text:
Back to Journals » Neuropsychiatric Disease and Treatment » Volume 15
The association between HTR1B gene rs13212041 polymorphism and onset of alcohol abuse
Authors Svob Strac D , Nedic Erjavec G, Nikolac Perkovic M, Nenadic-Sviglin K, Konjevod M, Grubor M , Pivac N
Received 19 October 2018
Accepted for publication 24 December 2018
Published 24 January 2019 Volume 2019:15 Pages 339—347
DOI https://doi.org/10.2147/NDT.S191457
Editor who approved publication: Dr Roger Pinder
Dubravka Svob Strac,1 Gordana Nedic Erjavec,1 Matea Nikolac Perkovic,1 Korona Nenadic-Sviglin,2 Marcela Konjevod,1 Mirko Grubor,3 Nela Pivac1
1Laboratory for Molecular Neuropsychiatry, Division of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia; 2Center for Alcoholism and other Addictions, University Psychiatric Hospital Vrapce, Zagreb, Croatia; 3Faculty of Pharmacy and Biochemistry University of Zagreb, Zagreb, Croatia
Background: Alcohol dependence displays a wide variety of clinical phenotypes. Various typology classifications of alcoholism include age of onset of alcohol abuse as one of the major phenotypic features. Serotonergic changes have been associated with alcoholism, while serotonin receptors type 1B (5-HT1B) play an important role in regulating serotonergic neurotransmission. The rs13212041 polymorphism modulates the expression of HTR1B gene coding for 5-HT1B receptor. This study examined the association of platelet serotonin (5-HT) and HTR1B gene with the onset of alcohol abuse in alcohol-dependent subjects.
Materials and methods: Determination of platelet 5-HT concentration and genotyping of rs13212041 HTR1B gene polymorphism were performed in 613 alcohol-dependent patients, subdivided according to early/late onset (before/after 25 years of age) of alcohol abuse.
Results: Alcohol-dependent individuals with CC genotype were more frequent in the group with early onset of alcohol abuse compared to carriers of T allele. Besides HTR1B genotype, age and gender, but not platelet 5-HT, were major variables associated with the onset of alcohol abuse. Platelet 5-HT concentration was not significantly different between patients with early and late onset of alcohol abuse, or patients carrying various HTR1B genotypes. Although we observed no influence of co-variables such as age, gender, or somatic and psychiatric comorbidities, platelet 5-HT concentration was significantly affected by smoking.
Conclusion: These findings support potential involvement of 5-HT1B receptors in the onset of alcohol abuse and development of alcohol dependence. Additionally, the results of our study emphasize the importance of controlling for smoking status, as one of the significant confounding factors influencing platelet 5-HT concentration.
Keywords: alcoholism, age of onset, 5-HT1B, gene variants, platelet serotonin, smoking
Patients with alcohol dependence display individual differences in clinical symptoms and phenotypic characteristics, including disease severity, course and prognosis, comorbidity, and treatment response, which may be the result of different underlying neurobiological mechanisms, such as genetic and environmental influences.1,2 In order to reduce the heterogeneity of this complex disease, different authors proposed various typology classifications to divide alcohol-dependent subjects into more specific subtypes or endophenotypes.3 Many proposed classifications of alcohol dependence include the age of onset of alcohol abuse as one of the major phenotypic features with potential usefulness in elucidating underlying neurobiological pathways and improvement of the therapy.4,5 The age of onset of alcohol abuse might be due to the individual's genetic predisposition, as well as to a number of environmental factors.6 The Cloninger classification,7 among the most widely used classification schemes for alcohol dependence,8 also uses onset of alcohol abuse to differentiate between alcohol-dependent subjects type I and II, which differ in the course of the disease, extent of inheritance, and personality traits.9
Subjects with an early onset (before 25 years of age) of alcohol abuse (type II alcoholism) are more likely to drink heavily, to have more alcohol-related problems, more severe symptoms, and higher rates of somatic and psychiatric comorbidity.4,10 In addition, early onset alcoholism has been often associated with elevated levels of antisocial behavior and delinquency during adolescence and characterized as strongly heritable and male-limited.7 These subjects use alcohol for its euphoric effects and demonstrate high novelty seeking and low harm-avoidance personality traits.11 On the other hand, type I alcoholics have later onset of alcohol abuse (after 25 years of age) and are more strongly influenced by social environmental factors. Moreover, alcoholism with later onset affects both men and women, who drink alcohol for its anxiolytic properties and have high harm-avoidance personality traits.7 These two subtypes of alcohol-dependence are suggested to have different neurobiological backgrounds. Namely, it has been proposed that type I and type II alcohol-dependent individuals, differing in the age of alcoholism onset, have a deficit in the dopaminergic or serotonergic neurotransmission, respectively.12 This has been supported by studies demonstrating that type II alcoholics seem to have reduced levels of serotonin transporter (5-HTT) already in early age, whereas in type I alcoholics, the serotonergic alterations may be secondary and possibly reflecting the alterations in the dopaminergic system.13,14
Variations in the 5-HTT gene15 and tryptophan hydroxylase gene16 have been associated with an increased risk of alcohol dependence with an early onset as well as with alcohol treatment response.17 Moreover, decreased serotonergic neurotransmission18 and reduced concentrations of 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of serotonin (5-HT), have been found in the cerebrospinal fluid of early onset alcohol-dependent subjects.19 Low plasma ratio of tryptophan to large neutral amino acids (TRYP/LNAA ratio), a marker of serotonergic function, has also been observed in patients with an early onset of alcohol dependence.20 The findings suggest that these individuals might have a preexisting 5-HT deficit and therefore increased vulnerability to fluctuations in precursor availability, leading to higher alcohol intake early in life.10 In line with these results, low activity of monoamine oxidase (MAO), the enzyme degrading 5-HT, has been associated with type II subtype of alcoholism.21 In addition, the classification based on the age of onset of alcohol abuse seems to be an effective predictor of treatment response to various serotonergic drugs.22 Namely, ondansetron has been useful in therapy of early onset alcoholic patients,23 whereas sertraline has shown positive effects in the late onset alcohol-dependent subjects.24 Conversely, fluoxetine reduced the beneficial effects of cognitive–behavioral therapy in early onset alcoholics.25
The involvement of 5-HT system in the onset-based alcoholism typologies has been supported by both animal and human studies demonstrating that serotonergic disturbances have been closely related to reduced inhibitory control of behavior, including extensive alcohol use.10,26 Low central serotonergic activity has been mostly associated with increased alcohol consumption and alcohol dependence.26 Central 5-HT type 1B (5-HT1B) receptors have an important role in the physiologic synaptic feedback mechanism and regulation of serotonergic neurotransmission27 and are involved in various neurological disorders such as migraine.28 Moreover, 5-HT1B receptors have been suggested to modulate the activity of dopaminergic neurons in the ventral tegmental area, which is involved in the reward mechanisms underlying addictions, including alcohol dependence.29 Various animal studies have also implicated 5-HT1B receptor in the control of alcohol preference and consumption.30,31
Previous human studies reported the associations between different polymorphisms in the gene coding for 5-HT1B receptor (HTR1B) and alcohol dependence,32,33 especially alcoholism with early onset and antisocial behavior.4,34,35 The majority of reports assessing the association of HTR1B gene and alcoholism investigated G-861C polymorphism,33,34 which is in strong linkage disequilibrium with other functional polymorphisms in the HTR1B gene promoter, such as T-261G, A-161T, and C-129T.33,36,37 On the other hand, other authors failed to confirm these findings,37–39 perhaps due to the variability of alcohol-dependent phenotypes. However, only few studies investigated rs13212041 polymorphism, shown to modulate HTRIB gene expression,40 and its role in alcohol dependence.41,42
As the majority of peripheral 5-HT is stored in platelets, which possess many other components of serotonergic system, including 5-HTT, MAO-B as well as 5-HT1A, 5-HT2A, 5-HT3A, and 5-HT4 receptors,43–48 platelets are suggested as a limited peripheral model of central serotonergic functions.49 Moreover, some reports indicated that human platelets also contain 5-HT1B receptors,50 although their function in platelets is not known. However, since upon activation, platelets release 5-HT into circulation,51 one might speculate that similar to its role in the brain, platelet 5-HT1B receptors might regulate 5-HT levels at the periphery. It is generally accepted that serotonergic components in both platelets and neurons are encoded by the same genes and have similar structural and functional properties.52,53 Hence, the rs13212041 HTR1B gene polymorphism via its influence on the 5-HT1B receptor expression might subsequently affect central as well as peripheral 5-HT turnover.
In order to investigate potential changes in the serotonergic activity associated with different alcoholism subtypes, the aim of this study was to examine the association of platelet 5-HT and rs13212041 HTR1B gene polymorphism, with the early/late onset of alcohol abuse in alcohol-dependent subjects. To our knowledge, this is first such study, with appropriate sample size and carefully determined alcohol-related phenotypes, including possible confounding factors. The findings of our study might provide novel insights in the serotonergic regulation mechanisms underlying the early/late onset of alcohol abuse, which could help in further differentiation of alcoholism subtypes and potential improvement of the therapy for this complex disease.
The study enrolled 613 medication-free patients (499 males and 114 females) with alcohol dependence, recruited from the Center of Alcoholism and Other Addictions, University Psychiatric Hospital Vrapce, Zagreb, Croatia. Patients with alcohol dependence were admitted to hospital due to acute intoxication or alcohol-related withdrawal symptoms, and were left overnight to sober up. Demographic and clinical characteristics of the alcohol-dependent patients are listed in Table 1. The alcohol dependence as well as comorbid psychiatric disorders were diagnosed using a structured clinical interview (SCID), based on the DSM-IV criteria.54 If alcohol-dependent patients had any other comorbid substance abuse or dependence (except nicotine addiction) or had used any kind of drugs in the previous 12 months, they were excluded from the study. The alcohol-dependent patients were divided according to the onset of alcohol abuse into subjects with early (before 25 years of age) and late (after 25 years of age) onset of alcohol abuse.7 The data regarding somatic history, including current somatic complaints, were collected from hospital medical records and obtained by an interview. Participants were Caucasians of the European origin from Zagreb County, Croatia, and they all agreed to give a blood sample, participate in the study, and gave their written informed consent. The study was approved by the Ethics Committee of University Psychiatric Hospital Vrapce, Zagreb, Croatia and carried out in accordance with the Helsinki Declaration (1964).
