Increased serum extrachromosomal circular DNA SORBS1circle level is associated with insulin resistance in patients with newly diagnosed type 2 diabetes mellitus.

BACKGROUND: Extrachromosomal circular DNAs (eccDNAs) exist in human blood and somatic cells, and are essential for oncogene plasticity and drug resistance. However, the presence and impact of eccDNAs in type 2 diabetes mellitus (T2DM) remains inadequately understood. METHODS: We purified and sequenced the serum eccDNAs obtained from newly diagnosed T2DM patients and normal control (NC) subjects using Circle-sequencing. We validated the level of a novel circulating eccDNA named sorbin and SH3-domain- containing-1circle97206791-97208025 (SORBS1circle) in 106 newly diagnosed T2DM patients. The relationship between eccDNA SORBS1circle and clinical data was analyzed. Furthermore, we explored the source and expression level of eccDNA SORBS1circle in the high glucose and palmitate (HG/PA)-induced hepatocyte (HepG2 cell) insulin resistance model. RESULTS: A total of 22,543 and 19,195 eccDNAs were found in serum samples obtained from newly diagnosed T2DM patients and NC subjects, respectively. The T2DM patients had a greater distribution of eccDNA on chromosomes 1, 14, 16, 17, 18, 19, 20 and X. Additionally, 598 serum eccDNAs were found to be upregulated, while 856 eccDNAs were downregulated in T2DM patients compared with NC subjects. KEGG analysis demonstrated that the genes carried by eccDNAs were mainly associated with insulin resistance. Moreover, it was validated that the eccDNA SORBS1circle was significantly increased in serum of newly diagnosed T2DM patients (106 T2DM patients vs. 40 NC subjects). The serum eccDNA SORBS1circle content was positively correlated with the levels of glycosylated hemoglobin A1C (HbA1C) and homeostasis model assessment of insulin resistance (HOMA-IR) in T2DM patients. Intracellular eccDNA SORBS1circle expression was significantly enhanced in the high glucose and palmitate (HG/PA)-induced hepatocyte (HepG2 cell) insulin resistance model. Moreover, the upregulation of eccDNA SORBS1circle in the HG/PA-treated HepG2 cells was dependent on generation of apoptotic DNA fragmentation. CONCLUSIONS: These results provide a preliminary understanding of the circulating eccDNA patterns at the early stage of T2DM and suggest that eccDNA SORBS1circle may be involved in the development of insulin resistance.

A novel nonsense variant of the AGXT identified in a Chinese family: special variant research in the Chinese reference genome.

BACKGROUND: Primary hyperoxaluria(PH)is a rare autosomal recessive genetic disease that contains three subtypes (PH1, PH2 and PH3). Approximately 80% of PH patients has been reported as subtype PH1, this subtype of PH has been related to a higher risk of renal failure at any age. Several genetic studies indicate that the variants in gene AGXT are responsible for the occurrence of PH1. However, the population heterogeneity of the variants in AGXT makes the genetic diagnosis of PH1 more challenging as it is hard to locate each specific variant. It is valuable to have a complete spectrum of AGXT variants from different population for early diagnosis and clinical treatments of PH1. CASE PRESENTATION: In this study, We performed high-throughput sequencing and genetic analysis of a 6-year-old male PH1 patient from a Chinese family. Two variants (c.346G > A: p.Gly116Arg; c.864G > A: p.Trp288X) of the gene AGXT were identified. We found a nonsense variant (c.864G > A: p.Trp288X) that comes from the proband's mother and has never been reported previously. The other missense variant (c.346G > A: p.Gly116Arg) was inherited from his father and has been found previously in a domain of aminotransferase, which plays an important role in the function of AGT protein. Furthermore, we searched 110 pathogenic variants of AGXT that have been reported worldwide in healthy local Chinese population, none of these pathogenic variants was detected in the local genomes. CONCLUSIONS: Our research provides an important diagnosis basis for PH1 on the genetic level by updating the genotype of PH1 and also develops a better understanding of the variants in AGXT by broadening the variation database of AGXT according to the Chinese reference genome.

