Mediating effect of subclinical inflammation on the process of morning hypertension leading to atrial fibrillation in community-based older adults.

BACKGROUND: The impacts and mechanisms of morning hypertension (MHT) on the risk of new-onset atrial fibrillation (AF) in the elderly have not been clarified. We aimed to investigate an association between MHT and new-onset AF and explore a mediating effect of subclinical inflammation on this association. METHODS: From 2008 to 2010, 1789 older adults aged ≥60 years were recruited in Shandong area, China. Morning blood pressure (BP) was assessed using 24-hour ambulatory BP monitoring. MHT was defined as BP ≥ 135/85 mm Hg during the period from wake time to 0900 a.m. Subclinical inflammation was assessed by hypersensitive C-reactive protein (hsCRP), tumor necrosis factor-alpha (TNF-α), systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and galectin-3. New-onset AF was rated during the follow-up period. RESULTS: Over an average 129.0 [standard deviation (SD): 21.58] months of follow-up, the hazard ratio of new-onset AF in MHT patients was 1.39 (95% confidence interval: 1.01 to 1.91) compared with non-MHT participants (Padjusted = 0.027). The risk of new-onset AF was 1.17-fold with one-SD increment of morning systolic BP. Subclinical inflammation was significantly associated with new-onset AF. The hazard ratios of new-onset AF were 2.29, 2.04, 2.08, 2.08, 2.03, and 3.25 for one-SD increment in hsCRP, TNF-α, SII, NLR, PLR, and galectin-3, respectively (Padjusted < 0.001). The analysis showed that hsCRP, TNF-α, SII, NLR, PLR, and galectin-3 separately mediated the process of MHT inducing new-onset AF (Padjusted < 0.05). CONCLUSIONS: MHT is associated with an increased risk of new-onset AF. The subclinical inflammation might play a mediating role in this association.

Orthostatic change in systolic blood pressure associated with cold pressor reflection and heart rate variability in the elderly.

Background: Impaired orthostatic blood pressure (BP) response is a frequent finding in the elderly. The goal of the study was to investigate the association of variability of supine-to-orthostatic BP with cold pressor reflection and heart rate variability in the elderly.Methods: From June 2010 to September 2013, 287 elderly aged ≥ 60 years were enrolled in Jinan area, China. The elderly were classified into lower (n = 96), intermediate (n = 95), and higher (n = 96) tertile groups according to the tertile of the percentage change of supine-to-orthostatic systolic BP.Results: There were significant increasing trends in systolic BP response to the CPT at 0 and 60 sec; the plasma levels of epinephrine, norepinephrine, and angiotensin II; and decreasing trends in DNN, SDNN index, and SDANN from the lower to the higher tertile group, and differences between any two groups were significant (P < .05). The percentage change of supine-to-orthostatic systolic BP was positively correlated with systolic BP response to CPT at 0 and 60 sec, VLF, epinephrine, norepinephrine, and angiotensin II (P < .001) and negatively correlated with SDNN, SDNN index, SDANN, rMSSD, pNN50, LF, and ratio of LF/HF (P < .001). The BP response to CPT, parameters of HRV, and the plasma levels of norepinephrine and angiotensin II were independently associated with the percentage change of supine-to-orthostatic systolic BP after adjustment for confounders.Conclusion: Aggressive variability of supine-to-orthostatic systolic BP might be significantly associated with the imbalance of sympathetic and parasympathetic activity, especially high sensitivity sympathetic response in the elderly.Abbreviations: BP: blood pressure; BMI: body mass index; CPT: cold pressor test; HRV: heart rate variability; SDNN: standard deviation of all normal-to-normal R-R intervals; SDNN index: mean of the standard deviations of all 5-min normal-to-normal R-R intervals of the entire recording; SDANN: standard deviation of the averages of normal-to-normal R-R intervals during all 5-min periods of the entire recording; rMSSD: square root of the mean squared differences between successive normal R-R intervals; pNN50: number of adjacent normal R-R intervals differing by more than 50 ms; VLF: very low frequency; LF: low frequency; HF: high frequency; TCHO: total cholesterol; HDL-c: high-density lipoprotein cholesterol; LDL-c: low-density lipoprotein cholesterol; FPG: fasting plasma glucose; SD: standard deviation.

In vitro evaluation of photon and carbon ion radiotherapy in combination with cisplatin in head and neck squamous cell carcinoma cell lines.

