5 (95% CI = 14.7, 20.8) for mortality. Patients with NGT placement for more than 6 months had a higher odds ratio (1.58, 95% CI = 1.13, 2.20) of pneumonia than those with NGT placement for less than 6 months. Only 13% and 0.62% of the patients underwent rehabilitation therapy and percutaneous endoscopic gastrostomy, respectively. Long-term NGT use was associated with a higher risk of comorbidities and mortality. Stroke was the main illness contributing to long-term NGT use. Further interventions are necessary to improve the negative effects of long-term TF.

Smoking Status and Functional Outcomes in Young Stroke.

Objective: Stroke in young adults is uncommon, and the etiologies and risk factors of stroke in young adults differ from those in older populations. Smoker's paradox is an unexpected favorable outcome, and age difference is used to explain the association between smoking and the favorable functional outcome. This study aimed to investigate the existence of this phenomenon in young stroke patients. Methods: We analyzed a total of 9,087 young stroke cases registered in the nationwide stroke registry system of Taiwan between 2006 and 2016. Smoking criteria included having a current history of smoking more than one cigarette per day for more than 6 months. After matching for sex and age, a Cox model was used to compare mortality and function outcomes between smokers and non-smokers. Results: Compared with the non-smoker group, smoking was associated with older age, higher comorbidities, and higher alcohol consumption. Patients who report smoking with National Institutes of Health Stroke Scale scores of 11-15 had a worse functional outcome (adjusted odds ratio, 0.81; 95% confidence interval, 0.76 - 0.87). Conclusion: Smokers had a higher risk of unfavorable functional outcomes at 3 months after stroke, and therefore, we continue to strongly advocate the importance of smoking cessation.

NMD-12: A new machine-learning derived screening instrument to detect mild cognitive impairment and dementia.

INTRODUCTION: Using machine learning techniques, we developed a brief questionnaire to aid neurologists and neuropsychologists in the screening of mild cognitive impairment (MCI) and dementia. METHODS: With the reduction of the survey size as a goal of this research, feature selection based on information gain was performed to rank the contribution of the 45 items corresponding to patient responses to the specified questions. The most important items were used to build the optimal screening model based on the accuracy, practicality, and interpretability. The diagnostic accuracy for discriminating normal cognition (NC), MCI, very mild dementia (VMD) and dementia was validated in the test group. RESULTS: The screening model (NMD-12) was constructed with the 12 items that were ranked the highest in feature selection. The receiver-operator characteristic (ROC) analysis showed that the area under the curve (AUC) in the test group was 0.94 for discriminating NC vs. MCI, 0.88 for MCI vs. VMD, 0.97 for MCI vs. dementia, and 0.96 for VMD vs. dementia, respectively. DISCUSSION: The NMD-12 model has been developed and validated in this study. It provides healthcare professionals with a simple and practical screening tool which accurately differentiates NC, MCI, VMD, and dementia.

An Informant-Based Simple Questionnaire for Language Assessment in Neurodegenerative Disorders.

BACKGROUND/AIMS: Language dysfunction is a crucial feature of brain disorders. This study investigated language dysfunction in patients with dementia with or without parkinsonism by using an informant-based simple questionnaire. METHODS: Language dysfunction in normal controls (NCs), and patients with Parkinson disease (PD), Parkinson disease dementia (PDD), dementia with Lewy bodies (DLB), or Alzheimer disease (AD) were analyzed and compared. RESULTS: A total of 1,662 individuals were studied: 285 NCs, 157 PD patients, 161 PDD patients, 248 DLB patients, and 811 AD patients. Patients with PD displayed higher frequency of language dysfunction in several language domains than NC. Patients with PDD and DLB showed higher frequency of language dysfunction in most of the language domains than those with AD. A composite score of our simple questionnaire was comparable with the score for the language domain of the Cognitive Abilities Screening Instrument (CASI) in different stages of dementia due to Lewy body diseases or not. CONCLUSION: Our study showed that the informant-based simple questionnaire is a practical screening tool and is comparable with the language subscale of CASI. This tool can be applied in clinical practice and in the registration platform for rapid language dysfunction screening.

Reduced vascular risk factors in Parkinson's disease dementia and dementia with Lewy bodies compared to Alzheimer's disease.