Table 1 The demographic and clinical characteristics of alcohol-dependent patients
Blood collection and processing
The samples of blood (8 mL) from alcohol-dependent patients were collected in the morning after overnight fasting by using a plastic syringe containing 2 mL anticoagulant (acid citrate dextrose). The whole blood was centrifuged at 1100 g for 3 minutes at 4°C. Obtained platelet-rich plasma was further centrifuged at 5087 g for 15 minutes, 4°C to sediment the platelets. The platelet pellet was washed with saline and centrifuged again. The obtained pellet was stored at −20°C.
Platelet 5-HT measurement
Platelet 5-HT concentration was measured by the spectrofluorometric method.55 Briefly, platelets were broken down by sonication. Specimens of standard, blank (water), and platelet sonicates were analyzed in duplicates. All samples were deproteinized with 10% ZnSO4 and 1N NaOH, and then 0.1% L-cysteine and 0.05% ortho-phthalaldehyde were added for the preparation of fluorophore. The 5-HT fluorescence was measured on a Varian Spectrophotofluorimeter Cary Eclipse (Varian Optical Spectroscopy Instruments, Mulgrave, VIC, Australia) (exciting wavelength: 345 nm; emitted wavelength: 485 nm). Protein concentrations in platelets were determined by the method of Lowry et al.56
Genomic DNA was isolated from peripheral blood leukocytes by a salting out method.57 Genotyping was performed according to the procedure described by Applied Biosystems, using TaqMan-based allele-specific polymerase chain reaction on ABI Prism 7000 Sequencing Detection System apparatus. The rs13212041 (C__32252506_10) single nucleotide polymorphism in the HTR1B gene, located on chromosome 6, was analyzed. Briefly, 20 ng of genomic DNA was PCR amplified in 96-well plates using a 10 μL reaction volume. The conditions of PCR reaction were: 40 cycles at 92°C for 15 seconds and 60°C for 60 seconds.
Statistical analyses were performed with GraphPad Prism version 4.00 for Windows (GraphPad Software, Inc., San Diego, CA, USA) and MedCalc Statistical Software version 14.8.1 (MedCalc Software bvba, Ostend, Belgium). Normality of distribution was assessed with the D'Agostino–Pearson omnibus normality test. Age of male and female subjects enrolled in the study was compared using Student's t-test. The frequency of smoking and early/late onset of alcohol abuse between male and female alcohol-dependent patients was evaluated by a chi-squared test of independence. Platelet 5-HT concentrations were analyzed by Kruskal–Wallis test followed by Dunn's multiple comparison test or with Mann–Whitney test, as normality of the data failed. Possible deviations from Hardy–Weinberg equilibrium (HWE) were tested using goodness of fit chi-squared test. Genotype and allele frequencies (presented as numbers and percentages) were evaluated by a chi-squared test of independence. Multiple regression analysis assessed the influence of various demographic and clinical data (independent variables), such as age, gender, smoking, somatic and psychiatric comorbidities, on alcohol abuse onset and platelet 5-HT concentration (dependent variables).
G*Power 3 Software58 was used for conducting power analyses, ie, to determine a priori sample size and to post hoc compute the achieved power. For F test (Kruskal–Wallis test) involving three groups (with α=0.025; power =0.80; a small effect size =0.30), total desired sample size was 132. For F test (Kruskal–Wallis test), evaluating four groups (with α=0.025; power =0.80; a small effect size =0.30), total desired sample size was 152. For Mann–Whitney test (with α=0.025; power =0.80; a median effect size =0.30), total desired sample size was 368. For analyses with a χ2-test (with α=0.025; power (1−β)=0.80 and a small effect size (ω=0.20)), for df =2 total desired sample size was 288, and for df =1, total desired sample size was 238. As the actual total sample size was 613, the power analysis revealed that the study included appropriate sample size and statistical power to detect significant differences.
Alcohol-dependent participants were predominantly male (81.40%). The group of female subjects with alcohol dependence (51.89±11.62) was significantly older (t=2.42, df =611, P=0.016; Student's t-test) than the group of male patients (49.32±9.89). There were no significant differences in frequency of smoking (χ2=2.01, df =1, P=0.148) between male (61.72%) and female (54.39%) alcohol-dependent patients. Our study demonstrated that 395 (64.44%) of alcohol-dependent patients (67.13% of males and 52.63% of females) had some somatic comorbidity, with liver diseases present in 386 (62.97%) of enrolled subjects. Hence, most (92.72%) somatic diseases in subjects with alcoholism were liver diseases. Moreover, 279 (45.51%) alcohol-dependent patients, ie, 223 (44.69%) males and 56 (49.12%) females reported some psychiatric comorbidity. These psychiatric comorbidities include personality disorders (49.10%), stress-related disorders (37.27%) including anxiety, acute stress reaction and post-traumatic stress disorder, mood disorders (12.19%) primarily depression, and psychotic disorders such as schizophrenia (1.43%). There were no significant differences in the frequency of psychiatric comorbidities between male and female patients (χ2=0.73, df =1, P=0.391); however, male patients (67.13%) had more often somatic comorbidities (χ2=8.52, df =1, P=0.0035) than female patients (52.63%).
As shown in Table 1, alcohol-dependent subjects enrolled in the study had more often late (64.93%) rather than early (35.07%) onset of alcohol abuse. However, we observed significantly lower frequency of female patients with early, rather than with late, onset of alcohol abuse in comparison with male subjects (χ2=15.30, df =1, P<0.0001). Moreover, there were significantly more smokers in the group of early-onset alcoholics than in subjects with late onset of alcohol abuse (χ2=6.94, df =1, P=0.008). There were no significant differences in the frequency of somatic comorbidities (χ2=3.47, df =1, P=0.062) or liver diseases (χ2=3.31, df =1, P=0.069) between patients with early and late onset of alcohol abuse. However, early onset alcohol-dependent subjects more often had psychiatric comorbidities (52.09%) than patients with late onset alcohol abuse (41.96%) (χ2=5.78, df =1, P=0.016), although they did not differ in frequency of depression (χ2=0.51, df =1, P=0.477) (Table 1).
Genotype distributions for rs13212041 HTR1B polymorphism in alcohol-dependent subjects were in HWE (χ2=0.03, P=0.866). No significant differences in the frequency of the genotypes (χ2=2.13, df=2, P=0.344) or alleles (χ2=1.98, df =1, P=0.160) between male and female alcohol-dependent patients were detected using χ2-test (Table 2); therefore, in further analysis, patients were not divided according to gender. The genotype distribution for HTR1B gene polymorphism was significantly different (χ2=7.54, df =2, P=0.023) between patients with early and late onset of alcohol abuse (Table 2). Namely, the individuals carrying the CC genotype were significantly more frequent (χ2=7.25, df =1, P=0.007) in the group of alcohol-dependent subjects with early onset of alcohol abuse than in carriers of T allele. This strong evidence of HTR1B was also confirmed using multiple regression analysis (P=0.024), with age (P<0.0001) and gender (P=0.001) as major variables influencing the onset of alcohol abuse.
Table 2 Genotype and allele counts and frequencies of rs13212041 HTR1B gene polymorphism in alcohol-dependent patients subdivided according to the gender and early/late onset of alcohol abuse
As recent analysis suggested that the early onset of alcohol dependence is best defined as beginning before the age of 22 years,5 we additionally divided alcohol-dependent patients into subjects with early and late onset of alcohol abuse by using cut-off point at 22 years. Although the number of patients with early onset of alcohol abuse was, in this case, significantly lower (N=107), the results obtained after making cut-off at 22 years supported and even strengthened the findings obtained with cut-off at 25 years. Both the genotype (χ2=12.07, df=2, P=0.0024) and allele (χ2=8.456, df=1, P=0.0036) distribution for HTR1B gene polymorphism was significantly different between patients with early and late onset of alcohol abuse. Namely, the individuals carrying the CC genotype (χ2=10.63, df =1, P=0.0011) or C allele (χ2=4.269, df =1, P=0.0388) were significantly more frequent in the group of alcohol-dependent subjects with early onset of alcohol abuse than in carriers of the T allele or TT genotype, respectively.
Platelet 5-HT concentrations (mean±SD) were not significantly different between male (0.84±0.49) and female (0.75±0.46) alcohol-dependent subjects (U=25795, df =611, P=0.121; Mann–Whitney test). Moreover, the Kruskal–Wallis test failed to detect any significant differences in platelet 5-HT concentration between carriers of CC (0.84±0.46), CT (0.79±0.48), or TT (0.84±0.48) HTR1B rs13212041 genotypes, in the whole sample of alcohol-dependent patients (H=1.556, df=610, P=0.459), as well as when alcohol-dependent patients were subdivided into subjects with early and late onset of alcohol abuse (H=6.643, df =607, P=0.249).
Significant differences in platelet 5-HT concentrations were found between alcohol-dependent patients with early (0.88±0.48) and late (0.79±0.48) onset of alcohol abuse (U=38035, df=611, P=0.023; Mann–Whitney test; Table 1), and when these patients were additionally subdivided according to smoking status (H=36.49, df=609, P<0.0001; Kruskal–Wallis ANOVA; Figure 1). However, as shown in Figure 1, the results of post-hoc Dunn's multiple comparison test revealed significant differences only between smokers and nonsmokers, both in the group with early (P=0.0004) and late (P=0.0005) onset of alcohol abuse, suggesting an effect of smoking on platelet 5-HT concentration. There were no significant differences in platelet 5-HT levels between smokers with early and late onset of alcohol abuse (P=0.309) or between nonsmokers with early and late onset of alcohol abuse (P>0.9999) (Dunn's multiple comparison test; Figure 1). Multiple regression analysis also confirmed that there was no association of platelet 5-HT levels (P=0.104) with the onset of alcohol abuse. Therefore, observed differences in platelet 5-HT concentrations between alcohol-dependent patients with early and late onset of alcohol abuse were probably due to higher frequency of smokers in the group of alcoholics with early onset of alcohol abuse.