Intermediate analysis of magnesium alloy covered stent for a lateral aneurysm model in the rabbit common carotid artery.

OBJECTIVE: To analyze the outcomes of a magnesium alloy covered stent (MACS) for a lateral aneurysm model in common carotid artery (CCA). METHODS: In 32 rabbits, a MACS (group A, n = 17) or a Willis covered stent (WCS; group B, n = 15) was inserted and the rabbits were sacrificed 1, 3, 6, or 12 months after stenting. Angiography and intravascular ultrasound (IVUS) were performed at 3, 6, and 12 months. Scanning electron microscopy was performed for six stents in each group at 1, 3, and 6 months, and histopathology and histomorphology were conducted at 3 (n = 4), 6 (n = 4), and 12 (n = 12) months. RESULTS: Final angiography showed complete occlusion of the aneurysms in 12 cases. IVUS at 6 and 12 months revealed a significant increase in mean lumen area of the stented CCA in group A and also showed greater mean lumen area in group A than in group B. The endothelialization process was quicker in group A than in group B. CONCLUSION: MACS is effective for occlusion of lateral aneurysms and is superior to WCS in growth of the stented CCA and endothelialization. Further work is needed to make this device available for human use. KEY POINTS: • The MACS is an effective approach for occlusion of a lateral aneurysm. • IVUS showed that the CCA could grow following degradation of the MACS. • The lumen area of the stented CCA was excellent in MACS. • HE staining displayed the degradation of the magnesium alloy stent. • Combination of IVUS and DSA were applied in this study.

Application of esophageal irradiation stents coated with 125I particles in advanced esophageal cancer.

PURPOSE: The current study was designed to investigate the primary efficacy of esophageal irradiation stents coated with 125I particles in the treatment of elderly patients with advanced esophageal cancer. METHODS: Forty-three elderly patients with advanced esophageal cancer were treated with esophageal stents in the First Affiliated Hospital of Xinxiang Medical University between September 2009 and December 2010. Patients were randomly divided into group A (N=18), treated with irradiation stents, and group B (N=25), treated with ordinary stents. There were no significant intergroup differences in age, lesion length, degree of stenosis, or cancer stage. The stent implantation success rate, relief of dysphagia and complication rate, and survival were assessed. RESULTS: The stent implantation success and short-term dysphagia relief rates were 100.0% in both groups. The mean survival time was 9.8 months and 4.8 months in groups A and B, respectively (p<0.01). However, no significant difference in pain (5/18) or esophageal restenosis (7/25) was found (both p>0.05). CONCLUSION: Dysphagia was relieved and survival was prolonged in advanced esophageal cancer cases treated with 125I particle-coated esophageal stents. This method may be superior to the traditional stents method.

Obesity increases the risk of renal involvement in children with Henoch-Schönlein purpura.

UNLABELLED: The main aim of this study was to evaluate the relationship between obesity and renal involvement in children with Henoch-Schönlein purpura (HSP). A retrospective study of 141 pediatric patients with HSP was conducted in our hospital. The clinical data of all patients were collected from the electronic medical record management system from January 2010 to June 2014. The possible risk factors of renal involvement, especially obesity, were analyzed using univariate and multivariate analyses. Renal involvement occurred in 45/141 of the patients. A univariate analysis showed that an age more than 7 years at onset, persistent purpura, obesity, time from symptoms onset to diagnosis more than 14 days, and decreased C3 all increased the risk of renal involvement in HSP. The forward stepwise logistic regression analysis indicated obesity (odds ratio (OR) 4.43, 95 % confidence interval (CI) 1.896 to 10.358), age more than 7 years at onset (OR 2.81, 95 % CI 1.142 to 6.907), and persistent purpura (OR 2.57, 95 % CI 1.119 to 5.909) were independent risk factors for renal involvement. CONCLUSIONS: Our results show that obesity can increase the hazard of renal involvement in children with HSP and reconfirm that older age at onset and persistent purpura are the independent risk factors for renal involvement. WHAT IS KNOWN: • There have been some reports that obesity was associated with the development of renal injury. • It is not clear whether obesity can increase the risk of renal involvement in children with HSP. What is New: • The main finding of this study is that obesity can increase the hazard of renal involvement in children with HSP.

