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Recent studies demonstrate that brain-derived neurotrophic factor (BDNF) might be associated with nicotine addiction, and circulating BDNF is a biomarker of memory and general cognitive function. Moreover, studies suggest that a functional polymorphism of the BDNF Val66Met may mediate hippocampal-dependent cognitive functions. We aimed to explore the relationships between smoking, cognitive performance and BDNF in a normal Chinese Han population. We recruited 628 male healthy subjects, inducing 322 smokers and 306 nonsmokers, and genotyped them the BDNF Val66Met polymorphism. Of these, we assessed 114 smokers and 98 nonsmokers on the repeatable battery for the assessment of neuropsychological status (RBANS), and 103 smokers and 89 nonsmokers on serum BDNF levels. Smokers scored lower than the nonsmokers on RBANS total score (p = 0.002), immediate memory (p = 0.003) and delayed memory (p = 0.021). BDNF levels among the smokers who were Val allele carriers were correlated with the degree of cognitive impairments, especially attention, as well as with the carbon monoxide concentrations. Our findings suggest that smoking is associated with cognitive impairment in a male Chinese Han population. The association between higher BDNF levels and cognitive impairment, mainly attention in smokers appears to be dependent on the BDNF Val66Met polymorphism.
Despite the significant health risks resulting from tobacco use, the prevalence of smoking worldwide remains high and approximately 20% of the world population still smokes tobacco1,2. In China, over 60% of adult men are current smokers3,4. Substantial evidence demonstrates that nicotine has high addiction liability as well as cognition-enhancing effects5. Individuals may self-medicate with nicotine to enhance cognitive and attentional processes6, which may partially account for the high prevalence of cigarette smoking among individuals with cognitive disorders such as schizophrenia, attention deficit/hyperactivity disorder, Alzheimer’s and Parkinson’s diseases, and age related cognitive decline7,8,9. A recent meta-analysis also showed that nicotine could enhance aspects of cognitive function, including motor abilities, attention and memory9. Moreover, this nicotine-induced enhancement of cognitive function has been observed both in nicotine-deprived smokers, in non-deprived smokers, and in non-smokers5,10. However, several studies suggest that smoking has an adverse effect on cognition11,12,13,14. Some studies show that long-term smokers perform more poorly on tests of cognition later in life than never-smokers, and ex-smokers perform better than those who continue to smoke14. Longitudinal studies have suggested a causal relationship between chronic smoking into late life and an increased risk of cognitive decline and dementia11,12,13. Thus, the smoking-cognition relationship warrants further investigation in a large sample of individuals.
Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, is widely expressed in the adult mammalian brain, the highest levels being found in the hippocampus, followed by the cerebral cortex15. BDNF plays an important role in the regulation of neuronal survival, differentiation, growth, and apoptosis16. Studies have shown that BDNF can modulate activity-dependent synaptic plasticity underlying learning and memory in the hippocampus17,18. More specifically, BDNF appears to play an important role in both early long term potentiation (LTP) and late phase LTP in hippocampal neurons19, a cellular model of learning and memory17. Previous studies indicate that circulating BDNF may be a biomarker of memory and general cognitive function in healthy adults20,21. Several studies have shown that BDNF serum levels are significantly decreased in individuals with cognitive decline-related diseases, such as mild cognitive impairment21, Alzheimer’s disease22, and Huntington’s disease23. Interestingly, our own recent study showed that decreased BDNF levels were associated with cognitive impairment, especially immediate memory in schizophrenia24,25.
A single-nucleotide polymorphism (SNP) in the BDNF gene (rs6265) produced a valine (Val)-to-methionine (Met) substitution in the proBDNF protein at codon 66 (Val66Met). This SNP altered the intracellular trafficking and activity dependent secretion of mature BDNF and affected hippocampal function18,26,27,28,29. Consistent with this, both normal controls and schizophrenia patients with Met alleles have significant deficiencies in episodic memory, suggesting that Met carriers show a poorer cognition in both schizophrenia and healthy subjects18,30,31. These findings support a role for the BDNF Val66Met polymorphism in normal hippocampal dependent memory function in healthy controls as well as in individuals with schizophrenia18.
Preclincal data show that acute nicotine administration decreases whereas chronic nicotine, but not cocaine or morphine, increases BDNF mRNA levels in the hippocampus32. Interestingly, genome-wide linkage scans indicate that the region of chromosome 11p13 where the BDNF gene is located likely harbors susceptibility genes for nicotine dependence specifically33. Moreover, Beuten et al. provide evidence of an association between allelic variants of BDNF and nicotine dependence in male European-American smokers34. A recent study demonstrated that the frequencies of both the Met/Met genotype and Met allele were significantly increased in current and in former smokers when compared to never smokers among Germans35, suggesting that carriers of the BDNF Met allele have an increased risk for smoking. While subsequent association studies did not corroborate these findings24,36, recent studies have linked this BDNF polymorphism with smoking initiation37, smoking cessation38 and the age of smoking initiation24. Moreover, a lower plasma concentration of BDNF was reported in the smoking group39. However, a recent study indicated that smoking was associated with increased plasma BDNF levels in depressed patients40. The most recent study by Jamal et al. showed that smokers with and without nicotine dependence had higher levels of serum BDNF than former and never-smokers. Moreover, total number of smoking years was a significant predictor of serum BDNF. However, there was no association of BDNF Val66Met, nor an interaction of this polymorphism and smoking status, with serum BDNF41. Interestingly, they further found that nicotine-dependent smokers had more severe depressive symptoms than non-dependent smokers, former and never-smokers. Moreover, in Val66Val carriers, nicotine-dependent smokers had more severe symptoms of depression and anxiety than the other three groups, suggesting that BDNF Val66Met genetic variants may be crucial for the worse behavioral outcome of nicotine42. Our recent study showed that smoking was associated with cognitive decline, but not with BDNF levels in a normal population. Concomitant alcohol use did not worsen the cognitive decline and had no effect on BDNF levels. However, smoking severity was positively associated with BDNF levels43. Taken together, these findings suggest that smoking may affect the peripheral BDNF levels, and BDNF system may be involved in the etiology of nicotine dependence.
Given the established association between smoking and cognitive performance and the important role of BDNF in cognition and in nicotine dependence, it would be of interest to explore the relationships between smoking, cognitive performance and BDNF in a healthy population. We hypothesized that smoking may enhance some aspects of cognitive function in a Chinese Han population. The underlying mechanisms by which smoking may enhance cognitive performance might be associated with higher BDNF serum levels. Furthermore, Met carriers might show a poorer cognitive performance in smokers or non-smokers, or both. In addition, the relationship between serum BDNF levels and cognitive function may be dependent on the BDNF Val66Met polymorphism in smokers. Because smoking is substantially more common among Chinese men than in women with normal population44, as well as gender differences in smoking behaviors45, we included only male subjects in the present study.
Table 1 shows demographic and clinical characteristics of the smokers and nonsmokers. The mean age, education, marriage, and body mass index (BMI) did not differ between the two groups (all p > 0.05).
Distributions of the BDNF genotypes were consistent with HWE in both smokers and nonsmokers (both p > 0.05). We found no significant differences in BDNF genotype and allele distributions between smokers and nonsmokers (x2 = 2.26, df = 2, p > 0.05; and x2 = 1.11, df = 1, p > 0.05, respectively) (Table 1).
Genotype effects on cognitive functioning between smokers and nonsmokers
RBANS data were available from 114 smokers and 98 nonsmokers. Table 2 shows RBANS total and index scores, and the effects of the BDNF Val66Met polymorphism on the RBANS total and index scores.
Smokers performed significantly worse than nonsmokers on the RBANS total score (t = 3.09, df = 210, p = 0.002), immediate memory (t = 3.02, df = 210, p = 0.003) and delayed memory (t = 2.32, df = 210, p = 0.021). After the Bonferroni correction (α = 0.05/6 = 0.0083), only the significant difference in the RBANS total score and immediate memory remained significant. After adjusting for age, education and BMI, these results still remained significant for RBANS total score (F4,204 = 7.95, p = 0.005), and for immediate memory (F4,204 = 9.60, p = 0.002). However, there were no significant differences in other cognitive measures between smokers and nonsmokers (all p > 0.05).
As shown in Table 2, the three genotypes significantly differed on the language index (F = 4.25, p < 0.02), and using the Bonferroni test to control for the two potential comparisons only the Val/Met vs. Met/Met difference was significant (p = 0.027). There were no significant genotype effects for other indices or RBANS total scores.
Genotype effects on serum BDNF levels between smokers and nonsmokers
Serum BDNF levels were available from 103 smokers and 89 nonsmokers. These 192 subjects with BDNF level test overlapped with those subjects who had the RBANS test. Serum BDNF levels were normally distributed in both smokers and nonsmokers (Kolmogorov–Smirnov one-sample test: both p > 0.05). There was not a significant main effect of smoking status on BDNF levels (11.6 ± 2.3 ng/ml for smokers versus 11.5 ± 3.0 ng/ml for nonsmokers, p > 0.05). Furthermore, there was no main effect of genotype on serum BDNF levels (p > 0.05) nor genotype × smoking status effect (p > 0.05).
Differential effects of BDNF genotype on the relationships between BDNF serum levels and cognitive functioning
Since some cognitive domain impairments existed in smokers, we explored whether the cognitive impairments may be related to serum BDNF levels and whether such relationships differed between genotype groupings in smokers. We first tested the overall effect of the BDNF levels on all five cognitive domain scores in a multivariate ANCOVA test. BDNF was the independent variable, and the 5 cognitive domains and RBANS total scores were entered simultaneously as dependent variables. Covariates in the multivariate ANCOVA test were age, education and BMI. A BDNF level-by-genotype interaction term was also entered in the model. The results showed a trend toward significant overall main effect of BDNF on neurocognition (F = 1.96, p = 0.08). The BDNF level-by-genotype interaction term was statistically significant (F = 2.98, p = 0.012), which indicated that the relationships between BDNF levels and cognitive domain scores differed between genotype groupings. Further, post hoc univariate analyses found significant BDNF effects on attention (F = 6.92, p = 0.01), and a trend toward significant effect on RBANS total score (F = 2.89, p = 0.09). Moreover, we also found a significant BDNF level-by genotype interaction effect on language score (F = 3.91, p = 0.024). However, these significances did not pass the Bonferroni corrections (all p > 0.05).