Figure 1 Platelet 5-HT concentration in alcohol-dependent smokers and nonsmokers subdivided according to the early/late onset of alcohol abuse.
Note: *P<0.0005 smokers vs nonsmokers (Kruskal–Wallis test and post-hoc Dunn's multiple comparison test).
Our findings also suggested that there was significant difference in the smoking frequency between alcohol-dependent subjects with and without comorbid depression (χ2=6.71, df=1, P=0.0096; χ2-test). Namely, 81.82% of alcohol-dependent subjects with comorbid depression were smokers in comparison with 59.14% smokers in the group of alcoholic patients without comorbid depression. However, there was no significant difference in the frequency of comorbid depression between patients with early and late onset of alcohol abuse (Table 1), as well as no significant difference in the platelet 5-HT concentration between alcohol-dependent subjects with (0.94±0.57) and without (0.81±0.48) comorbid depression (U=8368, df=611, P=0.2257; Mann–Whitney test). In general, we observed no significant differences in platelet 5-HT concentration between alcohol-dependent patients with and without psychiatric (U=45371, df=611, P=0.576; Mann–Whitney test) as well as somatic comorbidities (U=42972, df=611, P=0.969; Mann–Whitney test).
Finally, multiple regression analysis demonstrated no significant influence of age (P=0.632), gender (P=0.270), onset of alcohol abuse (P=0.157), HTR1B rs13212041 genotype (P=0.473), somatic (P=0.584), and psychiatric comorbidities (P=0.993), but significant effect of smoking (P<0.0001) on platelet 5-HT concentration in patients with alcoholism.
The main finding of our study is an association of rs13212041 HTR1B gene polymorphism with an onset of alcohol abuse in alcohol-dependent patients, demonstrating that homozygous individuals with CC genotype were more frequent in the group with early onset of alcohol abuse compared to carriers of T allele. Besides HTR1B genotype, age and gender, but not platelet 5-HT, were major variables influencing the onset of alcohol abuse. Platelet 5-HT concentration was not significantly different between subjects with early and late onset of alcohol abuse as well as between patients carrying different HTR1B genotypes. Although we observed no influence of co-variables such as age, gender, or somatic and psychiatric comorbidities, platelet 5-HT concentration was significantly affected by smoking.
Only few studies investigated the association of rs13212041 HTR1B gene polymorphism with alcohol dependence,41,42 but not with early- and late-onset alcoholism subtypes. This transition substitution (A1997G) in the distal 3′-untranslational region (UTR) of HTR1B messenger RNA disrupts a binding site for the microRNA, miR-96.40 MiR-96 is expressed in the brain,59 and various environmental factors, such as stress,60 can modulate its expression and epigenetically underlie some of the diversity in human behavior,40 including alcoholism endophenotypes. As A-allele carriers of rs13212041 HTR1B gene polymorphism demonstrate reduced HTR1B expression compared to G-allele carriers,40 we can presume that subjects with early onset of alcohol abuse, more frequently carrying the CC genotype, have higher levels of 5-HT1B receptors than patients with late onset of alcohol abuse.
In general, alcohol dependence has been associated with increased density of 5-HT1B receptors in specific brain regions.61 5-HT1B receptors have been shown to modify the effects of alcohol and regulate its voluntary intake,62 whereas 5-HT1B receptor ligands reduce extensive alcohol drinking and alcohol-related aggressive or impulsive behavior, observed in more severe forms of alcohol dependence.31,63 Therefore, our findings might suggest increased expression of 5-HT1B receptors in more severe types of alcoholism, characterized with an early onset of alcohol abuse.
Our results demonstrating that early onset alcohol-dependent patients more often have psychiatric comorbidities agree with findings that these subjects have more alcohol-related problems, more severe symptoms, and higher rates of somatic and psychiatric comorbidity.4,10 In our study, besides HTR1B genotype, age and gender were major variables influencing the onset of alcohol abuse. This is not surprising as male patients were younger and more often present in the group with an early onset of alcohol abuse, in line with suggestions that type II alcoholism is male predominant.7
The HTR1B rs13212041 polymorphism, by influencing 5-HT1B receptor expression, can subsequently affect 5-HT turnover. Namely, 5-HT1B receptors function as inhibitory autoreceptors or heteroreceptors on both serotonergic and non-serotonergic neurons, and modulate serotonergic activity. However, despite presumably higher density of 5-HT1B receptors in early-onset alcoholics, platelet 5-HT concentrations did not differ between patients with early and late onset of alcohol abuse, suggesting no association of platelet 5-HT with the onset of alcohol abuse.
Many components of serotonergic system, such as 5-HTT, MAO, and some 5-HT receptors, in both platelets and neurons are encoded by the same genes and have similar structural and functional properties.52,53 However, the role of 5-HT1B receptors might differ depending upon their specific location.64 In addition, activation of presynaptic 5-HT1B receptors inhibits 5-HT release, while 5-HT1B postsynaptic heteroreceptors are involved in the modulation of addictive behaviors.65 Therefore, platelet 5-HT1B receptors might not regulate 5-HT concentration in platelets, or their function could be affected by other 5-HT receptors66,67 or interaction with 5-HTT.68 No differences in platelet 5-HT levels, between carriers of different HTR1B rs13212041 genotypes in all alcohol-dependent patients, as well as in subjects with early and late onset of alcohol abuse, suggest that this polymorphism does not influence platelet 5-HT concentration.
Although previous studies found decreased platelet 5-HT concentration in alcohol-dependent subjects,69–71 only one small study reported higher platelet 5-HT uptake in subjects with early than with late-onset of alcohol dependence, suggesting differences in platelet 5-HTT function.72 However, in this study as well as these in many other studies, somatic and psychiatric comorbidities and tobacco smoking have been neglected as confounding factors, in spite of reports suggesting their effects on platelet 5-HT.49,73 We observed no significant influence of somatic and psychiatric comorbidities, including depression, but smoking significantly affected platelet 5-HT levels in alcohol-dependent patients in our present and previous study.74 In agreement with previous results,71 we detected higher platelet 5-HT concentrations in smoking alcoholics than in alcohol-dependent subjects who did not smoke. Patkar et al75 reported correlation of smoking with decreased density of platelet 5-HTT sites, whereas various studies reported metabolic effects of smoking on the breakdown of dopamine and 5-HT,76,77 as well as decreased platelet MAO-B activity due to cigarette smoking.78,79
In addition to appropriate sample size and statistical power, other advantages of this study include ethnically homogenous and medication-free alcohol-dependent patients and carefully determined specific alcohol-related phenotypes, including somatic and psychiatric comorbidities and other potential confounding factors such as age, gender, and smoking. However, one of the study limitations is a lack of replication of obtained results in the independent sample.
As far as we know, this is the first study reporting the association of rs13212041 polymorphism, located in the HTR1B gene coding for 5-HT1B receptor, with the onset of alcohol abuse in alcohol-dependent subjects. Our results suggest that homozygous individuals with CC genotype are more likely to develop a more severe form of alcoholism, characterized by the early onset of alcohol abuse, than carriers of T-allele. As rs13212041 polymorphism affects microRNA regulation of HTR1B gene expression, these data might suggest the involvement of epigenetic mechanisms in the modulation of serotonergic functions in alcohol dependence. Our findings might provide novel insights in the serotonergic regulation mechanisms underlying the early/late onset of alcohol abuse, which could help in further differentiation of alcoholism subtypes and potential improvement of the therapy for this complex disease. The results of our study also emphasize the importance of controlling for various confounding factors, such as smoking, which significantly influence platelet 5-HT levels.
Enoch MA. Genetic and environmental influences on the development of alcoholism: resilience vs. risk. Ann N Y Acad Sci. 2006;1094(1):193–201.
Litten RZ, Ryan ML, Falk DE, Reilly M, Fertig JB, Koob GF. Heterogeneity of alcohol use disorder: understanding mechanisms to advance personalized treatment. Alcohol Clin Exp Res. 2015;39(4):579–584.
Leggio L, Kenna GA, Fenton M, Bonenfant E, Swift RM. Typologies of alcohol dependence. From Jellinek to genetics and beyond. Neuropsychol Rev. 2009;19(1):115–129.
Chen YC, Prescott CA, Walsh D, et al. Different phenotypic and genotypic presentations in alcohol dependence: age at onset matters. J Stud Alcohol Drugs. 2011;72(5):752–762.
Le Strat Y, Grant BF, Ramoz N, Gorwood P. A new definition of early age at onset in alcohol dependence. Drug Alcohol Depend. 2010;108(1–2):43–48.
Liu IC, Blacker DL, Xu R, Fitzmaurice G, Tsuang MT, Lyons MJ. Genetic and environmental contributions to age of onset of alcohol dependence symptoms in male twins. Addiction. 2004;99(11):1403–1409.
Cloninger CR, Sigvardsson S, Gilligan SB, von Knorring AL, Reich T, Bohman M. Genetic heterogeneity and the classification of alcoholism. Adv Alcohol Subst Abuse. 1988;7(3–4):3–16.
Pombo S, Lesch OM. The alcoholic phenotypes among different multidimensional typologies: similarities and their classification procedures. Alcohol Alcohol. 2009;44(1):46–54.
Johnson BA, Cloninger CR, Roache JD, Bordnick PS, Ruiz P. Age of onset as a discriminator between alcoholic subtypes in a treatment-seeking outpatient population. Am J Addict. 2000;9(1):17–27.
Buydens-Branchey L, Branchey MH, Noumair D. Age of alcoholism onset. I. Relationship to psychopathology. Arch Gen Psychiatry. 1989;46(3):225–230.
Cloninger CR. Neurogenetic adaptive mechanisms in alcoholism. Science. 1987;236(4800):410–416.
Cloninger CR. The psychobiological regulation of social cooperation. Nat Med. 1995;1(7):623–624.
Storvik M, Haukijärvi T, Tupala E, Tiihonen J. Correlation between the SERT binding densities in hypothalamus and amygdala in Cloninger type 1 and 2 alcoholics. Alcohol Alcohol. 2008;43(1):25–30.
Tupala E, Hall H, Bergström K, et al. Different effect of age on dopamine transporters in the dorsal and ventral striatum of controls and alcoholics. Synapse. 2003;48(4):205–211.
Hallikainen T, Saito T, Lachman HM, et al. Association between low activity serotonin transporter promoter genotype and early onset alcoholism with habitual impulsive violent behavior. Mol Psychiatry. 1999;4(4):385–388.
Chung IW, Kim H, Sribney W, et al. Tryptophan hydroxylase polymorphism is associated with age of onset of alcoholism related behaviors. Alcohol. 2005;36(1):1–3.