Association of peripheral immunity and cerebral small vessel disease in older adults without dementia: A longitudinal study.

This study explored the associations between peripheral immunity with cerebral small vessel diseases. Older adults without dementia from the Alzheimer's Disease Neuroimaging Initiative were investigated. Peripheral blood was obtained, and magnetic resonance imaging was performed to measure cerebral microbleeds (CMB), lacunar infarctions (LI), and white matter hyperintensities (WMH). Multivariable-adjusted regression models, linear mixed-effects models, and the Spearman correlations were used to evaluate the associations. At baseline, individuals with greater neutrophils (odds ratio [OR] =1.10, 95% confidence interval [CI] 1.00-1.20, p=0.042) and monocytes (OR=1.12, 95% CI 1.02-1.22, p=0.016) had higher WMH volume. On the contrary, a higher lymphocyte-to-monocyte ratio (LMR) was related to lower WMH volume (OR=0.91, 95% CI 0.82-1.00, p=0.041). Longitudinally, higher neutrophils (ρ=0.084, p=0.049) and NLR (ρ=0.111, p=0.009) predicted accelerated progression of WMH volume, while a greater LMR (ρ=-0.101, p=0.018) was linked to slower growth of WMH volume. Nevertheless, associations between peripheral immunity with CMB or LI were not observed at baseline and follow-up. Our study found that peripheral immune indexes could serve as convenient noninvasive biomarkers of WMH.

Identifying modifiable factors and their joint effect on brain health: an exposome-wide association study.

Considerable uncertainty remains regarding the associations of multiple factors with brain health. We aimed to conduct an exposome-wide association study on neurodegenerative disease and neuropsychiatry disorders using data of participants from the UK Biobank. Multivariable Cox regression models with the least absolute shrinkage and selection operator technique as well as principal component analyses were used to evaluate the exposures in relation to common disorders of central nervous system (CNS). Restricted cubic splines were conducted to explore potential nonlinear correlations. Then, weighted standardized scores were generated based on the coefficients to calculate the joint effects of risk factors. We also estimated the potential impact of eliminating the unfavorable profiles of risk domains on CNS disorders using population attributable fraction (PAF). Finally, sensitivity analyses were performed to reduce the risk of reverse causality. The current study discovered the significantly associated exposures fell into six primary exposome categories. The joint effects of identified risk factors demonstrated higher risks for common disorders of CNS (HR = 1.278 ~ 3.743, p < 2e-16). The PAF varied by exposome categories, with lifestyle and medical history contributing to majority of disease cases. In total, we estimated that up to 3.7 ~ 64.1% of disease cases could be prevented.This study yielded modifiable variables of different categories and assessed their joint effects on common disorders of CNS. Targeting the identified exposures might help formulate effective strategies for maintaining brain health.

Genetic architectures of cerebral ventricles and their overlap with neuropsychiatric traits.

The cerebral ventricles are recognized as windows into brain development and disease, yet their genetic architectures, underlying neural mechanisms and utility in maintaining brain health remain elusive. Here we aggregated genetic and neuroimaging data from 61,974 participants (age range, 9 to 98 years) in five cohorts to elucidate the genetic basis of ventricular morphology and examined their overlap with neuropsychiatric traits. Genome-wide association analysis in a discovery sample of 31,880 individuals identified 62 unique loci and 785 candidate genes associated with ventricular morphology. We replicated over 80% of loci in a well-matched cohort of lateral ventricular volume. Gene set analysis revealed enrichment of ventricular-trait-associated genes in biological processes and disease pathogenesis during both early brain development and degeneration. We explored the age-dependent genetic associations in cohorts of different age groups to investigate the possible roles of ventricular-trait-associated loci in neurodevelopmental and neurodegenerative processes. We describe the genetic overlap between ventricular and neuropsychiatric traits through comprehensive integrative approaches under correlative and causal assumptions. We propose the volume of the inferior lateral ventricles as a heritable endophenotype to predict the risk of Alzheimer's disease, which might be a consequence of prodromal Alzheimer's disease. Our study provides an advance in understanding the genetics of the cerebral ventricles and demonstrates the potential utility of ventricular measurements in tracking brain disorders and maintaining brain health across the lifespan.