In the smoking group, partial Pearson correlations were significant between BDNF levels and attention (r = −0.28, df = 98, p = 0.014) and non-significant between BDNF and RBANS total score (r = −0.21, df = 98, p = 0.06). Interestingly, BDNF levels were significantly associated with CO levels (r = 0.38, df = 96, p < 0.01), and non-significantly with FTND (r = 0.24, df = 95, p = 0.06). However, only the significant association between BDNF and CO levels passed the Bonferroni corrections (p < 0.05).
Table 3 shows Pearson partial correlation coefficients for the relationships between BDNF levels and cognitive domain scores within each genotype group in the smoking group. Among the Val/Met genotype, BDNF levels were significantly associated with worsening attention performance (r = −0.34, df = 65, p = 0.019). Further, this association was observed especially in Val allele (Val/Met + Val/Val) carriers (r = −0.38, df = 86, p = 0.002). In addition, among the Val/Met genotypes, BDNF was significantly associated with CO concentrations (Val/Met: r = 0.33, df = 65, p = 0.022). Further, this association was observed especially in Val allele carriers (r = 0.38, df = 86, p = 0.006). However, these significant associations did not pass the Bonferroni test (all p > 0.05).
In nonsmoking groups, no significant correlation was found between BDNF level and any RBANS index or total scores. Moreover, no significant correlation between BDNF level and any RBANS index and total scores was observed when being grouped by BDNF genotype (all p > 0.05), indicating no significant effects of BDNF level, BDNF genotype and their interaction on cognitive performance in the nonsmoking group.
To our best knowledge, this is the first study to investigate the effect of smoking on BDNF and cognition as well as their relationship in a normal Chinese population. The main findings of the present study were that, (1) smokers had significantly lower cognitive scores on the RBANS total score, immediate memory and delayed memory; (2) there was no significant difference in BDNF serum levels and BDNF Val66Met genotype between smokers and nonsmokers; (3) there was a significant negative association between serum BDNF levels and attention only in the smoking group. Moreover, this association was only observed in Val allele carriers; (4) BDNF level was found to be significantly associated with CO levels in the smoking group. Moreover, this association was only observed in Val allele carriers.
The finding of lower cognitive performance in smokers is concordant with numerous studies evaluating cognitive function in smokers among the normal population11,12,13,14, suggesting that chronic smoking may increase the cognitive decline in a normal population. However, some previous studies suggest that nicotine could enhance aspects of cognitive function, including motor abilities, attention and memory9, especially in some diseases that have cognitive deficits, such as schizophrenia, attention deficit/hyperactivity disorder, Alzheimer’s and Parkinson’s diseases, and age related cognitive decline6,7,8. Nicotine’s cognition-enhancing effects have been attributed to enhancing DA signaling in mesolimbic and mesocortical DA pathways5, an up-regulation of nicotinic acetylcholine receptors (nAChRs), or possibly protection from the neurotoxicity induced by free radicals8. However, nicotine also can produce neuronal toxicity, and chronic cigarette smoking potently increases free radical production and antioxidant depletion46. Moreover, the other 4700 components of tobacco smoke include a variety of carcinogens as well as other toxic compounds such as carbon monoxide, heavy metals and cyanide47, and could account for some of the cognitive, intellectual, and behavioral impairments in the non-demented elderly48. Interestingly, a previous study showed that nicotine’s effects may be dose dependent, and low dose nicotine may be an antioxidant and be neuroprotective, whereas high dose nicotine may induce neurotoxicity through oxidative stress and cellular injury49. Taken together, we hypothesize that smoking or nicotine use, especially at low dose and acute administration, may improve cognition in those patients with established cognitive deficits, but long-term use at high doses may damage cognition in healthy controls, suggesting that regular smoking or nicotine use may have a different effect on cognitive function in healthy controls compared to patients with cognitive deficits.
We found no association between the BDNF Val66Met polymorphism and smoking among male Chinese, which is consistent with two recent studies in a healthy Caucasian population36,41,42, but not with two other studies in European-Caucasians34,35. A possible reason for the inconsistencies in genetic association studies is related to ethnic background. For example, the allele frequency distribution of Val66Met has varied significantly between Chinese and Caucasian subjects. The Met allele frequency is around 50% in Chinese consistent with the 48.8% Met allele frequency found in our current study, but it is only around 20% in Caucasian subjects50. Thus, interethnic differences in the genotype frequencies of the BDNF Val66Met polymorphism may play an important role in accounting for the inconsistent results across the different populations. Other factors may include different sample sizes, the methodologies for measuring smoking, and ethnic stratification effects10. Thus, the association of the BDNF gene polymorphism and smoking behavior deservers further investigation.
Interestingly, we found a significant negative association between serum BDNF levels and attention only in the smoking group, and this association was only observed in Val allele carriers. Thus, BDNF was implicated in cognitive function only in smokers. Furthermore, the BDNF Val66Met polymorphism affected the correlation between BDNF and different aspects of cognitive function only in smokers, not in nonsmokers. The BDNF serum level displayed a negative association with attention, but the association was opposite to our expected direction. Studies have shown that BDNF plays a critical role in activity dependent neuroplasticity underlying learning and memory in the hippocampus17,18. Recent studies have shown that BDNF levels are significantly decreased in individuals with cognitive decline-related diseases, such as mild cognitive impairment, Alzheimer disease, and Huntington’s disease20,21,22,23. Moreover, higher BDNF levels are associated with better neuropsychological test performance in these diseases21. However, it is noteworthy that in our present study, smokers had some cognitive deficits, but not lower BDNF levels. Hence, it is possible that smoking-induced cognitive deficits (maybe through free radical mechanisms) lead to an increase in BDNF levels in order to reverse smoking’s harmful effects, and prevent further damage. Hence, increases in BDNF levels may be compensatory processes to attain homeostasis in the cognition-BDNF system, which might lead to higher BDNF levels in smokers. However, in our current study, we found no significant difference in BDNF levels between smokers and nonsmokers, suggesting that smokers had already failed to have sufficient BDNF. Moreover, comparatively high BDNF being associated with more cognitive impairment in smokers needs to be viewed in the context of no overall differences in BDNF in these smokers compared to nonsmokers. In addition, our findings of the significant association between BDNF levels and CO concentrations and the trend toward significant association between BDNF and FTND total score seem to support this hypothesis that greater nicotine dependence or smoking severity elevates BDNF in smokers.
Furthermore, BDNF Val66Met genotype groupings had a significant impact on the relationship between BDNF levels and cognitive impairments in smokers. The correlations between BDNF levels and cognition especially attention was only observed for Val allele carriers, but not for the Met/Met genotype. These divergent serum BDNF- cognitive function relationships across BDNF genotypes in smokers may also provide a clue about the unusual finding of higher BDNF levels with more cognitive impairment. A direct effect of the BDNF Val66Met polymorphism itself may have contributed toward the present findings. This polymorphism has been found to be associated with altered intracellular trafficking of pro-BDNF and secretion of the mature peptide18,27,28, suggesting that the BDNF Val66Met variant is a kind of functional polymorphism. Moreover, the Met66 allele has been associated with impaired depolarization-dependent secretion and intracellular trafficking of BDNF protein in the hippocampus18. Thus, the functional Val66Met polymorphism of the BDNF gene may exert its effect on the cognitive performance of smokers by affecting BDNF expression and protein production. Our failure to observe an association between BDNF levels and cognition in the smoking group with the Met/Met genotype could be due to lack of enough BDNF to counteract the smoking-induced cognitive impairment. However, while the functional effect of the Met66 allele on trafficking of the protein makes this polymorphism a strong candidate for direct involvement in attention function in smokers, we cannot exclude linkage disequilibrium with another polymorphism nearby as an explanation for this association.
Further, it is worthy of mentioning that Met allele carriers have demonstrated poorer episodic memory than their respective Val-homozygous counterparts in healthy controls or in patients with schizophrenia18,31. Moreover, Met allele carriers have lower hippocampal function and have reduced hippocampal and prefrontal gray matter30, brain regions known to participate in memory. However, the current study showed association with other aspect of neuropsychological functioning, such as attention and language, but not in the memory domain. We could not provide the reasonable explanations for the mechanisms by which the BDNF Val66Met variant affects attention, but not memory due to our cross-sectional design in our current study. It is possible that this discrepancy might be related to the study design differences.