Thompson MD, Kenna GA. Variation in the serotonin transporter gene and alcoholism: risk and response to pharmacotherapy. Alcohol Alcohol. 2016;51(2):164–171.
Berglund K, Fahlke C, Berggren U, Eriksson M, Balldin J. Personality profile in type I alcoholism: long duration of alcohol intake and low serotonergic activity are predictive factors of anxiety proneness. J Neural Transm. 2006;113(9):1287–1298.
Fils-Aime ML, Eckardt MJ, George DT, Brown GL, Mefford I, Linnoila M. Early-onset alcoholics have lower cerebrospinal fluid 5-hydroxyindoleacetic acid levels than late-onset alcoholics. Arch Gen Psychiatry. 1996;53(3):211–216.
Swann AC, Johnson BA, Cloninger CR, Chen YR. Relationships of plasma tryptophan availability to course of illness and clinical features of alcoholism: a preliminary study. Psychopharmacology. 1999;143(4):380–384.
Sullivan JL, Baenziger JC, Wagner DL, Rauscher FP, Nurnberger JI, Holmes JS. Platelet MAO in subtypes of alcoholism. Biol Psychiatry. 1990;27(8):911–922.
Roache JD, Wang Y, Ait-Daoud N, Johnson BA. Prediction of serotonergic treatment efficacy using age of onset and type A/B typologies of alcoholism. Alcohol Clin Exp Res. 2008;32(8):1502–1512.
Kranzler HR, Pierucci-Lagha A, Feinn R, Hernandez-Avila C. Effects of ondansetron in early- versus late-onset alcoholics: a prospective, open-label study. Alcohol Clin Exp Res. 2003;27(7):1150–1155.
Pettinati HM, Volpicelli JR, Kranzler HR, Luck G, Rukstalis MR, Cnaan A. Sertraline treatment for alcohol dependence: interactive effects of medication and alcoholic subtype. Alcohol Clin Exp Res. 2000;24(7):1041–1049.
Kranzler HR, Burleson JA, Brown J, Babor TF. Fluoxetine treatment seems to reduce the beneficial effects of cognitive-behavioral therapy in type B alcoholics. Alcohol Clin Exp Res. 1996;20(9):1534–1541.
Lemarquand D, Pihl RO, Benkelfat C. Serotonin and alcohol intake, abuse, and dependence: Clinical evidence. Biol Psychiatry. 1994;36(5):326–337.
Barnes NM, Sharp T. A review of central 5-HT receptors and their function. Neuropharmacology. 1999;38(8):1083–1152.
Thompson MD, Noble-Topham S, Percy ME, Andrade DM, Ebers GC. Chromosome 1p36 in migraine with aura: association study of the 5HT(1D) locus. Neuroreport. 2012;23(1):45–48.
O'Dell LE, Parsons LH. Serotonin1B receptors in the ventral tegmental area modulate cocaine-induced increases in nucleus accumbens dopamine levels. J Pharmacol Exp Ther. 2004;311(2):711–719.
Crabbe JC, Phillips TJ, Feller DJ, et al. Elevated alcohol consumption in null mutant mice lacking 5–HT1B serotonin receptors. Nat Genet. 1996;14(1):98–101.
Fish EW, McKenzie-Quirk SD, Bannai M, Miczek KA. 5-HT(1B) receptor inhibition of alcohol-heightened aggression in mice: comparison to drinking and running. Psychopharmacology. 2008;197(1):145–156.
Lappalainen J, Long JC, Eggert M, et al. Linkage of antisocial alcoholism to the serotonin 5-HT1B receptor gene in 2 populations. Arch Gen Psychiatry. 1998;55(11):989–994.
Sun HF, Chang YT, Fann CS, et al. Association study of novel human serotonin 5-HT(1B) polymorphisms with alcohol dependence in Taiwanese Han. Biol Psychiatry. 2002;51(11):896–901.
Hasegawa Y, Higuchi S, Matsushita S, Miyaoka H. Association of a polymorphism of the serotonin 1B receptor gene and alcohol dependence with inactive aldehyde dehydrogenase-2. J Neural Transm. 2002;109(4):513–521.
Soyka M, Preuss UW, Koller G, Zill P, Bondy B. Association of 5-HT1B receptor gene and antisocial behavior in alcoholism. J Neural Transm. 2004;111(1):101–109.
Duan J, Sanders AR, Molen JE, et al. Polymorphisms in the 5′-untranslated region of the human serotonin receptor 1B (HTR1B) gene affect gene expression. Mol Psychiatry. 2003;8(11):901–910.
Kranzler HR, Hernandez-Avila CA, Gelernter J. Polymorphism of the 5-HT1B receptor gene (HTR1B): strong within-locus linkage disequilibrium without association to antisocial substance dependence. Neuropsychopharmacology. 2002;26(1):115–122.
Sander T, Ostapowicz A, Samochowiec J, et al. Evaluation of an allelic association of the serotonin 5-HT1B G681C polymorphism with antisocial alcoholism in the German population. Addict Biol. 2000;5(2):167–172.
Sinha R, Cloninger CR, Parsian A. Linkage disequilibrium and haplotype analysis between serotonin receptor 1b gene variations and subtypes of alcoholism. Am J Med Genet B Neuropsychiatr Genet. 2003;121B(1):83–88.
Jensen KP, Covault J, Conner TS, Tennen H, Kranzler HR, Furneaux HM. A common polymorphism in serotonin receptor 1B mRNA moderates regulation by miR-96 and associates with aggressive human behaviors. Mol Psychiatry. 2009;14(4):381–389.
Contini V, Bertuzzi GP, Polina ER, et al. A haplotype analysis is consistent with the role of functional HTR1B variants in alcohol dependence. Drug Alcohol Depend. 2012;122(1–2):100–104.
Plemenitas A, Kastelic M, O Porcelli S, Serretti A, Dolžan V, Kores Plesnicar B. Alcohol dependence and genetic variability in the serotonin pathway among currently and formerly alcohol-dependent males. Neuropsychobiology. 2015;72(1):57–64.
Cook EH, Fletcher KE, Wainwright M, Marks N, Yan SY, Leventhal BL. Primary structure of the human platelet serotonin 5-HT2A receptor: identify with frontal cortex serotonin 5-HT2A receptor. J Neurochem. 1994;63(2):465–469.
Mercado CP, Kilic F. Molecular mechanisms of SERT in platelets: regulation of plasma serotonin levels. Mol Interv. 2010;10(4):231–241.
Ruchkin VV, Koposov RA, af Klinteberg B, Oreland L, Grigorenko EL. Platelet MAO-B, personality, and psychopathology. J Abnorm Psychol. 2005;114:477–482.
Serebruany VL, El Mouelhi M, Pfannkuche HJ, Rose K, Marro M, Angiolillo DJ. Investigations on 5-HT4 receptor expression and effects of tegaserod on human platelet aggregation in vitro. Am J Ther. 2010;17(6):543–552.
Stratz C, Trenk D, Bhatia HS, Valina C, Neumann FJ, Fiebich BL. Identification of 5-HT3 receptors on human platelets: increased surface immunoreactivity after activation with adenosine diphosphate (ADP) and thrombin receptor-activating peptide (TRAP). Thromb Haemost. 2008;99(4):784–786.
Zhang ZJ, Wang D, Man SC, et al. Platelet 5-HT(1A) receptor correlates with major depressive disorder in drug-free patients. Prog Neuropsychopharmacol Biol Psychiatry. 2014;53:74–79.
Mück-Šeler D, Pivac N. Serotonin. Period Biol. 2011;113:29–41.
Massot O, Rousselle JC, Fillion MP, Januel D, Plantefol M, Fillion G. 5-HT1B receptors: a novel target for lithium. Possible involvement in mood disorders. Neuropsychopharmacology. 1999;21(4):530–541.
Warkentin TE, Arnold DM, Nazi I, Kelton JG. The platelet serotonin-release assay. Am J Hematol. 2015;90(6):564–572.
Oreland L. Platelet monoamine oxidase, personality and alcoholism: the rise, fall and resurrection. Neurotoxicol. 2004;25(1–2):79–89.
Yubero-Lahoz S, Robledo P, Farré M, de Latorre R, Torre R. Platelet SERT as a peripheral biomarker of serotonergic neurotransmission in the central nervous system. Curr Med Chem. 2013;20(11):1382–1396.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington DC: American Psychiatric Press; 1994.
Pivac N, Mück-Seler D, Barisić I, Jakovljević M, Puretić Z. Platelet serotonin concentration in dialysis patients with somatic symptoms of depression. Life Sci. 2001;68(21):2423–2433.
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193(1):265–275.
Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16(3):1215.
Faul F, Erdfelder E, Lang AG, Buchner A. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods. 2007;39(2):175–191.
Sempere LF, Freemantle S, Pitha-Rowe I, Moss E, Dmitrovsky E, Ambros V. Expression profiling of mammalian microRNAs uncovers a subset of brain-expressed microRNAs with possible roles in murine and human neuronal differentiation. Genome Biol. 2004;5(3):R13.
Smalheiser NR, Lugli G, Rizavi HS, et al. MicroRNA expression in rat brain exposed to repeated inescapable shock: differential alterations in learned helplessness vs. non-learned helplessness. Int J Neuropsychopharmacol. 2011;14(10):1315–1325.
Furay AR, Neumaier JF, Mullenix AT, Kaiyala KK, Sandygren NK, Hoplight BJ. Overexpression of 5-HT(1B) mRNA in nucleus accumbens shell projection neurons differentially affects microarchitecture of initiation and maintenance of ethanol consumption. Alcohol. 2011;45(1):19–32.
Hoplight BJ, Sandygren NA, Neumaier JF. Increased expression of 5-HT1B receptors in rat nucleus accumbens via virally mediated gene transfer increases voluntary alcohol consumption. Alcohol. 2006;38(2):73–79.
Bannai M, Fish EW, Faccidomo S, Miczek KA. Anti-aggressive effects of agonists at 5-HT1B receptors in the dorsal raphe nucleus of mice. Psychopharmacology. 2007;193(2):295–304.
Drago A, Alboni S, Brunello N, Nicoletta B, de Ronchi D, Serretti A. HTR1B as a risk profile maker in psychiatric disorders: a review through motivation and memory. Eur J Clin Pharmacol. 2010;66(1):5–27.
Sari Y. Serotonin1B receptors: from protein to physiological function and behavior. Neurosci Biobehav Rev. 2004;28(6):565–582.
Berg KA, Clarke WP. Regulation of 5-HT(1A) and 5-HT(1B) receptor systems by phospholipid signaling cascades. Brain Res Bull. 2001;56(5):471–477.
Tournois C, Mutel V, Manivet P, Launay JM, Kellermann O. Cross-talk between 5-hydroxytryptamine receptors in a serotonergic cell line. Involvement of arachidonic acid metabolism. J Biol Chem. 1998;273(28):17498–17503.
Montañez S, Munn JL, Owens WA, Horton RE, Daws LC. 5-HT1B receptor modulation of the serotonin transporter in vivo: studies using KO mice. Neurochem Int. 2014;73:127–131.
Bailly D, Vignau J, Lauth B, et al. Platelet serotonin decrease in alcoholic patients. Acta Psychiatr Scand. 1990;81(1):68–72.
Pivac N, Mück-Seler D, Mustapić M, Nenadić-Sviglin K, Kozarić-Kovacić D. Platelet serotonin concentration in alcoholic subjects. Life Sci. 2004;76(5):521–531.
Schmidt LG, Dufeu P, Heinz A, Kuhn S, Rommelspacher H. Serotonergic dysfunction in addiction: effects of alcohol, cigarette smoking and heroin on platelet 5-HT content. Psychiatry Res. 1997;72(3):177–185.
Javors M, Tiouririne M, Prihoda T. Platelet serotonin uptake is higher in early-onset than in late-onset alcoholics. Alcohol Alcohol. 2000;35(4):390–393.
Lowery CL, Elliott C, Cooper A, et al. Cigarette smoking-associated alterations in serotonin/adrenalin signaling pathways of platelets. J Am Heart Assoc. 2017;6(5):e005465.
Nenadic-Sviglin K, Nedic G, Nikolac M, et al. Suicide attempt, smoking, comorbid depression, and platelet serotonin in alcohol dependence. Alcohol. 2011;45(3):209–216.
Patkar AA, Gopalakrishnan R, Berrettini WH, Weinstein SP, Vergare MJ, Leone FT. Differences in platelet serotonin transporter sites between African-American tobacco smokers and non-smokers. Psychopharmacology. 2003;166(3):221–227.
Fowler JS, Volkow ND, Wang GJ, et al. Inhibition of monoamine oxidase B in the brains of smokers. Nature. 1996;379(6567):733–736.
Fowler JS, Volkow ND, Wang GJ, et al. Brain monoamine oxidase A inhibition in cigarette smokers. Proc Natl Acad Sci U S A. 1996;93(24):14065–14069.
Berlin I, M. Anthenelli R. Monoamine oxidases and tobacco smoking. Int J Neuropsychopharm. 2001;4(01):33–42.
Whitfield JB, Pang D, Bucholz KK, et al. Monoamine oxidase: associations with alcohol dependence, smoking and other measures of psychopathology. Psychol Med. 2000;30(2):443–454.