Background: Heavy ion radiotherapy, such as carbon ion radiotherapy (CIRT), has multiple advantages over conventional photon therapy. Cisplatin, as a classic anti-tumor drugs, has been tested and discovered as a photon radiosensitizer in several cell lines, including head and neck squamous cell carcinoma (HNSCC). Hence, the aim of our study is to evaluate whether cisplatin can sensitize CIRT towards HNSCC cell lines in vitro. Methods: Human nasopharyngeal carcinoma cell line CNE-2, human tongue squamous carcinoma cell line TCA 8113 and human hypopharynx squamous carcinoma cell line FADU were all irradiated with photon beam of 2, 4, 6, 8 Gy (physical dose) and carbon ion beam of 1, 2, 3, 4 Gy (physical dose) and treated with cisplatin. Cell survival was assessed by clonogenic survival assay. Results: CIRT showed significantly stronger cytotoxic effect than standard photon radiotherapy. The relative biological effectiveness (RBE) of carbon ion beam at 10% survival ( R B E 10 ) was calculated 3.07 for CNE-2, 2.33 for TCA 8113 and 2.36 for FADU. Chemoradiotherapy (both photon radiotherapy and CIRT) was more effective than radiotherapy alone. In vitro sensitizer enhancement ratios (SERs) of cisplatin in CNE-2, TCA 8113 and FA DU cell lines after photon irradiation were 1.33, 1.14 and 1.21, while after carbon ion irradiation were 1.02, 1.00 and 0.96, showed that cisplatin sensitized photon irradiation but showed no sensitization effect in carbon ion irradiation in all tested cell lines. Conclusions: In conclusion, high linear energy transfer (LET) CIRT was more effective than photon irradiation to prevent the proliferation of HNSCC cell lines. Additional treatment with cisplatin could sensitize photon irradiation but showed no effect on carbon ion irradiation.

Attenuating the Variability of Lipids Is Beneficial for the Hypertension Management to Reduce the Cardiovascular Morbidity and Mortality in Older Adults.

Objective: To investigate the beneficial of attenuating the variability of lipids to the hypertension management in older adults. Methods: Between April 2008 and November 2010, 1,244 hypertensive patients aged ≥60 years were recruited and randomized into placebo and rosuvastatin groups. Outcomes and inter-visit plasma lipids variability were assessed. Results: Over an average follow-up of 83.5 months, the coefficients of variation (CVs) in total cholesterol (TCHO), triglycerides, high-density lipoprotein cholesterol (HDL-c), and low-density lipoprotein cholesterol (LDL-c) were significantly lower in the rosuvastatin group than the placebo group (p < 0.05). The risks of composite cardiovascular event, myocardial infarction, coronary revascularization, heart failure, total stroke, ischemic stroke, cardiovascular death, and all-cause death were significantly lower in the rosuvastatin group than the placebo group (all p < 0.05). The differences in the risks were significantly diminished after the CVs for TCHO, triglycerides, HDL-c, and LDL-c were separately included as confounders. One-SD of CVs for TCHO, triglycerides, HDL-c, and LDL-c increment were significantly associated with the risks of composite cardiovascular event, myocardial infarction, heart failure, total stroke, ischemic stroke, cardiovascular death, and all-cause death, respectively (all p < 0.05). Conclusions: Rosuvastatin significantly attenuated the intra-visit variability in lipids and decreased the risk of cardiovascular mortality and morbidity. Controlling the variability of lipids is as important as antihypertensive treatment to reduce the cardiovascular morbidity and mortality in the management of older hypertensive patients. Clinical Trial Registration: ChiCTR.org.cn, ChiCTR-IOR-17013557.

Carbon ion triggered immunogenic necroptosis of nasopharyngeal carcinoma cells involving necroptotic inhibitor BCL-x.