Characteristics of Subjective Cognitive Decline Associated with Alzheimer's Disease Amyloid Pathology: Findings from The CABLE Study.

BACKGROUND: Subjective cognitive decline (SCD) is considered as a preclinical hallmark of Alzheimer's disease (AD). However, the characteristics of SCD associated with amyloid pathology remain unclear. OBJECTIVE: We aimed to explore the associations between SCD characteristics with amyloid pathology. METHODS: Using logistic regression analyses, we analyzed the associations between cerebrospinal fluid (CSF) amyloid pathology with AD risk factors, SCD-specific characteristics (onset of SCD within the last five years, age at onset ≥60 years, feelings of worse performance, informant confirmation of complaints, worries, other domains of cognition complaints), as well as subthreshold depressive and anxiety symptoms among individuals with SCD. RESULTS: A total of 535 SCD individuals with available CSF Aß42 information from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study (mean age of 63.5 years, range 40 to 88 years; 47.10% female) were enrolled. The characteristics of informant confirmation of complaints (OR, 95% CI = 2.00, 1.19-3.36), subthreshold depressive symptoms (OR, 95% CI = 2.31, 1.05-5.09), and subthreshold anxiety symptoms (OR, 95% CI = 2.22, 1.09-4.51) were found to be significantly associated with pathological amyloid in multivariate analyses when adjusting for age, sex, education, and APOE ɛ4. Besides, age and females were observed risks for amyloid pathology in subscale analyses. Nonetheless, we did not find any associations of other SCD-specific characteristics with amyloid pathology in this study. CONCLUSION: Our study suggested that informant confirmed complaints and subthreshold psychiatric symptoms might be critical for discriminating AD-related SCD from non-AD related SCD.

Association between Life's Simple 7 and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in cognitively intact adults: the CABLE study.

INTRODUCTION: This study sought to explore the association between Life's Simple 7 (LS7) and cerebrospinal fluid (CSF) Alzheimer's disease (AD) pathological biomarkers in the cognitively normal northern Chinese population. METHODS: From the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study, 1106 cognitively normal participants were enrolled. The mean age was 62.34 years, and 39.6% were female. LS7 scores were summed with each metric assigned 0, 1, or 2 scores. The multiple linear regression models were used to investigate the association between LS7 scores and CSF AD biomarkers. RESULTS: We found that LS7 scores were significantly associated with CSF AD pathologies, including Aß42/40 (ß = 0.034, P = .041), p-tau181 (ß = - 0.043, P = .006), and t-tau (ß = - 0.044, P = .003). In subscales, the biological metrics (blood pressure, cholesterol, glucose) were significantly related to CSF tau-related biomarkers. These associations were observed in the APOE ε4 allele non-carriers, yet not in carriers. The relationship of behavior metrics was found in the middle age and males. CONCLUSION: Improving LS7 scores might do a favor to alleviate the pathology of AD in the preclinical stage, especially among the APOE ε4 allele non-carriers.

Association between air pollution and CSF sTREM2 in cognitively normal older adults: The CABLE study.