Objectives: The association of vascular risk factors (VRFs) with incidence of Alzheimer's disease (AD) and vascular dementia (VaD) has been well studied. However, the association between VRFs and non-AD dementia is seldom investigated. In this study, we aim to compare the concurrence of VRFs of Lewy body dementia (LBD) to AD. Materials & Methods: We consecutively enrolled patients with dementia with Lewy bodies (DLB), Parkinson's disease dementia (PDD), and AD, and the prevalence of arterial hypertension, diabetes mellitus, hypercholesterolemia, hyperlipidemia, smoking, and obesity was assessed and compared. Results: A total of 167 consecutive patients were studied. Among them, 55 had DLB, 34 had PDD, and 78 had AD. History of any VRF among three groups was not significantly different. In addition, the patients with AD had significantly higher systolic pressure (SBP), diastolic pressure (DBP), waist, body mass index (BMI), ac glucose, and HbA1c (all p-value < .005). After a stepwise procedure that considered age, sex, disease severity, antiparkinson drugs, systolic and diastolic blood pressures, glycated hemoglobin, body mass index, triglyceride, total cholesterol, and low-density lipoprotein, SBP in the third tertile (144-198 mmHg), BMI in the second tertile (23.6-26.4), and TG in the third tertile (127-310) were significantly lower in LBD than in AD. Conclusions: The VRFs are less associated with LBD than with AD. DLB and PDD showed a similar pattern of the association of VRFs. SBP, BMI, and TG were significantly lower in LBD compared with AD.

Renal function is associated with 1-month and 1-year mortality in patients with ischemic stroke.

BACKGROUND AND AIMS: Renal dysfunction is a potent risk factor for cardiovascular diseases, including stroke. This study aimed to evaluate the impact of admission estimated glomerular filtration rate (eGFR) levels on short-term (1-month) and long-term (1-year) mortality in patients with acute ischemic stroke. METHODS: From the Taiwan Stroke Registry data, we classified ischemic stroke patients, identified from April 2006 to December 2015, into 5 groups by eGFR at admission: ≥ 90, 60-89, 30-59, 15-29, and <15 mL/min/1.73 m2 or on dialysis. Risks of 1-month mortality and 1-year mortality after ischemic stroke were investigated by the eGFR level. RESULTS: Among 52,732 ischemic stroke patients, 1480 died within one month. The 1-month mortality rate was over 5-fold greater in patients with eGFR <15 mL/min/1.73 m2 or dialysis than in patients with eGFR ≥90 mL/min/1.73 m2 (2.88 versus 0.56 per 1000 person-days). The adjusted hazard ratio (HR) of 1-month mortality increased from 1.31 (95% CI = 1.08-1.59) for patients with eGFR 60-89 mL/min/1.73 m2 to 2.33 (95% CI = 1.80-3.02) for patients with eGFR < 15 mL/min/1.73 m2 or on dialysis. 3226 patients died within one year. The adjusted HR of mortality increased from 1.38 (95% CI = 1.21-1.59) for patients with eGFR 60-89 mL/min/1.73 m2 to 2.60 (95% CI 2.18-3.10) for patients with eGFR < 15 mL/min/1.73 m2 or on dialysis, compared to patients with eGFR ≥ 90 mL/min/1.73 m2. CONCLUSIONS: After acute ischemic stroke, patients with reduced eGFR are at elevated risks of short-term and long-term deaths in a graded relationship.

Protective effect of wogonin on endotoxin-induced acute lung injury via reduction of p38 MAPK and JNK phosphorylation.

Acute lung injury (ALI) is a serious inflammatory disorder which remains the primary cause of incidence and mortality in patients with acute pulmonary inflammation. However, there is still no effective medical strategy available clinically for the improvement of ALI. Wogonin, isolated from roots of Scutellaria baicalensis Georgi, is a common medicinal herb which presents biological and pharmacological effects, including antioxidation, anti-inflammation, and anticancer. Preadministration of wogonin inhibited not only lung edema but also protein leakage into the alveolar space in murine model of lipopolysaccharide (LPS)-induced ALI. Moreover, wogonin not only reduced the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 but also inhibited the phosphorylation of mitogen-activated protein kinase (MAPK) induced by LPS. We further found wogonin inhibited the phosphorylation of p38 MAPK and JNK at a concentration lower than ERK. In addition, inhibition of lung edema, protein leakage, expression of iNOS and COX-2, and phosphorylation of p38 MAPK and JNK were all observed in a parallel concentration-dependent manner. These results suggest that wogonin possesses potential protective effect against LPS-induced ALI via downregulation of iNOS and COX-2 expression by blocking phosphorylation of p38 MAPK and JNK. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 397-403, 2017.

The Value of 99mTc ECD SPECT With Statistical Image Analysis on Enhancing the Early Diagnosis of Primary Progressive Aphasia.

A 64-year-old woman with poor short-term memory was first suspected as early Alzheimer disease. Tc ECD brain SPECT was arranged for differential diagnosis. A small area of mild hypoperfusion was noted in the left temporal lobe on conventional display. Further statistical analysis of SPECT with an easy Z-score imaging system showed large areas of distinct hypoperfusion in left precentral and perisylvian cortical areas, compatible with typical pictures of nonfluent variant primary progressive aphasia (PPA), but no involvement in areas characteristic for Alzheimer disease. Further detailed neuropsychological examination and 6 months of clinical follow-up confirmed the final diagnosis of PPA.