To explore the potential and mechanisms of necroptosis, a form of immunogenic cell death, induced by carbon ion as compared to photon beams in established photon resistant- (PR-) and sensitive nasopharyngeal carcinoma (NPC) cells. MLKL is considered a central executor of necroptosis and phosphorylation of MLKL (p-MLKL) was a critical event of necroptosis. The clonogenic survival and DNA microarray demonstrated that after repeated photon irradiation, radiosensitive NPC cells became apoptosis-resistant but could be effectively inhibited by carbon ion irradiation. The relative biologic effectiveness (RBE) at D10 and D37 were 2.15 and 2.78 for PR-NPC cells. Carbon ion induced delayed DNA damage repair, cell cycle arrest, cytogenetic damage, morphological change and cell necrosis, indicating the possibility of necroptosis in both PR- and sensitive NPC cell types. The lower expression of necroptotic inhibitors (caspase-8 and Bcl-x) and higher level of MLKL in PR-NPC cells showed it was relatively more predisposed to necroptosis compared to the sensitive cells. Subsequent experiments demonstrated the significant upregulation of p-MLKL in the PR-NPC cells treated by carbon ion (4 Gy) compared with photon irradiation at both physical (4 Gy) and RBE (10 Gy) doses (P≤0.0001). Moreover, carbon ion induced a robust (up to 28 folds) p-MLKL in the PR-NPC cells as well as sensitive cells (up to 6-fold) coupled with a lower level of BCL-x expression and increased GM-CSF implicated in resculputure of immune system. These results suggested that carbon ion could induce necroptosis of NPC cells, especially in PR-NPC cells, and its mechanisms involve BCL-x.

Intensity-Modulated Radiation Therapy for Esthesioneuroblastoma: 10-Year Experience of a Single Institute.

Objectives: To evaluate efficacy and safety of intensity-modulated radiotherapy (IMRT) in the management of esthesioneuroblastoma (ENB). Methods and Materials: A retrospectively analysis of 52 ENB patients treated with IMRT between 8/2008 and 8/2018 was performed. Thirteen of the 44 patients (29.5%) with newly diagnosed and 2 of the 8 patients with recurrent disease presented regional lymph node metastasis. The median dose of IMRT was 66 (range 52.5-75) Gy for all patients. Elective nodal irradiation (ENI) was provided to all excluding 6 patients in this cohort. Results: With a median follow-up time of 32.5 (6~121) months, the 3-year overall survival (OS), progression-free survival (PFS), local progression-free survival (LPFS), regional progression-free survival (RPFS), and distant metastasis-free survival (DMFS) rates for the entire cohort were 89.7, 69.5, 89.7, 95.1, and 85.4%, respectively. Multivariate analysis revealed that N-classification (N- vs. N+) at presentation was the only significant prognosticators for PFS. No significant prognosticator was identified for other survival outcome. No severe (i.e., grade 3 or 4) IMRT-induced acute toxicity was observed. Severe late toxicities were infrequent (11.5%), which included dysosmia (3.8%), hearing loss (3.8%), radiation brain injury (1.9%), and temporal lobe necrosis (1.9%). Moreover, late ocular toxicity secondary to IMRT was not observed. Conclusion: IMRT produced acceptable 3-year outcomes in terms of OS (89.7%), LPFS (89.7%), and RPFS (95.1%) rates without substantial late adverse effects. Further investigations for a more effective systemic strategy for distant disease control as well as a precision radiation technique for further improvement in local control are needed.

The Impacts of Different Types of Radiation on the CRT and PDL1 Expression in Tumor Cells Under Normoxia and Hypoxia.

INTRODUCTION: Hypoxia is a hallmark of cancer that may contribute to an immunosuppressive microenvironment and promote radioresistance. High linear energy transfer (LET) radiation is considered to be able to overcome the negative effects of hypoxia. However, the anti-tumorigenic effects induced by low or high LET radiation have not been fully elucidated. This study aimed to compare the effects of different types of radiation on the immune response, particularly the impact on calreticulin (CRT), and programmed cell death ligand 1 (PDL1) expression. METHODS: Four human tumor cell lines were investigated in this study. Cells in normoxic and hypoxic groups were irradiated with 4Gy (physical dose) photon, proton, and carbon-ion radiation, respectively. The expression of CRT and PDL1 was detected 48 h after irradiation, and the median fluorescence intensities (MFIs) were compared by flow cytometry. Meanwhile, the radiosensitivity of tumor cells in each group was also compared by colony formation assays and flow cytometry. RESULTS: All types of radiation could significantly inhibit the colony formation of tumor cells under normoxia. However, the efficacy of photon and proton radiation was impaired under hypoxia. Carbon-ion radiation could still inhibit colony formation. The percentage of viable cells after irradiation was higher under hypoxia compared with those under normoxia. The CRT expression under normoxia was significantly increased after radiation. Carbon-ion radiation enhanced CRT expression compared to photon and proton radiation. Conversely, under hypoxia, the CRT expression level was significantly upregulated at baseline (0Gy). Radiation could not increase the expression further. PDL1 expression was also significantly increased by radiation under normoxia in all cell lines except the Ln18 cell line. Carbon-ion radiation induced the most significant increase. Under hypoxia, the PDL1 expression level was also upregulated at baseline and radiation could not increase expression further. CONCLUSION: Tumor cells were resistant to photon and proton but sensitive to carbon-ion radiation under hypoxia. Carbon-ion radiation could induce the highest CRT and PDL1 expression under normoxia. However, under hypoxia, radiation could not further enhance the high baseline expression of CRT and PDL1.