Several limitations of this study should be noted. First, this is a cross-sectional study design and cannot show direct causality, although there were many significant associations or correlations in our study. That means, they are not etiology. For example, the BDNF correlation with cognition was only presented in smokers, but not in non-smokers, suggesting that BDNF changes and cognition changes are all downstream effects of smoking, which are pathological changes. Second, both smokers and nonsmokers had a relatively limited sample size, especially when being divided into subgroups by the BDNF genotype. This could lead to false positive or negative results due to the lack of statistical power and selection of samples. Moreover, after the Bonferroni correction, none of the associations remained significant, suggesting a small effect. Hence, a replication study would be needed with a larger sample size. Third, due to the shortcoming of the design for this study and the limits of the experimental and clinical conditions, we only had about 200 subjects who carried out the cognitive test and were on serum BDNF level test, although all the 628 subjects were genotyped with BDNF- Val66Met polymorphism. This might lead to bias in the statistical analysis due to the imbalance in the number of the subjects who took cognitive test, BDNF serum assay and BDNF- Val66Met polymorphism genotyping differentially. Fourth, we only measured the BDNF serum levels following an overnight fast, but not during and after smoking in smokers. Previous studies have shown that smoking influenced the BDNF serum levels39,40. We speculate that BDNF serum levels might change at the different time points of smoking, which warrants further investigation. Besides smoking, exercise level, alcohol and food may affect the BDNF serum levels, which had not been collected in this study and will be remedied in the future investigation. Fifth, our sample was limited to only males and can not be applied to females. It would be interesting to evaluate whether our findings in the present study could generalize to female subjects. Sixth, we focused on the Val66Met polymorphism, because it is functional and previously associated with cognitive performance. However, in our current study, we found that the serum BDNF levels were not related to val66met genotype. We speculated that other genetic variants within BDNF may influence subsequent BDNF expression or activity, suggesting more extensive genotyping to identify haplotype blocks of greater association with cognition. Although we did not find the effects of Val66Met polymorphism on serum BDNF levels, we did find a significant negative association between serum BDNF levels and attention only in Val allele carriers in the smoking group, suggesting the important role of this polymorphism in adjusting the relationship of cognition and serum BDNF levels. Seventh, several cognitive performance tests were used, but there was only a correlation with the attention index and BDNF in the smoker group. We could not give a reasonable explanation why only one domain of cognitive performance was associated with BDNF in the smoker group due to the nature of our cross sectional design. Moreover, the significance is weak, and the positive results were based on a comparatively small sample size. Eighth, we measured BDNF in serum, not in cerebral spinal fluid (CSF). It is still uncertain whether peripheral BDNF levels reflect similar changes in the central nervous system (CNS).
In summary, we have provided new evidence to support that smoking is associated with significant cognitive impairment in a male Han Chinese population, especially on immediate and delayed memory, and total cognitive performance. Although we did not find any associations of BNDF levels or the BDNF Val66Met polymorphism with smoking, we found a significant negative association between serum BDNF levels and attention and a positive association between BDNF levels and CO concentrations in the smoking group. Moreover, these associations in smokers appear to be dependent on the presence of BDNF Val66Met polymorphism, with these associations observed only in Val allele carries. However, these findings still need to be regarded as preliminary because of the relatively small sample size and the cross-sectional design in this study. Future large controlled prospective studies would help clarify the interrelationships between smoking, cognitive functioning and BDNF.
Six hundred and twenty-eight healthy unrelated male volunteers (aged 22–70 years, mean age: 46.3 ± 12.7 years) were recruited from the Haidian district in Beijing. The participants were interviewed by trained investigators, using a detailed questionnaire including general information, socio-demographic characteristics, current and previous smoking behavior, and medical and psychological conditions. All subjects met the following inclusion criteria: 1) age 20–70 years, Han Chinese; 2) no DSM-IV Axis I psychiatric diagnosis by a research psychiatrist using the basis of the Structured Clinical Interview for DSM-IV (SCID); 3) being able to provide the signed informed consent for participating in the study and to complete the cognitive test.
A complete medical history, physical examination and lab test were obtained from all subjects. Those subjects with physical diseases were excluded. All of the subjects were excluded from alcohol or illegal drug abuse/dependence by self-report.
Subjects meeting one or more of the following criteria were excluded: (1) documented disease of the central nervous system that could interfere with the cognitive assessments including, but not limited to epilepsy, stroke, tumor, Parkinson’s disease, Huntington’s disease, seizure disorder, history of brain trauma resulting in significant impairment; (2) acute, unstable and/or significant and untreated medical illness (e.g., infection, diabetes, hypertensions); (3) chronic infection; (5) a clinically significant electrocardiogram (ECG) abnormality in the opinion of the investigator; (6) use of any medication; (7) history of severe allergy or hypersensitivity; (8) dependence on alcohol or illicit drugs.
The Institutional Review Board (IRB) at Beijing HuiLongGuan hospital approved this study and each subject gave written informed consent for participating after the study had been fully explained. In addition, all methods were performed in accordance with Declaration of Helsinki promulgated by the National Institute of Health.
In order to maintain consistency in the use of various terms while gathering data on smoking behavior, the US Centers for Disease Control and Prevention have developed and updated the following definitions2: Never smokers – Adults who have never smoked a cigarette or who have smoked fewer than 100 cigarettes in their entire lifetime. Former Smokers – Adults who have smoked at least 100 cigarettes in their lifetime, but they currently do not smoke. Nonsmokers – Adults who currently do not smoke cigarettes, including both former smokers and never smokers. Current Smokers – Adults who have smoked 100 cigarettes in their lifetime and currently smoke cigarettes every day (daily) or some days (nondaily). Former smokers were excluded from the present study.
In addition, the Chinese translation of the standardized Fagerstrom Test for Nicotine Dependence (FTND) was employed to measure the degree of nicotine dependence (ND)51. Additional visits were requested for subjects with missing or ambiguous data. Exclusion criteria included a history of -Diagnostic and Statistical Manual of Mental Disorders—Fourth Edition | (DSM-IV) psychiatric disorder, alcohol abuse, and other drug abuse. Demographic data are summarized in Table 1.
We assessed cognitive functioning using the repeatable battery for the assessment of neuropsychological status (RBANS, Form A)52 from 212 subjects on the same day as the blood samples were taken. The RBANS is comprised of 12 subtests that are used to calculate 5 age-adjusted index scores and a total score. Test indices are Immediate Memory (comprised of List Learning and Story Memory tasks); Visuospatial/Constructional (comprised of Figure Copy and Line Orientation tasks); Language (comprised of Picture Naming and Semantic Fluency tasks); Attention (comprised of Digit Span and Coding tasks); and Delayed Memory (comprised of List Recall, Story Recall, Figure Recall, and List Recognition tasks). The RBANS was previously translated into Chinese by our group and its clinical validity and test–retest reliability were established among controls53.
Measurement of carbon monoxide
Measurement of carbon monoxide (CO) concentrations in exhaled air was performed using BreathICO (Vitalograph Buckingham, UK). Three hundred and thirty-six participants (143 smokers and 193 non-smokers) were instructed to hold their breath for 15 seconds and then exhale into a disposable tube attached to the BreathICO. Breath CO concentrations were expressed in parts per million (ppm).
Serum BDNF measurement
Blood samples were collected between 06:00 and 08:00 following an overnight fast. We measured fasting serum BDNF levels from 192 subjects by sandwich ELISA using a commercially available kit as described in our previous report54. All samples were assayed by a research assistant blind to the clinical situation. Inter- and intra-assay variation coefficients were 7 and 5%, respectively.
The genotypes of the BDNF Val66Met polymorphisms from all subjects (n = 628) were identified as reported in our previous study43. A research assistant who was blinded to the clinical status genotyped every subject twice for accuracy of genotyping55,56,57,58.
Deviation from Hardy–Weinberg equilibrium was calculated by chi-square (χ2) goodness-of-fit test. The BDNF Val66Met allele and genotype frequencies were compared between smokers and nonsmokers using x2 tests. Group differences were compared using Student’s two-sample t-test or one-way analysis of variance (ANOVA) for continuous variables and chi-squared for categorical variables. Correlation between variables was studied using Pearson product moment correlations.
We tested associations between the BDNF Val66Met polymorphism and the cognitive measures or serum BDNF levels using a general factorial design in PASW statistical software version 18.0 (SPSS Inc, Chicago, Illinois). For the main models, the BDNF Val66Met genotype and smoking status (smokers vs nonsmokers) were entered as fixed effects. Scores for each cognitive domain and the total scores of RBANS were entered as the dependent variables, with age, education and body mass index (BMI) included as covariates as appropriate. In each model, the main effect of smoking status group, the main effect of genotype and smoking group × genotype interaction were tested. The smoking group × genotype interaction term in the model detects the differential effects that alleles might have on cognitive scores between smoking status groups. Similarly, the main effect of the BDNF genotype on serum BDNF levels was also analyzed using analyses of covariance (ANCOVA). We applied Bonferroni corrections to adjust for multiple testing. Lastly, we performed exploratory analyses to examine whether the relationships between BDNF serum levels and cognitive function were different across BDNF Val66Met genotype groups. Partial Pearson’s product moment correlation coefficients were used to assess associations of cognitive performance with serum BDNF levels while adjusting for various potentially confounding demographic variables of age, education and BMI. Statistical significance was defined as p < 0.05.
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Zhou, D. H. et al. The study of BDNF Val66Met polymorphism in Chinese schizophrenic patients. Progress in Neuropsychopharmacology and Biological Psychiatry 34, 930–933 (2010).
Funding for this study was provided by grants from the Science and Technology Program of Guangdong (2016A020216004), Science and Technology Program of Guangzhou (201704020168, 201807010064), Suzhou Key Project (Psychiatry) (Szxk201515), Suzhou Key Medical Center for Psychiatric Diseases (Szzx201509), Suzhou Key Diagnosis and Treatment Program (LCZX201316), Jiangsu Province Natural Science Fund Project (BK20151197), and Suzhou Key Medical Center for Psychiatric Diseases (Szzx201509).
The authors declare no competing interests.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Cite this article
Xia, H., Du, X., Yin, G. et al. Effects of smoking on cognition and BDNF levels in a male Chinese population: relationship with BDNF Val66Met polymorphism. Sci Rep 9, 217 (2019). https://doi.org/10.1038/s41598-018-36419-8
Demographics, clinical characteristics and cognitive symptoms of heavy smokers and non-heavy smokers in Chinese male patients with chronic schizophrenia
European Archives of Psychiatry and Clinical Neuroscience (2022)