Liam Payne is the latest celebrity to express concerns for his home due to the California wildfires.
The former One Direction singer has expressed his condolences for those affected by the devastating Woolsey Fire and believes he could lose his own home in the tragedy.
The 25-year-old tweeted on Saturday: My heart goes out to everyone caught in the fires please stay safe and dont take unnecessary risks.
I think Im about to lose my house and its memories even worse tragically people have died thoughts and prayers with everyone its been a tough day lets hope it gets better.
Liam is said to own a sprawling mansion in the Calabasas area of Los Angeles, which he bought in 2015 for a reported £10 million.
The 9,659-square foot property boasts five bedrooms, eight bathrooms, a spa, vineyard and a meditation centre.
In July, it was reported that Liam was renting the mansion out for a cool £46,000 a month. The Strip That Down singer was previously hoping to sell the property and listed it back on the market for £9.8 million.
Its where Liam spent a significant amount of time with his ex-girlfriend Cheryl, when she was pregnant with their one-year-old son Bear.
Many other celebrities have been affected by the California wildfires, including Kim Kardashian and Kanye West who also have a home in Calabasas.
The couples property caught fire on Friday afternoon and Kim, 38, was said to have evacuated their entire security team.
However, the reality TV star later confirmed that the fire had been contained and nobody was hurt.
Unfortunately, Kims stepfather Caitlyn Jenner suffered great loss with the former Olympic athletes Malibu home reportedly burning down.
Will Smith posted terrifying footage of billowing plumes of smoke near his $42 million house, while Lady Gaga also shared similar footage.
Can cruise ships help repair the damage wrought by Caribbean storms?
Last September, Hurricane Irma was recorded as the strongest ever storm in the open Atlantic. Winds ..