Telmisartan and Rosuvastatin Synergistically Ameliorate Dementia and Cognitive Impairment in Older Hypertensive Patients With Apolipoprotein E Genotype.

Objective: To investigate the effect of telmisartan, rosuvastatin, or their combination on dementia and to understand the impact of apolipoprotein E (APOE) genotype on the effect of the medications in older patients with hypertension. Methods: This is a double-blind, randomized, and placebo-controlled trial using a 2 × 2 factorial design. Between April 2008 and November 2010, 1,244 hypertensive patients aged ≥60 years without cognitive impairment were recruited from communities in six cities in Shandong area, China. Patients were randomized into telmisartan and rosuvastatin administration after a 2-week washout period. APOE genotype was identified at the baseline. Possible dementia was determined using the combination of the global cognitive function and Assessment of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Results: Over an average follow-up of 7 [interquartile range (IQR): 6.7-7.2] years, telmisartan and rosuvastatin significantly reduced the cognitive impairment progression and the incidence of dementia. There was a synergistic interaction between telmisartan and rosuvastatin to reduce the cognitive impairment and the incidence of dementia (P adjusted < 0.001). The cognitive impairment progression and the risk of dementia were higher in the hypertensive patients with APOE ε4 allele than in those without APOE ε4 allele. Rosuvastatin medication significantly alleviated the cognitive impairment progression and the risks of dementia in patients with APOE ε4 allele. Conclusion: The combination of telmisartan and rosuvastatin might be an effective prevention and/or treatment strategy for cognitive impairment and dementia, especially in hypertensive patients with the APOE ε4 allele. Clinical Trial Registration: www.ClinicalTrials.gov, ChiCTR.org.cn, identifier ChiCTR-IOR-17013557. Registered on April 12, 2017 - Retrospectively registered, http://www.chictr.org.cn/showproj.aspx?proj=23121.

Upregulated necroptosis-pathway-associated genes are unfavorable prognostic markers in low-grade glioma and glioblastoma multiforme.

BACKGROUND: Glioma accounts for 70% of primary brain malignancies in adults with unfavorable prognoses. In the past decades, much efforts have been invested to identify better biomarkers for predicting prognoses. Recently, necroptosis has been reported as a specialized pathway of programmed necrosis. Moreover, regulators of necroptosis-pathway-associated genes (RIPK1, RIPK3 and MLKL) were reported to be related to prognoses of many types of tumors. However, the prognostic value of these genes in diffuse glioma including low-grade glioma (LGG) and glioblastoma multiforme (GBM) remains unknown. METHODS: An online tool-Gene Expression Profiling Interactive Analysis (GEPIA) (http://gepia.cancer-pku.cn/) was used to analyze different expression of necroptosis-pathway-associated genes between tumor and normal tissue, correlation between RIPK1, RIPK3 and MLKL, the relationship between necroptosis-pathway-associated genes and prognosis [overall survival (OS) and disease-free survival (DFS)] in LGG and GBM. The median expression of RIPK1, RIPK3 and MLKL was used to divide patients into high- versus low-expression group. All graphic presentations were drawn by Gepia database. RESULTS: Expression of RIPK1 and RIPK3 were significantly higher in tumor tissue of GBM as compared with normal tissue. A moderate correlation between MLKL and RIPK3 was demonstrated in both LGG (R =0.79) and GBM (R =0.79). In LGG, higher expression of RIPK1, RIPK3, and MLKL were associated with poor OS and DFS with HR values of 2.2, 2, 1.9 for OS and 1.7, 1.8, 1.6 for DFS, respectively. In GBM, only a higher expression of MLKL was associated with worse OS and DFS with HR values of 1.5 and 1.6, respectively. CONCLUSIONS: Regulators of necroptosis-pathway-associated genes appear to have a potential to serve as biomarkers of prognosis in both LGG and GBM.