domain: medical


text:
Gherkin sold to Brazilian banker Joseph Safra for more than £700million
A Brazillian billionaire has paid more than £700million to buy The Gherkin – one of the most distinctive towers in the City of London.
Joseph Safra, the banker behind the Safra Group who has a personal fortune of around £10billion, bought the skyscraper at 30 St Mary Axe for £726million.
The 41-storey tower, designed by Sir Norman Foster, was completed in 2004 for insurance giant Swiss Re, which sold it for £600million in 2006 at the height of the last property boom.
Food for thought: A Brazillian billionaire has paid more than £700million to buy The Gherkin – one of the most distinctive towers in the City of London
The deal left the buyers - Germany property investor IVG Immobilien and British investment bank Evans Randall - mired in debt, and The Gherkin fell into receivership earlier this year.
Safra described the building as ‘truly special’ and added: ‘While only ten years old, this building is already a London icon that is distinguished from others in the market, with excellent value growth potential.
‘We intend to make the building even better and more desirable through active ownership that will lead to a range of enhancements.’
The Gherkin is still home to Swiss Re as well as a host of other companies, including Chicago-based law firm Kirkland and Ellis.
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domain: finance


words // Brandon Richard
If you've seen enough of Kanye West strolling about in the Black/Pink colorway of the upcoming Nike Air Yeezy 2, here's a closer look at the grey pair that he debuted during the Watch the Throne "Otis" performance at August's MTV Video Music Awards. In this picture shared by Def Jam VP of Promotion Shawn Pecas, we get a closer look at the grey-based shoe, which also features a white set of laces, watermelon-lined interior and glow-in-the-dark outsole.
We're still waiting for release details, but we'll keep you posted here at Sole Collector when we hear something. In the meantime, tell us what you think about this colorway.