A man has died in a three-vehicle crash in Cornwall.
Two cars and a lorry were involved in the crash on the eastbound A30, two miles from the Victoria Interchange, in the early hours of Saturday.
Devon and Cornwall Police said one car's driver was pronounced dead at the scene, two people in another car suffered "moderate injuries", and the lorry driver was unhurt.
The force has appealed for witnesses or dashcam footage of the crash.


text:
Q: Javascript Understanding functions I am having trouble trying to understand the code below. I'm coming from a Java background. How should I read this? Is there any good Java > Javascript books/tutorials I should be looking at?
function sum(numbers) {
   var total = 0;

   forEach(numbers, function (number) {
      total += number;
   });

   return total;
}
show(sum([1, 10, 100]));

Extracted from http://eloquentjavascript.net/chapter6.html
I'm looking at the forEach(numbers, function (number)... code. Where will the anonymous function get the 'number' from?

A: Look at the source of forEach:
function forEach(array, action) {
  for (var i = 0; i < array.length; i++)
    action(array[i]);
}

forEach accepts two arguments: an array and a callback (i.e. a function). You can see that it invokes the callback in a loop, passing it the "current" array element as an argument each time. That's what goes into the formal parameter number of the callback.
To put this another way -- you can easily understand this:
function hello(what) {
    alert("Hello " + what);
}

hello("world");

If you use hello as a callback you arrive at code much like the one you show:
function say(callback, what) {
    callback(what);
}

say(hello, "world");

See it in action.
Finally, you would likely benefit from examining how callbacks work and what their uses are; here is another answer of mine on this subject.

A: It gets the number from numbers. What the foreach says is that for each element in numbers call the anonymous function with that element. Then that element is called number but it could be called anything.

A: What you're being confused by is that you're not seeing the underlying mechanism of forEach... if you were to pry it open you'd see that that function expects an anonymous function as its second parameter, and it will pass whatever it needs to into IT. So you can expect that parm to be populated when you run your function.  It's definitely jarring when you come at it from a different language, but you have to trust that things work the way they're designed to work.

redpajama_set_name: RedPajamaStackExchange


text:
Wednesday 23 October 2019, 7.30pm
FROM HERE RECORDS PRESENT: SANDRA KERR & JOHN FAULKNER
Sandra Kerr & John Faulkner, best known for the music and songs of the much loved Bagpuss TV shows, come together after 45 years to present an evening of new and old music, both traditional & self-penned material - some of a distinctly political nature. Both have long and distinguished careers in folk music, having been mentored by Ewan MacColl and Peggy Seeger in the Critics Group through the 1960s and 1970s. Since then, John has worked with the best in Irish traditional music, appearing on over fifteen albums (four of which he either produced or co-produced), and having huge success with his song about Nelson Mandela 'Lion in a Cage' while working with De Danaan. Sandra, an EFDSS gold badge holder, is widely acclaimed for her work with Sisters Unlimited, as a feminist song-writer of note, as a vocal trainer and folk choir director, and for her work with young musicians as a lecturer on the Newcastle Folk Degree.
From Here Records is the label of Stick In The Wheel. It exists to further the reach of traditional and roots music that runs deep throughout the cultures of this country.
Delfina Muñoz de Toro + NEUMES
£10 £8 Advance £6 MEMBERS
Joshua Burkett + Ed Yazijian + Jon Collin
£10 £8 Advance FREE FOR MEMBERS
25 Aug 2019 – 7:30PM
William Tyler + Heather Woods Broderick
£18 £15 (SEE TICKETS)

redpajama_set_name: RedPajamaCommonCrawl


text:
Franchises for Sale in Maitland, FL
Discover business opportunities, in or around Maitland, with well-established brands, who are looking for people like you to help them grow.
As of the 2010 United States Census, Maitland, located in the Sunshine State, had a total population of 14,931 people. This makes Maitland the one hundred thirteenth-most populated city in the state of FL.
City Statistics and Other Information About Maitland
From a total population of 14,931, Maitland has a median age of 39.9. The average age of males, in Maitland, is 37.4 while the average age of females is 41.8. When you compare this to median age of Florida, Maitland is 1.3 years younger.
The median income of individuals, in Maitland, is $39,681 while the average household income is $69,080. When comparing the median income of people living in Maitland to the rest of Florida, the average income in Maitland is $13,182 more.
County Name Orange County
Explore Franchises For Sale in Florida Now


text:
See Related Anthropology Journals
Cultures of Technology and the Quest for Innovation
Edited by Helga Nowotny
ISBN 978-1-84545-116-5 25% OFF! $120.00/£85.00 $90.00/£63.75 Hb Published (February 2006)
ISBN 978-1-84545-117-2 25% OFF! $29.95/£21.00 $22.46/£15.75 Pb Published (February 2006)
"…a book that is fundamental to the understanding of technologically developed societies… Innovation matters. Culture matters. And only an understanding of the links between culture and innovation can help us make sense of the world we are building." • Technology and Culture
Underlying the current dynamics of technological developments, their divergence or convergence and the abundance of options, promises and risks they contain, is the quest for innovation, the contributors to this volume argue. The seemingly insatiable demand for novelty coincides with the rise of modern science and the onset of modernity in Western societies. Never before has the Baconian dream been so close to becoming reality: wrapped into a globalizing capitalism that seeks ever expanding markets for new products, artifacts and designs and new processes that lead to gains in efficiency, productivity and profit. However, approaching these developments through a wider historical and cultural perspectives, means to raise questions about the plurality of cultures, the interaction between "hardware" and "software" and about the nature of the interfaces where technology meets with economic, social, legal, historical constraints and opportunities. The authors come to the conclusion that inside a seemingly homogenous package and a seemingly universal quest for innovation many differences remain.
Helga Nowotny, who has a doctorate in law from the University of Vienna and a Ph.D. in sociology from Columbia University, New York, was Professor of Social Studies of Science at ETH Zurich since and Director of Collegium Helveticum. Currently she is Chair of the European Research Advisory Board (EURAB) of the European Commission and Director of the post-doctorate Branco Weiss Fellowship. She was Executive Director of the European Center in Vienna, which she founded, and for seven years Chairperson of the Standing Committee for the Social Sciences of the European Science Foundation.
Subject: General Anthropology General History
LC: HC79.T4 C85 2006
SOC002000 SOCIAL SCIENCE/Anthropology/General;
HIS000000 HISTORY/General
JHM Anthropology;
HBAH Historiography
Introduction: The Quest for Innovation and Cultures of Technology
Helga Nowotny
PART I: ON THE RELATIONSHIP BETWEEN CULTURE, TECHNOLOGY, AND INNOVATION
Chapter 1. Culture and Innovation
Thomas P. Hughes
Chapter 2. The Unintended Consequences of Innovation: Change and Community at MIT
Rosalind Williams
Chapter 3. The Vulnerability of Technological Culture
Wiebe E. Bijker
PART II: THE GENDER BIAS OF TECHNOLOGICAL INNOVATIONS
Chapter 4. Culture of Gender, and Culture of Technology: The Gendering of Things in France's Office Spaces between 1890 and 1930
Delphine Gardey
Chapter 5. Suspending Gender? Reflecting on Innovations in Cyberspace
PART III: PLURALIST HISTORIES OF SCIENCE, INNOVATION, AND WAR
Chapter 6. Innovation, Diverse Knowledges, and the Presumed Singularity of Science
John V. Pickstone
Chapter 7. Scientists on the Battlefield: Cultures and Conflicts
Jean-Jacques Salomon
PART IV: THE ADOPTION OF INNOVATIONS IN DIFFERENT CULTURAL CONTEXTS
Chapter 8. From Prophecies of the Future to Incarnations of the Past: Cultures of Nuclear Technology
Patrick Kupper
Chapter 9. The Mining Industry in Traditional China: Intraand Intercultural Comparisons
Hans Ulrich Vogel
Epilogue: Interdisciplinarity and the Innovation Process How to Organize Spaces of Translation, or, the Politics of Innovation
Joachim Nettelbeck


Flight layover? In between islands? Only have 12 hours to yourself after a business meeting? Whatever your reason for being in Honolulu for only a few short hours, there is no better place to take advantage of your newfound free time than Hawaii's cosmopolitan capital.
Whatever your interests are, there is a lot to do in the itinerary below to fill the next 12 hours.