Comparison of the effects of photon, proton and carbon-ion radiation on the ecto-calreticulin exposure in various tumor cell lines.

BACKGROUND: Accumulating evidence suggested that radiotherapy can activate anti-tumor immune responses by triggering immunogenic cell death (ICD) of tumor cells. Calreticulin is regarded as one of the most important markers of ICD. The cell surface translocation of calreticulin (ecto-CRT) serves as an "eat me" signal for phagocytosis of dying cells, which plays a pivotal role in activating anti-tumor immunity. However, there is limited knowledge describing the effects of proton and carbon-ion radiation on ecto-CRT exposure. Hence, we investigated ecto-CRT exposure in multiple human carcinoma cell lines irradiated by proton and carbon-ion in comparison to photon. METHODS: This study examined four human cancer cell lines including A549 (lung adenocarcinoma), U251MG (glioma), Tca8113 (tongue squamous carcinoma), and CNE-2 (nasopharyngeal carcinoma). Cell lines were irradiated with photon, proton or carbon-ion at 0, 2, 4, 10 Gy (physical dose). The ecto-CRT exposure level was analyzed by flow cytometry at 12, 24, and 48 h post-irradiation. The median fluorescence intensity was calculated by FlowJo. RESULTS: All three types of radial beam increased ecto-CRT exposure of the 4 tumor cell lines in a time-dependent manner. Ecto-CRT exposure significantly elevated 1.5-2.4 times over 48 h post-irradiation compared with controls (P<0.05). Proton and photon increased ecto-CRT exposure with dose escalation. Photon and proton at 10 Gy increased the most ecto-CRT exposure (P<0.05), while carbon-ion increased most ecto-CRT exposure at 4 Gy rather than 10 or 2 Gy. When compared with iso-physical dose at 48 h post-irradiation, proton showed a similar effectiveness with photon. While carbon-ion has significantly stronger effects on increasing ecto-CRT than proton and photon at 2 and 4 Gy, but changed oppositely at 10 Gy (P<0.05). CONCLUSIONS: All the three types of radiation can increase the ecto-CRT exposure in a time-dependent manner. Proton and photon radiation were equally effective in inducing ecto-CRT exposure, while carbon-ion revealed a different effectiveness in comparison to photon and proton.

Longitudinal association of carotid endothelial shear stress with renal function decline in aging adults with normal renal function: A population-based cohort study.

The aim of this study was to investigate the associations between carotid wall shear stress (WSS) and renal function impairment (RFI) and albuminuria in aging adults. A total of 1,447 subjects aged 60 years and older with normal estimated glomerular filtration rate (eGFR ≥ 60 mL·min-1·1.72 m-2) and albumin/creatinine ratio (ACR < 30 mg·g-1) were enrolled between April 2007 and October 2009 in the Shandong area, China. Carotid WSS was assessed at baseline, and eGFR, which is based on serum creatinine and cystatin C, and ACR were assessed at baseline and at the annual follow-up visits. After an average of 62.9 months of follow-up, the reduction in eGFR and the increase in ACR were significantly higher in the Q1+2+3 group than the Q4 group, as classified by either the interquartile of the mean WSS or the interquartile of the peak WSS after adjustment for multi-variabilities, including the average blood pressures at every annual visit and baseline eGFR and ACR. For groups classified by mean WSS, the hazard ratios (95% confidence intervals) were 3.45 (1.36-8.75, p = 0.008) in the incident RFI and 3.24 3.22 (1.37-7.57, p = 0.009) in the incident albuminuria for the Q1+2+3 group compared with the Q4 group. Similar results were observed among groups classified by peak WSS. The Q1+2+3 group was associated with endothelial dysfunction and inflammation with respect to the Q4 group as classified by mean or peak WSS. The results indicate that carotid WSS plays an important role in RFI and albuminuria progression in aging adults. Lower WSS was associated with a higher risk of RFI and albuminuria compared with higher WSS.

Depletion of MLKL inhibits invasion of radioresistant nasopharyngeal carcinoma cells by suppressing epithelial-mesenchymal transition.