OBJECTIVES: Ambient air pollution aggravates the process of Alzheimer's disease (AD) pathology. Currently, the exact inflammatory mechanisms underlying these links from clinical research remain largely unclear. METHODS: This study included 1,131 cognitively intact individuals from the Chinese Alzheimer's Biomarker and LifestylE database with data provided on cerebrospinal fluid (CSF) AD biomarkers (amyloid beta-peptide 42 [Aß42], total tau [t-tau], and phosphorylated tau [p-tau]), neuroinflammatory (CSF sTREM2), and systemic inflammatory markers (high sensitivity C-reactive protein and peripheral immune cells). The 2-year averaged levels of ambient fine particulate matter with diameter <2.5 µm (PM2.5 ), nitrogen dioxide (NO2 ), and ozone (O3 ) were estimated at each participant's residence. Multiple-adjusted models were approached to detect associations of air pollution with inflammatory markers and AD-related proteins. RESULTS: Ambient 2-year averaged exposure of PM2.5 was associated with changes of neuroinflammatory markers, that is, CSF sTREM2 (ß = -0.116, p = 0.0002). Similar results were found for O3 exposure among the elderly (ß = -0.111, p = 0.0280) or urban population (ß = -0.090, p = 0.0144). No significant evidence supported NO2 related to CSF sTREM2. For potentially causal associations with accumulated AD pathologies, the total effects of PM2.5 on CSF amyloid-related protein (CSF Aß42 and p-tau/Aß42) were partly mediated by CSF sTREM2, with proportions of 14.22% and 47.15%, respectively. Additional analyses found inverse associations between peripheral inflammatory markers with PM2.5 and NO2 , but a positive correlation with O3 . INTERPRETATION: These findings demonstrated a strong link between PM2.5 exposure and microglial dysfunction. Furthermore, CSF sTREM2 as a key mediator modulated the influences of PM2.5 exposure on AD amyloid pathologies.

Associations of Physical Activity with Alzheimer's Disease Pathologies and Cognition: The CABLE Study.

BACKGROUND: The associations of physical activity with Alzheimer's disease (AD) pathologies remain controversial. OBJECTIVE: To quantitatively assess the association between the frequency of physical activity with cerebrospinal fluid (CSF) biomarkers in AD and further explore the mechanism by which AD pathologies regulate the correlation between physical activity and cognition. METHODS: A total of 918 participants without dementia from Chinese Alzheimer's Biomarker and Lifestyle (CABLE) were examined in this population-based cross-sectional study. Multiple linear models were used to evaluate the associations of physical activity with CSF biomarkers and cognition. Moreover, mediation analyses were conducted to investigate the potential relationships between physical activity, AD pathologies, and cognitive function. RESULTS: Regular physical activity was positively associated with CSF Aß42 (p < 0.001) and Aß42/40 (p < 0.001), while it was negatively associated with p-tau/Aß42 (p < 0.001) and t-tau/Aß42 (p < 0.001). Of all participants, regular physical activity was associated with increased cognitive function (p < 0.001). The interaction effect indicated that age moderated the association between physical activity frequency and CSF Aß42 (p = 0.014) and p-tau/Aß42 (p = 0.041). The impact of physical activity on cognition was mediated in part by amyloid pathologies, accounting for 4.87% to 21.56% of the total effect (p < 0.05). CONCLUSION: This study showed the beneficial impact of physical activity on AD pathologies and cognition in participants without dementia.

[Risk factors for recurrent pneumonia in children: a case-control study].

OBJECTIVE: To study the risk factors for recurrent pneumonia in children without underlying diseases. METHODS: A case-control study was conducted in 106 children with recurrent pneumonia (case group) and 106 age, gender- and weight-matched children with pneumonia but no recurrence (control group). The children in both groups had no underlying disease. The risk factors for recurrent pneumonia were investigated by the Chi-Square analysis and the multivariate logistic regression model. RESULTS: The Chi-Square analysis showed that the percentages with the history of wheezing, allergy (food or medicine) and eczema and the percentage of transient neutropenia in the case group were significantly higher than those in the control group. The multivariate logistic regression analysis showed that the wheezing history (OR=13.387, 95% CI: 5.541-32.343), allergic history (food or medicine) (OR=4.267, 95% CI: 2.081-8.751) and transient neutropenia (OR=3.606, 95% CI: 1.806-7.202) were the independent risk factors of recurrent pneumonia. CONCLUSIONS The wheezing history, allergic history and transient neutropenia may increase the risk of recurrence of pneumonia in pneumonic children without underlying diseases.

Environmental factors and risks of cognitive impairment and dementia: A systematic review and meta-analysis.