(1) (Ozeias, Ozias, Codex Vaticanus a b): The son of Micah, a Simeonite, one of the 3 rulers of Bethulia in the days of Judith (Judith 6:15,16; 7:23; 8:9 ff; 10:6).
(2) (Ozeias, Codex Vaticanus and Swete; the King James Version has Ezias (1 Esdras 8:2), following Codex Alexandrinus Ezias): An ancestor of Ezra (1 Esdras 8:2; 2 Esdras 1:2) = "Uzzi" of Ezr 7:4; 1 Ch 6:51.
(3) Head of a family of temple-servants who returned with Zerubbabel (1 Esdras 5:31) = "Uzza" of Ezr 2:49; Neh 7:51.
(4) Greek form of UZZIAH (which see) in Mt 1:8,9 the King James Version. A king of Judah.
Orr, James, M.A., D.D. General Editor. "Definition for 'OZIAS'". "International Standard Bible Encyclopedia". bible-history.com - ISBE; 1915.


Taping drywall seems like a mindless job but it requires some experience to do it correctly and to achieve the best results. The Teel Tape makes it super easy for anyone to mud their drywall tape before application.
Simply attach a roll of drywall tape, load the mudbox with mud, then roll out desired amount of tape and cut and its ready to go. To clean just wipe out the box in water.
Thanks Paul and Bev for the demonstration at the 2010 Builders' Show.


DZIK, J. 1981. Evolutionary relationships of the early Palaeozoic 'cyclostomatous' Bryozoa. Palaeontology, 24, 4, 827–861.
Wolinella baltica gen. et sp. n. from the Arenig of Baltic province is the oldest known single-walled bryozoan. It is characterized by cylindrical zooecia, non-pseudoporous exterior wall, and well-developed communication canals between zooecia. Wolinella is a supposed ancestor of Corynotrypa, which occurs in the lowermost Llanvirn. Evolution from the latter genus to Dentalitrypa and to the boring ctenostome Ropalonaria originated in the Caradoc. The tendency to develop a common bud in Wolinella suggests that Diploclema also may be its descendant. The genera Sagenella, Clonopora, and Kukersella, which form a morphological sequence of increasing pseudopore concentration and complexity of communication canals may have also originated from Wolinella-like encrusting forms. All post-Palaeozoic Cyclostomata could have been derived from Kukersella-like bryozoans. The morphological sequence composed by genera Wolinella, Flabellotrypa, and Ceramopora illustrates evolutionary development of colony-wide hypostegal coelom from a marginal one. Ceramopora shows a well-developed single-walled ancestrula with a large hemispherical protoecium. Hederellida are somewhat isolated among Palaeozoic bryozoans in their morphology and astogeny. They resemble Recent phylactolaemate Plumatellida both in the mode of budding, with specialized stolozooids, and shape of zooecia. Corynotrypidae fam. n., Wolinella gen. n., Wolinella baltica sp. n., W. polonica sp. n., W. brevis sp. n., Dentalitrypa infundibuliformis sp. n., Clonopora primaeva sp. n., and Kukersella erratica sp. n. are proposed.


text:
#ifndef _M68K_SEMAPHORE_HELPER_H
#define _M68K_SEMAPHORE_HELPER_H

#include <linux/config.h>

/*
 * These two _must_ execute atomically wrt each other.
 */
static inline void wake_one_more(struct semaphore * sem)
{
	atomic_inc(&sem->waking);
}

static inline int waking_non_zero(struct semaphore *sem)
{
	int ret;
	unsigned long flags;

	spin_lock_irqsave(&semaphore_wake_lock, flags);
	ret = 0;
	if (atomic_read(&sem->waking) > 0) {
		atomic_dec(&sem->waking);
		ret = 1;
	}
	spin_unlock_irqrestore(&semaphore_wake_lock, flags);
	return ret;
}

/*
 * waking_non_zero_interruptible:
 *	1	got the lock
 *	0	go to sleep
 *	-EINTR	interrupted
 */
static inline int waking_non_zero_interruptible(struct semaphore *sem,
						struct task_struct *tsk)
{
	int ret;
	unsigned long flags;

	spin_lock_irqsave(&semaphore_wake_lock, flags);
	ret = 0;
	if (atomic_read(&sem->waking) > 0) {
		atomic_dec(&sem->waking);
		ret = 1;
	} else if (signal_pending(tsk)) {
		atomic_inc(&sem->count);
		ret = -EINTR;
	}
	spin_unlock_irqrestore(&semaphore_wake_lock, flags);
	return ret;
}

/*
 * waking_non_zero_trylock:
 *	1	failed to lock
 *	0	got the lock
 */
static inline int waking_non_zero_trylock(struct semaphore *sem)
{
	int ret;
	unsigned long flags;

	spin_lock_irqsave(&semaphore_wake_lock, flags);
	ret = 1;
	if (atomic_read(&sem->waking) > 0) {
		atomic_dec(&sem->waking);
		ret = 0;
	} else
		atomic_inc(&sem->count);
	spin_unlock_irqrestore(&semaphore_wake_lock, flags);
	return ret;
}

#endif

redpajama_set_name: RedPajamaGithub


To create an account, simply enter the registration form below. All required form fields are marked with an asterisk (*).
Yes, I would like to subscribe to littlecookie newsletter. Yes, I have read and agreed to the Terms & Conditions.


My interest in this area relates to my wish to consider the ethics of medical practice. In this instance, my interest is in public transparency of any financial transactions between healthcare workers/academics and wider commerce.
I should make it very clear: I understand that conflicts of interest are part of life.
My petition to the Scottish Government for A Sunshine Act is a request that transparency surrounding (non NHS) financial payments made to all those involved in healthcare (including academics and all those involved in medical education) to be a requirement by statute. In terms of the United Kingdom, I have suggested that Scotland might lead the way on this. America and France have introduced a Sunshine Act.
NHS Scotland has failed (in my view, most miserably) to follow Scottish Government guidance HDL 62. This Government Circular was issued to all NHS Scotland Chief Executives over a decade ago. The Scottish Government has, since my petition which was based on my research, accepted widespread failure across NHS Scotland to follow HDL 62.
Perhaps the Cabinet Secretary for Health, Wellbeing and Sport, will look upwards to the roof of the Corn Exchange which is celebrated for its "massive single-span". Sponsored Medical Education also celebrates a massive span across NHS Scotland. Please do not be fooled into thinking that this, like the Corn Exchange and the bartering it once housed, may be a thing of the past.
So go on, if you dare, be like me and shout about this from the roof-top! If we reach for the sunshine perhaps we might all be a little healthier. Sunshine on Leith!


text:
'use strict';

var util = require('../../common/');

/**
 * A Record represents a set of merged data. The hierarchy of a normalized Collection
 * can be traversed as normal using parent() and child() calls:
 *    - RecordSet: The root of a normalized collection; a set of merged Firebase paths
 *    - Record: A child of RecordSet obtained by calling .child(recordId)
 *    - RecordField: A child of Record or RecordField which represents a wrapped Firebase path (no longer normalized)
 *
 * We wrap all of these levels, including the RecordField's, so that the
 * parent() and child() calls work as expected and return the normalized chain instead
 * of reverting to the underlying Firebase instances.
 *
 * AbstractRecord provides common functionality around observables, event handling, and field maps
 * used by all three implementations.
 *
 * @param fieldMap the field map applied to Record objects
 * @param {String} name
 * @param {String} url
 * @constructor
 */
function AbstractRecord(fieldMap, name, url) {
  var self = this;
  self._ref = null;
  self._map = fieldMap;
  self._name = name;
  self._url = url;
  self.lastMergedValue = util.undef; // starts undefined since first value may be null
  self._obs = new util.Observable(
    ['child_added', 'child_removed', 'child_changed', 'child_moved', 'value'],
    {
      onAdd: function(event) {
        var count = self._obs.getObservers(event).length;
        if( count === 1 ) {
          self._start(event, self._obs.getObservers().length);
        }
      },
      onRemove: function(event) {
        var count = self._obs.getObservers(event).length;
        if( count === 0 ) {
          self._stop(event, self._obs.getObservers().length);
        }
      }
    }
  );
}