BACKGROUND: To examine whether MLKL participated in the invasion of radiosensitive nasopharyngeal carcinoma (NPC) cell (CNE-2) and radioresistant NPC cell (CR) through regulating epithelial-mesenchymal transition (EMT). METHODS: siRNA and CRISPR/Cas9 technique were used to decrease MLKL expression in NPC cell (CNE-2 and CR). Trans-well assay was conducted to evaluate invasion. Gene expression profiling was performed using Human U133 2.0 plus arrays (Affymetrix). Kyoto Encyclopedia of Genes and Genomes (KEGG) was adopted to analyze gene expression profiling. Hub genes at a functional level were accessed by protein-to-protein network (PPI). Quantitative real-time PCR and Western blot were used to access EMT markers. RESULTS: Invasion of CR was about 3~fold change higher than that of CNE-2. Silencing MLKL by siRNA inhibited invasion of CR, not CNE-2. Further, depleting MLKL by CRISPR-Cas9 in CR (CR-MLKL KO) also inhibited its invasion. KEGG pathway analysis showed invasion-related pathways were altered, such as adherent junction, TGF-ß signaling pathway. PPI demonstrated that compared with CNE-2, CR showed 9 elevated hub genes including EGFR, JUN, CD44, SPP1, VIM, IL-8, BCL2, WDFY2, PIK3CD and 1 downregulated hub gene CDH1. After MLKL depletion, 8 hub genes were downregulated (EGFR, JUN, CD44, SPP1, VIM, FGF13, PLAU, MMP1) and 2 hub genes were upregulated (MMP9, CDH1). Quantitative real-time PCR results showed that compared with CNE-2, CR displayed decreased epithelial markers significantly (E-Cadherin) and increased mesenchymal markers significantly (Vimentin, N-Cadherin, Zeb1), indicating irradiation-induced EMT. After depletion of MLKL in CR, the expression of E-Cadherin, Vimentin, N-Cadherin, Zeb1 was reversed to the level of CNE-2. Western blot confirmed the results from qRT-PCR. CONCLUSIONS: Depletion of MLKL efficiently inhibits invasion of radioresistant NPC by suppressing EMT. MLKL may be an important target to suppress distant metastasis of NPC patients who relapsed after radiotherapy.

Low carotid endothelial shear stress associated with cerebral small vessel disease in an older population: A subgroup analysis of a population-based prospective cohort study.

BACKGROUND AND AIMS: The association between carotid wall shear stress (WSS) and cerebral small vessel disease has yet to be fully elucidated. The major purpose of this study was to investigate this association in older subjects. METHODS: Common carotid artery WSS, endothelial function, white matter hyperintensities (WMH), lacunes, and microbleeds were assessed in 1396 older adults. Participants were followed-up for an average of 69.7 months. RESULTS: Mean (M) and peak (P) WSS and changes in endothelial function were independently associated with changes in WMH volume and fraction, lacune counts, and microbleed counts (all p < 0.05). The risks of new-incident Fazekas scale ≥2 [hazard ratio (HR) with 95% confidence interval (CI): 2.141 (1.469-3.119), p = 0.005 and 1.731 (1.197-2.505), p = 0.004, respectively], lacunes [HR (95% CI): 2.034 (1.369-3.022), p < 0.001 and 1.693 (1.151-2.490), p = 0.003, respectively], and microbleeds [HR (95% CI): 2.311 (1.509-3.541), p < 0.001 and 2.208 (1.299-3.751), p < 0.001, respectively] were significantly higher in the lowest quartile group than in the higher quartile group, as classified by either MWSS or PWSS, after adjustment for confounders. CONCLUSIONS: Low carotid WSS is an independent risk factor for the progression of cerebral small vessel disease in older adults.

Association of Circadian Rhythm of Blood Pressure and Cerebral Small Vessel Disease in Community-Based Elderly Population.