BACKGROUND: Dementia is a challenging neurodegenerative disease. This systematic review aimed to summarize natural, physical, and social environmental factors that are associated with age-related cognitive impairment and dementia. METHODS: We systematically searched PubMed, EMBASE, Web of Science, and PsychINFO till January 11, 2021 for observational studies. The hazard ratio (HR), relative risk (RR), and odds ratio (OR) with 95% confidence interval (CI) were aggregated using random-effects methods. The quality of evidence for each association was evaluated. RESULTS: Of the 48,399 publications identified, there were 185 suitable for review across 44 environmental factors. Meta-analyses were performed for 22 factors. With high-to-moderate quality of evidence, risks were suggested in exposure to PM2.5 (HR=1.24, 95%CI: 1.17-1.31), NO2 (HR=1.07, 95%CI: 1.02-1.12), aluminum (OR=1.35, 95%CI: 1.14-1.59), solvents (OR=1.14, 95%CI: 1.07-1.22), road proximity (OR=1.08, 95%CI: 1.04-1.12) and other air pollutions, yet more frequent social contact (HR=0.82, 95%CI: 0.76-0.90) and more greenness (OR=0.97, 95%CI: 0.95-0.995) were protective. With low-to-very low quality, electromagnetic fields, pesticides, SO2, neighborhood socioeconomic status, and rural living were suggested risks, but more community cultural engagement might be protective. No significant associations were observed in exposure to PM10, NOx, noise, silicon, community group, and temperature. For the remaining 22 factors, only a descriptive analysis was undertaken as too few studies or lack of information. CONCLUSIONS: This review highlights that air pollutions, especially PM2.5 and NO2 play important role in the risk for age-related cognitive impairment and dementia.

[Hyperbaric oxygen improves long-term learning-memory deficits and brain injury in neonatal rat with hypoxia-ischemia brain damage].

OBJECTIVE: To investigate the effect of hyperbaric oxygen (HBO) on long-term learning-memory disabilities and brain injury induced by hypoxia-ischemia in neonatal rat. METHODS: In the study, eighteen rats aged seven days were divid into three groups: (1) sham-operated group (SHAM), (2) hypoxia-ischemia group (HIBD), (3) HBO-treated hypoxia-ischemia group (HIBD + HBO). In hypoxia-ischemia groups, left common carotid artery was ligated permanently on the seventh postnatal day, two hours after the procedure; hypoxia (92% nitrogen and 8% oxygen) was induced for 2 h. In HBO-treated hypoxia-ischemia group, single HBO (2. 5 ATA, 1.5 h) was administered at one hour after the hypoxia period. At the six weeks old, step-down inhibitory avoidance test was used to evaluate the short-term memory of rats. Learning and long-term spatial memory deficits were tested using Morris water maze at eight weeks old of rats. Rats were then perfused and brains removed for macroscopic and microscopic evaluation. The cell density of hippocampus were used to evaluate the degree of brain injure. RESULTS: In HIBD+HBO group, the latency to step down the platform was significantly longer than that of HIBD group (P<0.05); in HIBD+HBO group, the mean latencies to reach the platform was significantly shorter than that of HIBD group (P < 0.05); in HIBD + HBO group, the time spent in the target quadrant was significantly lower than that in HIBD group (P<0.05). Histopathological evaluation demonstrated that HBO also significantly diminished brain injury and decreased the cell loss of hippocampal CA1 region. CONCLUSION: Single HBO (2.5 ATA, 1.5 h) can significantly improve long-term learning-memory deficits and attenuate brain injury in rats with hypoxia-ischemia brain damage.

The application of nasal synchronized intermittent mandatory ventilation in primary apnea of prematurity.