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The MSc Criminology and Criminal Justice programme continues to attract high quality students from around the world. This year we welcomed to the Centre our biggest cohort yet of MSc students, with 33 taking up places in October 2015. In addition, seven new DPhil students began their doctoral study and we welcomed our first two part time DPhil students, Brett Hartley and Arthur Rizer.
Our thriving graduate community participates fully in the intellectual life of the Centre, attending formal seminars as well as the informal lunchtime seminar series and Research Stream meetings. The DPhil students run their own Criminology discussion group and many are members of other student groups in the wider law faculty.
Our students organize high-profile events for partners within and beyond the academy, produce reports for external criminal justice and governmental bodies (e.g., Lyndon Harris and Gabrielle Watson) and serve on committees within the UN (Rudina Jasini). Two of our DPhils (Rob Blakey and Mia Harris) were appointed to the Independent Monitoring Board at HMP Bullingdon. DPhil Criminology student Marie Tidball was heavily involved in another successful disability moot at Wadham College and in May was elected to represent the Labour Party in Hinksey Park, Oxford with 68% of the vote share, an impressive result at her first election.
Our students have also published their work in academic journals and given presentations at seminars and conferences within and beyond the UK, including – in Richard Martin’s case – in Australia. And they have successfully bid for external research funding for empirical and knowledge exchange projects (Laura Tilt and Leila Ullrich).
Some took up visiting positions in other universities to further develop their research. Rachel Wechsler was the McDougall Visiting Professor of International Law at West Virginia University College of Law from August - September 2015, where she taught International Human Rights Law. She was also a visiting PhD student at University College Dublin in autumn 2015. Roxana Willis has taken up a temporary associate professor position at Universitat Pompeu Fabra in Barcelona, lecturing on Crime Policy. Chloe Deambrogio, Marion Vannier, and Leila Ullrich spent time as visiting scholars at the Universities of Villanova in Pennsylvania, Edinburgh and Berkeley. And Rudina Jasini has recently been awarded a post-doctoral global fellowship at New York University.
Meanwhile, closer to home, our students have contributed to the work of the Oxford Human Rights Hub: Richard Martin was Managing Editor of the Hub Blog and Arushi Garg was Deputy Chairperson for Oxford Pro Bono Publico (OPBP). Dominic Aitken, Alice Gerlach, Andrew Roesch-Knapp and Valerie King are also involved in the work of Border Criminologies.
Finally, we congratulate our doctoral students who have been awarded their DPhil during the year: Rudina Jasina and Joanna Simons. We wish them all the best with their future careers.
More information about our alumni can be found here:
This year we welcomed a number of new staff.
Dr Francesca Menichelli, a British Academy postdoctoral fellow joined us in September 2015 and has been making good progress with her research, under the mentorship of Professor Ian Loader. Her project understands security as a governmental strategy and adopts a comparative perspective in order to analyse how its deployment has opened up new spaces for governing in three different countries: Italy, France and England and Wales.
Khadija von Zinnenburg Carroll joined the centre in July 2015 as a Researcher on Professor Mary Bosworth’s European Research Council (ERC) project on ‘Subjectivity and Penal Power’, contributing an artist and art historian’s perspective and working with Mary on the Immigration Detention Archive.
The quality of the research at the Centre is reflected in the high-level publications produced and in the amount and range of research funding we attract. A full list of publications produced by members of the Centre is provided below, as are details of new research funding. This year, Centre members have published 7 new monographs and 9 edited collections, as well as numerous articles in peer-reviewed journals and books.
Members also disseminate their work to audiences (academic, policy and practitioner) around the world. While many presentations were given in England and Wales, over the past year, Centre members have also been invited to present in the following countries: America, Australia, Belgium, Brazil, Canada, Finland, Germany, Holland, Ireland, Italy, Norway, Portugal, Scotland, and Spain. In addition, we have continued our ongoing collaboration with colleagues in universities in America, Australia, Belgium, Brazil, China, India, and Spain.
Run successfully by Leila Ullrich and her team, Oxford Transitional Justice Research (OTJR) continues to be at the forefront of new and bold research that explores justice processes in societies that undergo or recover from mass violence. OTJR’s weekly seminar series continues to bring leading scholars and practitioners including judges, artists and activists to Oxford. In 2015-2016, OTJR hosted ICTY Judge Theodor Meron, ICC Judge Cuno Tarfusser, Professor Ruti Teitel and Professor Kai Ambos among many others.
Centre members continue to build on research started in previous years: Mary Bosworth and her team of post-doc and doctoral researchers have made further progress on their various projects on immigration detention, border control, deportation, and the postcolonial prison; Lucia Zedner continues her research on preventive justice and security and criminal justice; our policing scholars, Ben Bradford, Ian Loader and Alpa Parmar are studying policing in the UK and beyond its borders; Carolyn Hoyle and colleagues are working on various projects on wrongful convictions; Julian Roberts and his students are focusing on various aspects of sentencing policy and practice, in particular, sentencing multiple and repeat crimes; Carolyn Hoyle and Roger Hood are still working on death penalty scholarship; Rachel Condry continues to disseminate her work on violence in the family; and Ian Loader has recently received funding to continue his work on politics and criminal justice. To find out more about our work see www.law.ox.ac.uk/centres-institutes/centre-criminology/research
Knowledge Exchange and Contributions to Public Life
Our commitment to knowledge exchange remains. In 2015-16, we continued with our series of one-day seminars for Thames Valley Police, providing the service with up-to-date empirical and theoretical research on the themes that are the focus of our scholarship.
Many of us have been interviewed for radio programmes and our research has been discussed in newspapers. We have hosted seminars aimed at disseminating our work and engaging with policy makers and practitioners within the academy and beyond, and presented our research at various practitioner conferences, as well as providing expert testimony to public reviews.
Dr Condry’s research on adolescent to parent violence has continued to attract a great deal of media coverage and is making a significant impact on government policy, not least through the presentation of her films about adolescent to parent violence. She serves on the MARAC Scrutiny Panel and has contributed to workshops bringing together practitioners and policy makers. Julian Roberts work on the Sentencing Council of England and Wales is a pertinent example of academic research feeding in to criminal justice practice, something his doctoral student Lyndon Harris is keen to continue. In May 2016 Mary Bosworth was awarded a grant from the ESRC Impact Acceleration Fund (IAA-ESRC) at the University of Oxford to host Dr Hindpal Singh Bhui, the inspection team leader on immigration from HM Prison Inspectorate, as KE Fellow. Hindpal will take up this post in August 2016.
In 2015, together with their partner, the media NGO, Fondation Hirondelle, OTJR launched the ‘Innovative Media for Change’ project to explore the role of new and traditional media in conflict and post-conflict contexts (funded by an IAA-ESRC Kick-Start Award, led by Julia Viebach and Leila Ullrich). They organized a two-day workshop in Oxford in June 2015 to bring together leading academics, practitioners and journalists to discuss the challenges of media cooperation in Transitional Justice. In May 2016, OTJR launched the project report, ‘Innovative Media for Change: What Role for the Media in Transitional Justice?’ This provides comprehensive analysis of the workshop presentations and discussions with many case studies ranging from Sierra Leone to Syria, from the former Yugoslavia to Colombia, Rwanda and Ethiopia. The report concludes that both new and traditional media are susceptible to manipulation, bias and misguided expectations in different ways. At the same time, it emphasizes that better cooperation between media, practice and academia can be a fruitful way to maximize their informational and analytical roles while reducing their divisive potential. The Final Report was published at our 50th Anniversary Conference on June 4.
Our students engage in other knowledge exchange activities too. From Shona Minson’s important work with the Prison Reform Trust, on the sentencing of mothers, to Rob Blakey’s engagement with visitors to the National Theatre to talk about their perceptions of young offenders, they demonstrate that the new generation of scholars are keen to make their research accessible and of use beyond the academy.
The Centre blog, twitter and Facebook accounts provide an active forum for showcasing our research and keeping in touch with alumni, visitors, and the wider academic and criminal justice community around the world. Our academics and students regularly write about their own research and the work of other scholars who present in our various seminar series. We have been extremely lucky to draw on the support and expertise of Dr Sarah Turnbull, our Blog and Social Media Manager, in keeping these accounts active and engaging.
50th Anniversary Celebrations
2016 marks the 50th Anniversary of the Centre for Criminology. We put together an exciting programme of events and activities to commemorate the Centre’s anniversary and to capture the life of the Centre in 2016.
Throughout the year we have hosted our 50th Anniversary lectures. These were launched in January by Professors David Downes, Tim Newburn, and Paul Rock, from the London School of Economics, who gave a lecture entitled ‘In the Beginning: Crime, Criminology and Criminal Justice’. Other lectures in Hilary term included: Professor Lisa Miller, Department of Political Science, Rutgers University, on ‘The Myth of Mob Rule’; and Frances Crook OBE, Chief Executive of the Howard League for Penal Reform, in conversation with Jamie Bennett, Governor, HMP Grendon.
Trinity term had anniversary lectures from David Anderson Q.C, Independent Reviewer of Terrorism legislation, in conversation with Professor Liora Lazarus, University of Oxford; and Professor David Garland, School of Law, New York University, on Penal Power: It’s forms, functions and foundations’.
In March, we also held a very successful conference in collaboration with (and funded by) Green Templeton College, on ‘Crime and Mental Health: Vulnerability and Resilience in the Face of Trauma’, hosted by Carolyn Hoyle, Rachel Condry and Jasmina Arnez. A few days later, the Centre hosted a drinks reception at the Howard League Conference in Keble College, Oxford. Professors Bosworth and Zedner presented plenary lectures at the conference.
In May, a lecture and reception was hosted on our behalf by Lady Edwina Grosvenor in London. The theme ‘Transforming Incarceration’ built on research conducted by Centre members and others over the past decades to improve the conditions of those held in British prisons and detention centres. This event provided an opportunity to further develop our working relationships with NGOs, government and other academics working in this field.
Professor Lucia Zedner, University of Oxford, delivered the 11th Annual Roger Hood lecture on Criminal Justice in the Service of Security on June 3. Finally, on June 4, the Centre hosted its Anniversary Conference on ‘Contemporary Dilemmas in Criminal Justice’ at the Andrew Wiles Building. This high profile event brought together MPs, QCs, senior police and many other well-known figures in the world of criminal justice to discuss ‘Criminal Justice, Security and Human Rights’, Women in Prison’, and ‘Criminal Justice in an Age of Austerity’.
Rachel Condry who was runner up in the ESRSC Outstanding Impact in Public Policy award;
Ben Bradford, who won an Oxford Teaching Excellence award;
Alpa Parmar who was nominated for an OUP Law Teacher of the Year award;
Rachel Weschler, winner of the Centre Book Review Competition;
Mary Bosworth, Andriani Fili, Ines Hasselberg, and Sarah Turbull who won an OxTALENT award for ‘Outreach and Public Engagement’ for their Border Criminologies website and blog;
Mary Bosworth for her John Fell Research Fund award on policing migration and her ESRC-IAA grant for a KE fellow;
Lucia Zedner who was elected as an Overseas Fellow of the Australian Academy of Law;
Andrew Ashworth who won the Halisbury Legal Award for Aacademic contribution in September 2015;
and Ian Loader who was awarded an ISRF Mid-Career Fellowship for a project on ‘In Search of a Better Politics of Crime’.
And, Finally, Goodbye To…
Ambrose Lee left us in April 2016 at the end of his 3 year Leverhulme post-doctoral fellowship to take up a new post at Derby University.
Sarah Turnbull will leave us in September to take up a lectureship in Criminology at Birkbeck university and Khadija von Zinnenburg Carroll will also be going, to take up a Professorship in Global Art at the University of Birmingham.