BACKGROUND: Although it is accepted that the etiology of cerebral small vessel disease (CSVD) is associated with cardiovascular risk factors, the association between CSVD and the circadian rhythm of blood pressure (BP) is unclear. We aimed to determine if such an association existed in the elderly population. METHOD: White matter hyperintensities (WMHs), lacunes, microbleeds, nocturnal dipping pattern (NDP), and morning surge in systolic blood pressure (SBP) were assessed in 2,091 participants ≥60 years of age. RESULTS: During an average of 63 months of follow-up, WMH and the WMH-to-intracranial volume ratio were significantly increased in extreme dippers, nondippers, and reverse dippers than those in dippers (p < .001). For new-incident Fazekas scale ≥2, the hazard ratios were 1.77 (95% confidence interval [CI], 1.09-2.86) for extreme dippers, 2.20 (95% CI, 1.48-3.28) for nondippers, and 2.43 (95% CI, 1.59-3.70) for reverse dippers compared with dippers, and 1.04 (95% CI, 0.81-1.35) for higher morning surge compared with lower morning surge. Nondippers and reverse dippers were associated with higher risks of new-incident lacunes and microbleeds than dippers (p < .05). Higher morning surge was associated with a higher risk of new-incident microbleeds than lower morning surge (p < .05). CONCLUSION: NDPs in SBP played an important role in CSVD, and the morning surge in SBP was associated with cerebral microbleeds in community-based elderly population beyond the average SBP level.

Effects of sartans and low-dose statins on cerebral white matter hyperintensities and cognitive function in older patients with hypertension: a randomized, double-blind and placebo-controlled clinical trial.

Cerebral white matter hyperintensities (WMHs) and cognitive impairment are common in elderly hypertensive patients, and more needs to be learned about their prevention and treatment. Our aim was to investigate the effect of low-dose statins on WMH and cognitive function in elderly patients undergoing antihypertensive treatment. A total of 732 elderly hypertensive patients taking hydrochlorothiazide as their baseline medication were randomized using a 2 × 2 factorial design with antihypertensive (telmisartan vs. placebo) and lipid-modulating (low-dose rosuvastatin vs. placebo) arms. Brain magnetic resonance imaging (MRI) and cognitive function data were obtained. After a mean follow-up time of 59.8 (range 12-65) months, there were no differences in WMH progression and cognitive function decline over time between the groups in the antihypertensive arm. The risks of new-incident WMH Fazekas scale scores ≥ 2 and the incidence of cognitive impairment did not differ between the telmisartan and placebo groups. Rosuvastatin use was associated with lower risks of new-incident Fazekas scale scores ≥2 (hazard ratio = 0.500; 95% confidence interval: 0.34-0.74) and cognitive impairment (hazard ratio = 0.54; 95% confidence interval: 0.36-0.80). Telmisartan interacted with rosuvastatin on reducing WMH progression and cognitive function decline. Findings suggest that low-dose rosuvastatin could reduce WMH progression and cognitive function decline in antihypertensive patients, as demonstrated by the interaction between telmisartan and low-dose rosuvastatin to this effect.

Low carotid wall shear stress independently accelerates the progression of cognitive impairment and white matter lesions in the elderly.

The association of hemodynamics with cognitive impairment and white matter lesions (WMLs) has come to the foreground in recent years. Six hundred eighty-nine elderly participants aged ≥60 years were eligible enrolled. After an average of 5.4 years follow-up, there was a significant decline in Mini-Mental State Examination (MMSE) scores and increases in total white matter hyperintensities (WMH), periventricular (P)WMH, and deep (D)WMH (P < 0.001). The participants were grouped by the tertiles of carotid mean wall shear stress (WSS). The decline in MMSE scores and the increases in total WMH, PWMH, and DWMH decreased from the lowest group to the highest group. There were significant differences between each group comparison (all P <0.05). Mean WSS was an independent and significant factor for the changes in MMSE scores, total WMH, PWMH, and DWMH after adjustment for confounders (P <0.001). The risk of developing cognitive impairment was higher in the lowest (hazard ratio: 2.753; 95% CI: 1.945 to 3.895; P < 0.001) and intermediate (hazard ratio: 1.531; 95% CI: 1.084 to 2.162; P = 0.015) groups than in the highest group after adjustment for confounders. Similar associations were yielded between peak WSS and the changes in MMSE scores, total WMH, PWMH, and DWMH. Our results indicated that carotid WSS is an independent factor for the progression of cognitive impairment and WMLs in the elderly. Low WSS significantly deteriorates the progression of cognitive impairment and WMLs.

Empty-nest-related psychological distress is associated with progression of brain white matter lesions and cognitive impairment in the elderly.