We aimed to evaluate the efficacy of nasal synchronized intermittent mandatory ventilation (nSIMV) in preterm infants with primary apnea of prematurity (AOP). Forty-four preterm infants with AOP were divided into the nSIMV group or nasal continuous positive airway pressure (nCPAP) group. Clinical symptoms, signs and blood gas results following nSIMV or nCPAP were compared between the two groups. Infants receiving nSIMV had a greater reduction in apneic spells and a greater decrease in bradycardia than those receiving nCPAP. Compared with the nCPAP group, the nSIMV group had a lower incidence of respiratory support failure (9.1% vs. 27.3%; p<0.05), a lower incidence of hypercarbia (4.5% vs. 18.2%; p<0.05) and a lower incidence of gastrointestinal complications (4.5% vs. 13.6%; p<0.05). This study showed that nSIMV was more effective in respiratory support in preterm infants with AOP.

RNA interference targeting adrenomedullin induces apoptosis and reduces the growth of human bladder urothelial cell carcinoma.

Adrenomedullin (ADM) is a potent, long-lasting angiogenic peptide that was originally isolated from human pheochromocytoma. ADM signaling is of particular significance in endothelial cell biology because the peptide protects cells from apoptosis, and ADM has been shown to be pro-tumorigenic in that it stimulates tumor cell growth and angiogenesis. ADM may be involved in micro-vessel proliferation and partially in the release of hypoxia in solid tumors, contributing to the proliferation of tumor cells as well as local tumor invasion and metastasis. However, the effect of hypoxia-induced ADM expression in bladder cancer remains unclear. Here, we found that the levels of ADM protein in tumor tissue from patients with bladder urothelial cell carcinoma were significantly increased compared to the adjacent non-tumor bladder tissues (p < 0.01). Under hypoxic conditions, the expression of ADM was significantly elevated in a time-dependent manner in human bladder cancer cell lines. Furthermore, the knockdown of ADM by shRNA in T24 cells showed obvious apoptosis compared to untransfected controls (p < 0.0001). In addition, the combination of cisplatin and ADM-shRNA significantly reduces the tumor growth in vivo compared to treatment with cisplatin (p = 0.0046) or ADM-shRNA alone (p < 0.0001). These data suggest that ADM plays an important role in promoting bladder cancer cell growth under hypoxia and that the inhibition of ADM may provide a target for bladder cancer therapy.

Hyperbaric oxygenation reduces long-term brain injury and ameliorates behavioral function by suppression of apoptosis in a rat model of neonatal hypoxia-ischemia.

Neonatal hypoxia-ischemia (HI) produces neurodegeneration and brain injury, and leads to behavioral and cognitive dysfunction. Hyperbaric oxygen (HBO) treatment may potentially be neuroprotective in HI injury. The aim of this study was to examine any neuroprotection by HBO treatment on long-term neurological function in the rat model of neontatal HI. Seven-day-old rats were subjected to HI or sham surgery. HBO treatment was administered (2.5 ATA for 90 min) 1h after hypoxia exposure. Sensorimotor (grip test and rota-rod) and cognitive tests (inhibitory avoidance and Morris water maze) were performed at postnatal day 28 to day 60. The extent of brain damage was determined by histological evaluation. Apoptosis, caspase-3 and apoptosis inducing factor (AIF) expression were assessed by immunohistochemistry 12, 24, and 48 h after HI. HI-treated animals had significantly worse sensorimotor and cognitive performances than those in the Sham group. HBO treatment led to significant improvements in neurobehavioral functions compared to the HI group, especially for cognitive performances. Morphological evaluation revealed a remarkable recovery of brain injury in the HBO group. Furthermore, the improvements in neurobehavioral impairments were correlated with the reduction in lesion size of the hippocampus and cerebral cortex. The proportion of apoptotic cells significantly increased with time after HI, and HBO significantly inhibited apoptotic cell death. The proportion of caspase-3 positive cells and nuclear AIF translocation increased and peaked at 24h after HI injury. HBO-treated rats showed decreased expression of these proteins compared to HI-treated animals. In conclusion, our results suggested that HBO treatment was effective in promoting long-term functional and histological recovery against neonatal HI brain injury. HBO-induced neuroprotection was associated with suppression of apoptosis by inhibiting caspase-3 and AIF-mediated pathways. Further studies evaluating its associated molecular and cellular mechanism are needed.

Effects of magnetic fields on intracellular calcium oscillations.