domain: news


text:
Stainless Steel Condiment Containers, 3pk
Packing lunch and snacks for children and adults is a breeze with Bits Kits condimentcontainers. Ideal for trips to the playground, camping, or after-school sports and activities.
- Food Grade 18/8 stainless steel containers keep food safe and sanitary perfect for on-the-go!
- Airtight and leak resistant set of 3 condiment containers feature a silicone gasket to reduce leaks and each hold 1.5 ounces or 3 tablespoons of your favorite dipping sauce or salad dressing without making a mess in the lunch box
- Hand wash or place in the top rack of a dishwasher

domain: food


text:
Binuclear Transition Metal Complexes Containing Macrocylcic Ligands: X-Ray Structure and Spectroscopy of a Series of Six-coordinate Cobalt(II), Cobalt(III), and Nickel(II) Complexes Incorporating Bridging Axial Ligands
Buetow, Tracy M.
MetadataShow full item record
Transition metal complexes containing several interacting metal atoms continue to attract a great deal ofresearch interest. Compounds that contain polynuclear transition metal centers as well as bridging ligands are being in a variety of areas including the modeling ofmetalloproteins, medicinal purposes where heavy metal ions are being used in drugs to treat diseases such as cancer and arthritis, and various materials applications. In the research for this thesis, our objective was to examine comparative structural properties ofbinuclear cobalt and nickel complexes, all containing a phenolate-imine macrocyclic ligand and bridging axial ligands with nitrogen and/or oxygen donor atoms. In addition, we examined the oxidation properties ofthe cobalt complexes, resulting in two mixed valence COIICOIIl compounds. All compounds were characterized by infrared and electronic absorption spectroscopy, and X-ray crystallography measurements were performed on three compounds. III
Showing items related by title, author, creator and subject.
Shrestha, Sonam (Kalamazoo College, 2016)Transition metal complexes are increasingly seen in metalloprotein modeling, energy generation, and materials applications due to their metal–metal interactions. In ongoing research di- and tetranuclear cobalt and nickel ...
Reactions of Cobalt(II) and Nickel(II) Complexes Containing Binucleating Macrocyclic and Pyridine Ligands with Carboxylic Acids: Formation of Binuclear Co(II), Ni(II) and Tetranuclear Co(II) and Ni(II) Complexes Marroquin, Geneci (Kalamazoo College, 2014)The synthesis of new electron transfer agents was studied. Binuclear and tetranuclear cobalt(II) and nickel(II) complexes were synthesized. Originating from a binucleating macrocyclic and tetra-pyridine ligand reactants. ...

domain: chemistry


text:
|Roy Lewis Brown, 92|
BENTON, Kent. - Roy Lewis Brown, age 92, of Benton, Kentucky, died Tuesday, Aug. 1, 2017, at Ray and Kay Eckstein Hospice Care Center in Paducah, Kentucky.
Arrangements are being handled by Collier Funeral Home Benton, Kentucky.
Internment was held at the Cole Cemetery.
The family ask memorial contributions be made to the First Baptist Church, P.O. Box 381, Benton, KY 42025. Designated for: Eastern KY Missions.


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Standing up for port fundingLast week, in honor of Wisconsin Ports Week, we recognized the significant role our ports play in commerce, shipping, transportation and recreation.
By: U.S. Rep. Sean Duffy, Superior Telegram
Last week, in honor of Wisconsin Ports Week, we recognized the significant role our ports play in commerce, shipping, transportation and recreation.
I have the great honor of representing the Port of Duluth-Superior, which supports 11,500 jobs and contributes over $1.5 billion to the local and regional economy. This port serves 1,000 ships each year, moving 40 million tons of cargo to destinations throughout the Great Lakes and around the world.
The port provides a crucial link for the miners, manufacturers, and farmers of northern Wisconsin and Minnesota.
As a co-chairman of the Great Lakes Task Force, I have focused my efforts on increasing commerce in the Great Lakes and ensuring our ports and harbors are properly maintained and dredged.
The Harbor Maintenance Trust Fund serves as one of the main federal sources of funding to accomplish these goals. Since 1997, however, Congress has not appropriated the full amount collected to the trust fund. Our harbors remain under maintained and the Great Lakes alone face a backlog of over $200 million in projects.
I’ve called on the House Appropriations Committee to fully allocate all of the trust fund money to ensure that the Great Lakes ports are sufficiently supported. This includes co-sponsoring the RAMP Act, which would require that all funds that are dedicated to the harbor maintenance trust fund are actually used for just that — harbor maintenance. It should not be raided by the treasury for general spending.
I also sponsored an amendment to the Energy and Water Appropriations Bill, which prohibited these funds from being used for other, unauthorized purposes. While our harbors continue to be under-maintained, these limited dollars must continue to be prioritized on dredging.
Finally, I’ve supported legislation to designate the Great Lakes as one navigation system for budgetary purposes. Our Great Lakes ports do not function separately and independently from one another, but rather as one large, interconnected system.
We need to guarantee that funding priorities reflect this reality and that Great Lakes ports are not continually underfunded.
Later this year, Congress will move forward with the reauthorization of the Water Resources Development Act — legislation that will outline federal priorities for our water-based transportation system. I look forward to continuing to stand up as a strong voice for Lake Superior and our Great Lakes watershed, and in particular, the Lake Superior ports that I have the honor to represent.
In celebration of Wisconsin Ports Week, thank you to the men and women who work day-in and day-out to keep our goods flowing on the Great Lakes.
U.S. Rep. Sean Duffy, R-Weston, represents Wisconsin’s 7th Congressional District.