This study evaluated the association between empty-nest-related psychological distress and the progression of white matter lesions (WMLs) and cognitive impairment in 219 elderly subjects aged 60 years or over. Psychological distress was assessed using the University of California at Los Angeles Loneliness Scale (UCLA-LS) and Geriatric Depression Scale (GDS) Short-Form. Cognitive function was evaluated using the MMSE and MoCA. White matter hyperintensities (WMH) were assessed using magnetic resonance imaging. After 5.2-year follow-up, the reductions in MMSE and MoCA scores and the increases in periventricular (P)WMH, deep (D)WMH, and total WMH volumes in the empty-nest elderly were greater than those in the non-empty-nest elderly (P < 0.05). The reduced MMSE and MoCA scores and increased volumes of PWMH and total WMH in the empty-nest elderly living alone were greater than those in the empty-nest elderly living with a spouse (P < 0.05). UCLA-LS and GDS scores were significantly and independently associated with reduced MMSE and MoCA scores and the increased volumes of PWMH, DWMH, and total WMH. The results indicate that empty-nest-related psychological distress is associated with progression of WMLs and cognitive impairment in the elderly.

Advances in dosimetry and biological predictors of radiation-induced esophagitis.

OBJECTIVE: To summarize the research progress about the dosimetry and biological predictors of radiation-induced esophagitis. METHODS: We performed a systematic literature review addressing radiation esophagitis in the treatment of lung cancer published between January 2009 and May 2015 in the PubMed full-text database index systems. RESULTS: Twenty-eight eligible documents were included in the final analysis. Many clinical factors were related to the risk of radiation esophagitis, such as elder patients, concurrent chemoradiotherapy, and the intense radiotherapy regimen (hyperfractionated radiotherapy or stereotactic body radiotherapy). The parameters including Dmax, Dmean, V20, V30, V50, and V55 may be valuable in predicting the occurrence of radiation esophagitis in patients receiving concurrent chemoradiotherapy. Genetic variants in inflammation-related genes are also associated with radiation-induced toxicity. CONCLUSION: Dosimetry and biological factors of radiation-induced esophagitis provide clinical information to decrease its occurrence and grade during radiotherapy. More prospective studies are warranted to confirm their prediction efficacy.

Prognostic significance of miR-126 in various cancers: a meta-analysis.

OBJECTIVE: Recent studies have demonstrated that microRNA-126 (miR-126) might be a promising prognostic factor for cancer patients. This meta-analysis was conducted to assess the effectiveness of miR-126 as a prognostic biomarker for various cancers. METHODS: The search of studies was performed by using PubMed and Embase until January 22, 2016. Pooled hazard ratio (HR) with 95% confidence interval (CI) for patients' survival was calculated. A fixed-effect or random-effects model was applied according to heterogeneity. The trim and fill method was used to adjust pooled HR. RESULTS: In all 17 articles comprising of 2,437 participants were included in this meta-analysis. The results indicated that a high level of miR-126 played a favorable role in the overall survival (HR 0.70, 95% CI: 0.62-0.79, random-effects model), with a heterogeneity measure index of I (2)=63.2% (P<0.01). Subgroup analyses showed that pooled HR was more significant in patients with digestive system cancers (HR 0.70, 95% CI: 0.59-0.83, fixed-effects model) and respiratory system cancers (HR 0.71, 95% CI: 0.59-0.85, random-effects model). Owing to publication bias, HR was adjusted to 0.59 (0.463-0.752, P<0.01) by the trim and fill method. CONCLUSION: miR-126 could be a promising biomarker for cancer prognosis prediction, especially in patients with digestive or respiratory system cancers.

Re-irradiation alternatives for recurrent high-grade glioma.

Despite advances in the fields of surgery, chemotherapy and radiotherapy, the prognosis for high-grade glioma (HGG) remains unsatisfactory. The majority of HGG patients experience disease recurrence. To date, no standard treatments have been established for recurrent HGG. Repeat surgery and chemotherapy demonstrate moderate efficacy. As recurrent lesions are usually located within the previously irradiated field, a second course of irradiation was once considered controversial, as it was considered to exhibit unsatisfactory efficacy and radiation-related toxicities. However, an increasing number of studies have indicated that re-irradiation may present an efficacious treatment for recurrent HGG. Re-irradiation may be delivered via conventionally fractionated stereotactic radiotherapy, hypofractionated stereotactic radiation therapy, stereotactic radiosurgery and brachytherapy techniques. In the present review, the current literature regarding re-irradiation treatment for recurrent HGG is summarized with regard to survival outcome and side effects.