Based on the model of the two calcium stores developed by Goldbeter, and the viewpoint that the cell membrane is a major site of interaction for extremely-low-frequency (ELF) electromagnetic fields, the permeability of ions can be changed by electromagnetic fields, a theoretical model of cytosolic calcium oscillations influenced by magnetic fields is presented. It is shown that, the field frequency condition will influence the pattern of calcium oscillation while the field strength was given, and the magnetic field strength will change the pattern of calcium oscillation when the frequency was 50Hz and 100Hz. Therefore, intracellular calcium oscillations can be influenced by ELF magnetic fields and then a series cellular response could be transformed.

[Optimal therapeutic window of hyperbaric oxygenation in neonatal rat with hypoxic-ischemic brain damage].

OBJECTIVE: Hyperbaric oxygenation (HBO) is an attractive procedure that has been used in treatment of hypoxic-ischemic encephalopathy (HIE). However, depending on the HBO protocol, especially the time point of starting treatment of HBO, different and conflicting results were obtained. This study was undertaken to search for the optimal therapeutic window of ABO in neonatal rat with hypoxic-ischemic brain damage (HIBD). METHODS: Eighty-four healthy seven-day-old SD rats were used as research subjects and were randomly divided into seven groups with 12 in each: sham group, HI group, HI (1 h) + HBO group (HBO starting 1 h after HI), HI (3 h) + HBO group (HBO starting 3 h after HI), HI (6 h) + HBO group (HBO starting 6 h after HI), HI (12 h) + HBO group (HBO starting 12 h after HI), HI (24 h) + HBO group (HBO starting 24 h after HI). Single HBO treatment (2.5 atmospheres absolute, ATA for 1.5 h) was used in this study. Two indexes were used to assess the effect of HBO that included short-term (48 h after HI) histology change (the cell density in CA1 of hippocampus and cortex) and long-term (5 w and 6 w after HI) neurobehavioral testing (grip test and treadmill test for evaluating the deficits of sensor motor; step-down avoidance test for assessing the deficits of memory). RESULTS: In HI (1 h) + HBO, HI (3 h) + HBO and HI (6 h) + HBO groups, neuron density of cortex and CA1 of hippocampus were 1981.76 +/- 299.55, 1841.53 +/- 241.21, 1525.78 +/- 189.00 and 4430.56 +/- 1180.31, 4507.54 +/- 1374.32, 3883.48 +/- 821.87, respectively, which were significantly higher than HIBD group (987.86 +/- 285.39 and 1813.59 +/- 295.33, P < 0.05, ANOVA). But in HI (12 h) + HBO and HI (24 h) + HBO, the neuron density of cortex and CA1 of hippocampus compared with those in HIBD group had no statistical significance (P > 0.05, ANOVA). In the sensor motor testing performed at 5 w after HI of rat, the grip time in grip test and the stay time in treadmill test of HI (1 h) + HBO, HI (3 h) + HBO and HI (6 h) + HBO groups were 193.39 +/- 51.19, 168.39 +/- 34.02, 168.95 +/- 34.93 and 130.34 +/- 42.56, 128.20 +/- 27.69, 125.74 +/- 36.99, respectively, which, compared with HIBD group, were significantly prolonged (P < 0.05, ANOVA). But in HI (12 h) + HBO and HI (24 h) + HBO groups, the time was not significantly longer compared with HI (P > 0.05, ANOVA). In the step-down avoidance test which was performed at 6 w after HI, the step-down latencies of HI (1 h) + HBO, HI (3 h) + HBO and HI (6 h) + HBO were 96.91 +/- 29.91, 90.35 +/- 28.44 and 76.46 +/- 38.70, respectively, which were significantly prolonged (P < 0.05, ANOVA), but in HI (12 h) + HBO and HI (24 h) + HBO, the latencies did not significantly increase compared with HIBD, P > 0.05, ANOVA. CONCLUSIONS: The optimal therapeutic window of HBO in neonatal rat with HIBD was within the first 6 hours after HI. In this therapeutic window, HBO was highly effective in reducing the cell loss in CA1 of hippocampus and cortex.