domain: geography


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The Iron Blood Release
Custom element Japanese name:
血液型, Chisioton |
Custom element English name:
Iron Blood Release | Similar to Calcium Release made by Mugiwara
The element is based on:
Water + Earth + Fire
Water chakra, is used to gather the iron in the blood into a certain spot of the human body, than the earthen chakra comes in to control the iron to give it form by manipulating it, but it still needs something the fire chakra to use the heat and solidify it making it harder than rocks as it is iron, but making it different from regular Iron Release, as it contains different proteins
Facts that prove the element to be possible (in the manga context): Fact #1
; (The Demon Sword which was broken in the fight against the current raikage, A) Well, we have seen the sword of zabuza the demon of the mist use his broken sword to absorb the hemoglobin also known as blood iron from his victims after he slices them up and doing so to make his sword whole again due to the absorbed iron, well that proves that it is possible to manipulate iron, that is running through the human blood. Fact #2
; Now, coming to the kaguyas they use their calcium and chakra to manipulate their bones giving it form, causing it to pop out of the ninja body, so this is perfored on an similar manner, instead of the calcium the user uses his chakra to control the Blood Iron, but too much of iron in the blood could kill one so avoiding that the user has the gater it on different places, not allowing the iron to spread through the users body,
and controlling it using their water, fire & earth chakra. Scientific Facts #3
; Hemoglobin is a protein in the blood which contains Iron and is used to transport oxygen around the body. Hemoglobin are found in the red blood cells. Because hemoglobin are red, red blood cells are red. Hemoglobin are very small, and several million can fit in each red blood cell. There are millions of hemoglobins in each red blood cell and millions of red blood cells in the human body. So there is scientific proof that there is iron in the human body, Red blood cells are very large in number; in women, there are 4.8 million red blood cells per microliter of blood. In men, there are 5.4 million red blood cells per microliter of blood, so it would be more fit for an male to have this type of KG as a male possess more of red blood cells meaning more iron to control with the chakra. Red blood cells are red because they have hemoglobin in them another word for Blood Iron. Wikipedia - Red Blood Cells
How it works:
It has been shown in the Naruto anime and manga that Kimimaro Kaguya can control the calcium in his body freely through his Kekkei Genkai. So it is shown that it is possible to control it inside the body, but never outside. It has also been shown that people can control Earth to great extents, even controlling Diamonds, Mud and Sand. Blood Iron is no different from any of the earth types and jutsus, because its a mineral, like any other minerals, and it can be found in the earth, and controlled like any other earth techniques. By extracting it from the earth, or from the users own body, he can control it in shape, and change the chemical compound. The different Iron compounds have different usage, both in real life, and in narutoverse. This release is similar to the Kaguya KG the Shikotsumyaku , but instead of bones the user uses the iron in their blood to control it, by using water chakra, to gather the iron in the blood into a certain spot of the human body (this could be the elbow, knee, knuckles, rib cage, on the back of the arm etc. On a similar way of the kaguyas bone techniques The shikotsumyaku, then the earthen chakra comes in to control the iron to give it form by manipulating it, making sharp like object with it, making knifes pop out of your knuckles. But it would be incomplete so it needs something that something is the fire chakra the fire chakra is used to heat the iron and solidify it making it harder than rocks as it is iron, withstanding even blades being on par with them, but the fire chakra is only used if there is enough iron gathered into the wished spot. The user cannot control the element to such extent where he can control the calcium in another persons body.
(Chisioton: Hōrin Maru-Ken) – Iron Blood Release: Striking Circle Blade
(Chisioton: Aka Odori) – Iron Blood Release: Bloody Dance
Chisioton: Shikio Gai) – Iron Blood Release: Death Scythe
Conditions to be able to use it:
It requires full mastery over Water, Earth & the Fire element, and to be at least at kage rank as it uses three different elements, also to be specialized in at least on of these elements.
Is weak to:
; As Iron conducts electricity so it would shock the user.
; It is able to melt the Iron releasing toxins inside the users body so it's definitely weak against fire.
; It's able to melt the Iron rendering it useless, andy fire based attacks are strong against Iron Blood Release.
; Dark release is an kg build of two elements lightning and fire so dark release is definitely strong against iron blood release.
Is strong against:
; It can shatter ice as ice is an combination of water and wind.
; It can't slice through Iron being the hard material that it is so Iron wins.
; Iron is a harder material than earth so Iron would be able to slice through earth attacks with ease.
; Iron is strong against water because water can't damage iron, however if it's a lightning water attack the combination will destroy the iron.
Students I passed this custom element on too:
There are many variations of earth and crystal KG's like almunium, titanium, diamond, jade etc. So i don't see a reason why my element isn't aprovable.


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Achieving a happy married life basically always easy. It is critical to remember that each individual is unique and will alter over time. For making your matrimony work, you should focus on growing as being a person in addition to a couple. Every tips to help you achieve a effective and happy relationship:
Retain an open conversation with your loved one. If mail order wives you are unable to do this, the marriage is usually doomed to failing. It will take several work on your part, when you both agree to open communication and knuckle down, your matrimony can be a happy one. Read more to learn some recommendations from five wives. In that case, find out what makes a happy relationship work for these people. You might be surprised by what you learn. If you have great communication, you can actually make your relationship work!
Be open to your partner’s variations. You’ve probably over heard that a sightless wife which has a deaf husband could have a happy marriage, nonetheless this is not automatically the case. Your most various couples can make a loving relationship. Couples who are still happily married interact with each other https://www.tshirtloot.com/2019/05/page/3/ every day to cultivate a happy marital life. Small signals and thoughtful words go a long way in making a relationship work. With some these tips, you’ll be well on your way to a happy married life.

domain: sociology


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Aliens in the Forest: The Cisco Grove UFO Encounter Paperback – December 7, 2011
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About the Author
Authors Noe Torres and Ruben Uriarte are active members of the UFO research community with many years of experience investigating UFO cases in the Southwestern U.S. and Northern Mexico. Their research has appeared on the History Channel's UFO Hunters and UFO Files TV shows. Their first book, "Mexico's Roswell: The Chihuahua UFO Crash," received wide critical acclaim and was the basis for a February 2008 episode of UFO Hunters, in which the authors appeared. The authors have also appeared frequently on many other UFO-related TV and radio shows and have spoken at many UFO conferences and events.
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It's the epitome of High Strangeness, with a botched alien abduction attempt in the forests near Lake Tahoe.
I loved this book, and would recommend it to anyone interested in the abduction phenomenon.
Great true story of an encounter with aliens plus the effects on the person it happened to. Trust me if you are a ufo believer this is a must read. Detailed with much data.
Some editorial cons:
* Repetitive (filler?) text and pictures, maps and drawings. E.g., How many low-resolution pictures of the "bow" described in the incident do I need to see? Do I really need to see more than one picture/drawing of the "tree" that the incident took place in, or the robots, etc.?
* Speculative text. For example, the authors spend a page or so of the book debating about the worldly makeup of the "knock-out" gas mentioned in the narrative (i.e. "nitrogen, argon, [or] helium[?]"). Really? They are writing about UFOs, aliens, and robots that are clearly non-terrestrial and have highly advanced ET technology and they are speculating which Earth-based gas it might have been made out of?
Finally, besides considering why someone would think being in a tree would protect you from tree-climbing bears, I wonder that instead of the witness spending years in "emotional terror" of the situation described in the book, it might instead have been a "spiritual awakening" moment, where you are gifted with the knowledge that we are ABSOLUTELY not alone in this Universe and all that such knowledge implies. Unfortunately, the book only brings forth Mr. Shrum's negative aspects of the encounter and we are not given any real insight into any positive (if any) changes that incident may have brought into Shrum's life.
After all, any human who goes into a forest (or crosses the street) runs the risk of being shot, abducted, or killed -- but very few of us are given an opportunity to meet ETs face-to-face, and it is up to us to see the experience, and how it affects our life, as Negative or Positive.

domain: literature


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“The world is a garden fenced by the state * The state is power supported by law * Law is the policy which guides the ruler * The ruler is order protected by the army * The army are supporters sustained by money * Money is sustenance produced by subjects * Subjects are servants protected by justice * Justice is ingrained and is the support of the world
Aristotle’s Circle of Politics was elaborated by Ibn Khaldun to create the eight self-sustaining links in the chain of medieval statecraft.”
Excerpted from: Rogerson, Barnaby. Rogerson’s Book of Numbers: The Culture of Numbers–from 1,001 Nights to the Seven Wonders of the World. New York: Picador, 2013.