The value of eZIS analysis of Tc-99m ECD SPECT on identifying cerebellar hypoperfusion in a patient with superficial siderosis: A case report.

INTRODUCTION: Brain perfusion single photon computed tomography (SPECT) is a functional imaging modality and has been widely utilized in evaluation of various kinds of neurological disorders. Easy z-score imaging system (eZIS) is a computer-assisted statistical analysis, based on the comparison with age-classified ethyl cysteinate dimer (ECD) normal database, which provides objectively interpretation of Tc-99m ECD brain perfusion SPECT.Here we presented a 64-year-old male with dizziness, spin sensation, nausea, and vomiting in the emergency room, and brain computed tomography scan showed only small hypodensity lesion in cerebellum. Tc-99m ECD SPECT was performed for evaluating occult cerebral ischemia, infarction, and/or degeneration, but no remarkable abnormality could be identified by experienced readers on conventional display. The result of eZIS showed remarkable hypoperfusion in cerebellum and mild hypoperfusion in bilateral frontal and parietal lobes. Magnetic resonance imaging (MRI) confirmed severe atrophy of anterior cerebellar lobe. In addition, MRI showed diffuse hypointensity signals along with cerebrospinal fluid spaces, especially those areas with hypoperfusion on SPECT, compatible with typical appearances of superficial siderosis. CONCLUSION: This presented case demonstrates the value of software analysis with eZIS on enhancing the diagnostic value of brain perfusion SPECT for detecting brain lesions at an uncommon location due to a rare disease.

Obstructive hydrocephalus as a result of giant cell tumor of the thoracic spine: A case report.

Giant cell tumors (GCTs) are rare bone tumors that account for ~5% of all primary bone tumors. When GCTs occur in the spine, patients usually present with localized pain and neurological symptoms, such as radiating pain or hyperesthesia. In the current report, an unusual case of a GCT of the thoracic spine associated with hydrocephalus is described. A 48-year-old male presented with urinary retention, loss of sensation in the lower limbs and inability to walk. The patient eventually developed hydrocephalus combined with altered consciousness, indicated by an inability to follow simple commands. Magnetic resonance (MR) imaging demonstrated the presence of a soft tissue mass at the T2 level, and biopsy examination of the tissue confirmed that it was a GCT. The patient experienced a sudden loss of consciousness due to an acute episode of obstructive hydrocephalus. A ventriculoperitoneal shunting procedure was performed to treat the hydrocephalus, and the patient regained normal consciousness, although the paraplegia persisted. An MR examination performed 30 months following surgery demonstrated that the tumor size was stable, consistent with the slow growth that is characteristic of GCTs. Diagnosis of GCTs may be challenging, and relies on radiographic and histopathologic findings. Although rare, acute hydrocephalus as a result of GCTs should not be excluded from a differential diagnosis.

The effect of different patient education methods on quality of bowel cleanliness in outpatients receiving colonoscopy examination.

AIMS: To investigate the effectiveness of an educational film intervention on the quality of bowel cleanliness of outpatients receiving colonoscopy examinations and also to understand the related factors affecting bowel cleanliness. METHOD: This is a quasi-experimental design. One hundred four patients in the experimental group and 114 patients in the control group are the participants in this study. An 8-minute "Preparation for Bowel Cleanliness" educational film was made based on clinical experience and references to related literature. We adopted a valid Aronchick scale evaluate bowel cleanliness. RESULTS: The patients in the experimental group had significantly better bowel cleanliness compared to the control group (80.8% vs. 48.2%, p<.001). Logistic regression showed that the experimental group, gender, and experience with colonoscopy were potentially important factors that may affect bowel cleanliness. CONCLUSIONS: The "Preparation for Bowel Cleanliness" educational film provides simple and easy-to-follow methods for the preparation of cleaning the colon and related information.

Encephalitis in Taiwan: a prospective hospital-based study.

To investigate encephalitis in Taiwan, a multicenter study was conducted with patients who had acute severe neurological dysfunction and suspected encephalitis from May 2000 to December 2001. Demographic data such as age, sex, and seasons were analyzed. Polymerase chain reaction analyses were performed to determine the microbiologic diagnosis. The patients included 73 males and 54 females, with a peak age of 10-40 years old. Microbiologic diagnoses in 86 (69%) of 124 cases involved herpes simplex virus (HSV, 45 cases), varicella zoster (16 cases), Mycobacterium tuberculosis (10 cases), cytomegalovirus (8 cases), adenovirus (5 cases), influenza (1 case), and enterovirus (1 case). Pathogens were found in 69% of the cases. Encephalitis was most likely to occur in June and July. Based on the results, HSV is still the major viral cause of encephalitis in Taiwan.