domain: library


About this Event
Come and join Full Moon singing circle in Amsterdam!
Every month we gather as a tribe during the full moon to sing.
The practise of mantra singing is a way of bringing yourself to a state where the mind quiets down, and the heart opens up.
No need for singing experience, it's all about sharing this wonderful practise. Singing mantra together brings so much joy and connection, exactly what we need right now.
Sharing your voice can be a vulnerable thing, you might experience those energies and patterns that are witholding you from singing freely. It asks for a certain maturity to meet those energies inside yourself. The singing circle is not therapy but a spiritual practice.
Event details will be send to you after purchase :)
Only 30 seats available
Event Venue & Nearby Stays
Paleis 180., 180-H Tweede Oosterparkstraat, Amsterdam, Netherlands


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My sister, who lives in Holland, is a Parkinson’s patient who is treating her condition with marijuana - or derivatives of it. In the last couple of months, Dutch doctors have been allowed to prescribe marijuana-based medication for Parkinson’s,
Q My 76-year-old father has recently developed tremors which his GP has diagnosed as Parkinson’s disease, but I would like a second opinion.
My sister has been treated for over five years at hospital for breast cancer. However, early last year, I asked if a doctor from our surgery would call as she felt unwell when she woke up (although she did improve during the day).

domain: health


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Enduring pain and suffering due to spine and back problems can be very debilitating. For many people, this type of pain can only be relieved by receiving treatment from an orthopedic surgeon. An orthopedic surgeon can perform an extensive range of different surgical procedures on different areas of the body. These are some of the most common types of spinal procedures an orthopedic surgeon performs.
Discectomies are commonly performed to remove herniated discs that are pressing on the nerves or spinal canal. If this type of spinal problem is not corrected it can lead to a variety of different neurological issues including permanent paralysis.
Discectomies are performed by removing the herniated discs, replacing them with prosthetic discs and attaching them to the spine to ensure they remain in place and no longer move into position to press on the spinal canal or nerves.
The lamina is a part of the vertebrae that forms the arch in the spine. Sometimes this piece of bone can also put pressure on the nerves and spinal canal and cause pain, numbness, or problems with mobility.
When a laminectomy is performed, part of the lamina is removed to stop the bone from pressing on the spinal canal or nerves. This procedure is often performed when other less invasive procedures have failed to correct the problem. If the patient also has bone spurs growing on the spine, these may be removed during a laminectomy.
Spinal Decompression and Fusion
This procedure is done to take pressure off the nerves and spinal canal and to strengthen the spine by holding it in position. Spinal decompression and fusion is a common procedure that orthopedic surgeons perform in the United States.
First, the pressure is removed by trimming the bony section away from the nerve or the spinal canal it has been compressing. Then surgical hardware is attached to the bony elements of the spine to make the spine better stabilized.
Anterior Cervical Discectomy and Fusion
Anterior cervical discectomy and fusion is a procedure that is performed on the neck area of the spine. This procedure is also very commonly performed by orthopedic surgeons in the US. However, this procedure differs from other spinal surgeries because it is done by going through the front of the spine instead of the back of the spine.
This procedure is performed when a disc in the cervical vertebrae is pinched against a nerve or the spinal cord. That disc is removed and then replaced by a prosthetic spacer that maintains the proper space between the vertebrae. Fusion is done by using surgical screws to attach the spacer to the spine which also stabilizes the spine.
The main purposes of spinal surgery are to decompress the nerves or spinal canal (or both) and to ensure the spine remains stabilized. This also relieves the pain of the patient and allows mobility to be maintained.


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On www.trenitalia,com click the Italian flag to find English, enter your 'hour' of departure e.g. enter '9' for 09.00, and enter Roma S. Pietro to Tarquinia. To see fares, use a date within the next seven days. Buy tickets in Italy and validate (time/date-stamp) before boarding.
Note that Roma S. Pietro train station is not in the same area as the Ottaviano San Pietro Metro station.
Where do you want to end up in Tarquinia? The train station is down in the valley near the port, which requires a bus to get up to the historic center of town
You can either take the train to Civitavecchia and get a bus from there, or to Tarquinia and get a bus from there. Once in Tarquinia it's easy to walk between the museum and the necropolis as they are less than a half mile apart.
Tarquinia has a decent tourism web site in English: tarquiniaturismo.it/pagina14_city-of-tarquin…Edited: 04 April 2015, 13:04
I just went to Tarquinia at the beginning of March from Rome. We got on the train at Trastevere station (near where we were staying). We bought tickets to come back at the same time which you can do since it is a regionale train with no fixed seating. Trastevere station is not manned after 2 pm or on weekends, so you have to buy the tickets from a machine it you go when there is not a person there. The Tarquinia station is unmanned period and you would have to buy tickets from a machine if you wait till you come back I get nervous myself about the machine not working/being broken. Last time before this when I was at Trastevere station only one of the ticket machines was working. Not sure what San Pietro is like?
When you get to Tarquina, you go to the front of the station and there are 2 bus lines that can take you into the city. You pay the driver for tickets so have some coins/small bills on you.
The bus leaves you off in front of the Museum. The people inside will help you with a map and how to get to the Necropolis. it is a pleasant walk to there. The tombs were awesome and there was a snack bar open when we were there.
Thankyou all for the valuable assistance,
Board the train at Roma Termini going to Tarquinia, rather than at Roma Trastevere The rest of the posting remains the same. Note that the Hotel San Marco in Tarquinia (mentioned in the hyperlinked posting) shut down two or three years ago. However, there are excellent bed and breakfast nearby, including the wonderful Palazzo Rosati b&b across the street from the Archeological Museum.


A Georgia man who embezzled more than $300,000 from his employer to spend at strip clubs has been sentenced to prison.
According to the United States Attorney's Office in the Northern District of Georgia, Scott Spillberg was sentenced to 2 1/2 years in prison to be followed by three years of supervised release in connection to the case.
“Spilberg was trusted by his employer and betrayed that trust by shelling out more than $300,000 of company funds at adult entertainment clubs,” said U.S. Attorney Ryan K. Buchanan.
The attorney's office stated that the Georgia man was hired as the manager at Houck's Grille in August 2020. In October 2020, at the height of the COVID-19 pandemic, Spillberg started to use his company-issued debit card to pay for expenditures at two adult entertainment clubs.
According to the attorney's office, Spillberg went to the strip clubs more than 50 times in an 11-month period, spending more than $300,000 of the company's money. Attorneys say the loss of money caused a significant hardship on the restaurant and threatened the livelihood of its 40 employees.
The attorney's office stated that the company was forced to borrow COVID relief funds to stay in business during that period.
“This greedy defendant abused his position to fund his own lifestyle. Because of his actions, the restaurant, and people he was chosen to lead suffered the impacts,” said Keri Farley, Special Agent in Charge of FBI Atlanta. “People who brazenly steal from their employers should expect to be held accountable.”
Spillberg, a Georgia man, pleaded guilty to the offense of wire fraud and was convicted on Sept. 19. As part of his sentencing, he will also have to pay restitution of $300,533.78.
The Roswell Police Department and FBI investigated the case. Assistant U.S. Attorney Christopher J. Huber prosecuted the case.


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Volkswagen Philippines continues to impart valuable driving skills to kids as they resume their award-winning Child Safety Initiative (CSI) this year. The 2016 campaign kicked off last January and will have its final leg this April and May.
The campaign aims to introduce early childhood safety awareness to children of 4-8 years of age. This is while imparting important road safety habits to their parents as well.
A miniature roadway is setup with stoplights wherein kids can board the small Volkswagen vehicles for the Junior Driving Course and maneuver their way to the mentioned road. Motoring media members will serve as “traffic assistants” during the driving course.
Children are also educated on road safety with the help of the Volkswagen Philippines’ partners such as the Philippine Global Road Safety Partnership, Metro Manila Development Authority Institute of Traffic Management, and the Department of Transportation and Communication.
If you would like to attend the campaign, Volkswagen Philippines will conduct the next CSI mall tour at the Glorietta Activity Center in Makati City on April 2 and 3 from 11AM to 7PM. They will also be heading to UP Town Center in Quezon City on May 21 and 22.
CPI started touring schools and establishments such as malls, trade shows and dealers in 2015. As of this writing, there are 4,997 children and 3,975 parents that participated the initiative. Last Februrary 26, 2016, the campaign received the Silver Anvil Award in the Public Relations: Specialized Advocacy Campaign.