AbstractRecord.prototype = {
  /**
   * Called internally by AbstractRecord whenever the first listener
   * is attached for a given event. Also includes a count of the
   * total number of listeners
   *
   * @param {string} type
   * @param {int} totalListeners
   * @abstract
   */
  _start: abstract('_start'),

  /**
   * Called internally by AbstractRecord whenever
   * the last listener is detached for a given type. Also provides
   * the total listener count
   *
   * @param {string} type
   * @param {int} totalListeners
   * @abstract
   */
  _stop:  abstract('_stop'),

  /**
   * Should return true if the snapshots provided contain the child key and if it
   * exists in the fields for this record type.
   *
   * @param {Array} snapshots
   * @param {string} key
   * @abstract
   */
  hasChild: abstract('hasChild'),

  /**
   * Given a list of snapshots to iterate, returns the valid keys
   * which exist in both the snapshots and the field map, in the
   * order they should be iterated.
   *
   * Calls iterator with a {string|number} key for the next field to
   * iterate only.
   *
   * If iterator returns true, this method should abort and return true,
   * otherwise it should return false (same as Snapshot.forEach).
   *
   * @param {Array} snaps
   * @param {function} iterator
   * @param {object} [context]
   * @return {boolean} true if aborted
   * @abstract
   */
  forEachKey: abstract('forEach'),

  /**
   * When .child() is called on a Snapshot, this will reconcile
   * the correct refs and data for each child and return an array
   * containing the child snapshots for the specified key. For
   * a RecordSet, this should return children for all the fields
   * in the field map. For a Record, this should return a child
   * from the correct snapshot, or the first if the child is not
   * in the map.
   *
   * @param {Array} snaps
   * @param {string} key
   * @abstract
   */
  getChildSnaps: abstract('getChildSnaps'),

  /**
   * This should take all the data from a set of snapshots and
   * merge it together appropriately. For a RecordSet, this should
   * return records ordered by the first reference. For a Record,
   * this should return the fields in the field map.
   *
   * @param {Array} snaps
   * @param {boolean} isExport
   * @abstract
   */
  mergeData: abstract('mergeData'),

  /**
   * Returns the specific implementing class for this instance.
   *
   * @returns {Function}
   */
  getClass: abstract('getClass'),

  /**
   * Saves data back to the correct paths
   *
   * @param data
   * @param {Object} props an object with callback[, context][, isUpdate]
   */
  saveData: abstract('saveData'),

  /**
   * Returns the priority for a given set of snapshots
   * @param {Array} snapshots
   * @return {int|string}
   */
  getPriority: abstract('getPriority'),

  /**
   * This returns the appropriate AbstractRecord type in the chain. Note that references
   * created here will not be usable until setRef() is called, so this should only be used
   * for passing into a Query. Use .child() for everything else.
   *
   * @param {String} childName
   * @return {AbstractRecord}
   */
  makeChild: abstract('makeChild'),

  /**
   * @param {string} event
   * @param {function} callback
   * @param {function} [cancel]
   * @param {object} [context]
   */
  watch: function(event, callback, cancel, context) {
    this._obs.observe(event, callback, cancel, context);
  },

  /**
   * @param {string} event
   * @param {function} [callback]
   * @param {object} [context]
   */
  unwatch: function(event, callback, context) {
    this._obs.stopObserving(event, callback, context);
  },

  getFieldMap: function() {
    return this._map;
  },

  getPathManager: function() {
    return this._map.getPathManager();
  },

  setRef: function(ref) {
    this._ref = ref;
  },

  getRef: function() {
    return this._ref;
  },

  /**
   * @param {String} key
   * @returns {Record}
   */
  child: function(key) {
    return this.getRef().ref.child(key).$getRecord();
  },

  /**
   * Returns an appropriate path name or merged set of names for this record type.
   * @return {String}
   */
  getName: function() {
    return this._name;
  },

  /**
   * Returns a Firebase URL or a merged set of URLs for the Record
   * @return {String}
   */
  getUrl: function() {
    return this._url;
  },

  trigger: function(snapshotFactory) {
    util.log.debug('AbstractRecord._trigger: %s', snapshotFactory.toString());
    this._obs.triggerEvent(snapshotFactory.event, snapshotFactory.create(this.getRef()));
  },

  /**
   * @param {object} error
   */
  _cancel: function(error) {
    util.error(error);
    this._obs.abortObservers(error);
  }
};

function abstract(method) {
  return function() {
    throw new Error('Classes implementing AbstractRecord must declare ' + method);
  };
}

module.exports = AbstractRecord;


Facebook-owned Oculus is following up the release of its $199 standalone virtual reality headset with a new bundle targeting big businesses.
Starting today, the Oculus Go business bundle is now available, a package designed for companies that want to deploy numerous headsets across the organization. The $299 bundle includes a 64GB headset and controller, an international wall charger, two facial pads, an extended commercial warranty and dedicated support.
The consumer version of the 64GB Oculus Go sells for $249 — $199 for the 32GB option — but does not include some of the accessories and features offered in the bundle.
Oculus Go represents an important step forward for virtual reality. It is unique as a standalone headset that doesn't need to be tethered to a PC or connected to a smartphone and also one of the least expensive options out there.
Conventional wisdom assumes that gaming and entertainment represent the main outlets for headsets like the Oculus Go, but virtual reality has plenty of business applications as well. Oculus frames its business bundle as an option for virtual training, demos and meetings.
Oculus is not alone in trying to make its virtual reality headsets into sought after enterprise products. The most notable is Microsoft, with the HoloLens mixed reality headset.


I hope you are enjoying December. It's a magical time of year where everyone seems to be joyful and in a happier mood. It's hard to believe but 2012 is almost over and a new year is beginning. Claude Hamilton, my mentor, would often tell me to start preparing myself now to hit the new year with momentum. To keep my "personal momentum" up during the holidays, so that when January hit I didn't miss a beat.
1. Focus & Purpose. You must have a goal! If you are truly focused, you will recognize when you need to give up a good opportunity in the moment so you can receive the best in the long run. As my business grew and I began experiencing success, many people wanted to know more on how I was achieving this. Many opportunities surfaced for me to speak publicly and these gigs paid extremely well. In the short term, I was making good money but I could also recognize that this same opportunity was causing my core business to suffer. I realized that these same speaking engagements were detrimental to my main focus; that forced me to make a tough decision. I made a pact with myself: no more than 1 speaking engagement per month in lieu of every weekend. That turned out to be one of the wisest things I ever did for my business. Today, my business takes way better care of me than these speaking engagement ever could. Despite the short term gratification, I maintained my purpose.
2. Success & Excellence. Spend 30 minutes with a successful person and it will become obvious to you that they always seek to self-improve. Get yourself and your pride out of the way! As soon as you begin thinking that you know it all, you are going down. Kaput. You're done. When you are successful, you know that the destination is not the ultimate prize. It's the journey you're on. Being a Canadian, hockey is my my favorite sport. Did you ever notice how the best paid professionals on this planet still consistently go through drills to stay on top of their game? They know that the minute you quit striving, their competition can get the upper hand. The person who strives a bit longer usually wins the game. Those who become super heroes at their game always continue striving to become even better. They strive for excellence.
3. Success & Making People Feel Good. It doesn't matter what field you are in, making people feel good is a crucial component. If you lack in relationship skills, you will not be successful. Plain and simple. Business and people go together. To build our new home, Lana and I knew that we had to look at this as a 3-year project. We also knew that we needed to have great relationships with the contractor, the construction crew, the electricians, the plumbers, etc… People skills were important to us. We visited every other day and made the conscious effort to treat each person with the utmost respect. We got to know these people very well and they shared at the end how they enjoyed the project of working with us, one of the best they'd had yet. It impacted the quality of their work to the extent that they wanted to go that extra mile to please us even more. The project was a success – I attribute it all to the relationships we built and the people skills we used. It doesn't matter what type of business you do. Successful people always leave people feeling better about themselves when they leave their presence. I would definitely say that the most important thing about a building project is people skills.
4. Success & Responsibility. Growing up, my brother loved to play hockey and he was a goalie. As I was watching one day, his team lost. He came bursting off the ice immediately blaming the defencemen and grumbling on how his teammates were just terrible. He wasn't the one that let that puck go in the net! Those defencemen failed at defending him. What he failed to recognize is that he would never get better at his game as long as he didn't own the problem. Blaming others would hinder his growth as a goalie and sabotage his own success. As soon as he began blaming others, he gave his power away. I remember pointing out to him that the best goalies are usually the ones with the worst defencemen – forcing them to get even better! You always have 2 choices: blame others and believe it's not your problem OR you can take responsibility. Play a bit more to compensate for others and it will propel your success.
5. Success & New Challenges. Get out of your comfort zone! You get comfortable at your position and you soon quit taking on new challenges. That means you are getting stale. As a leader in what you do, you need to keep sharpening your axe. It's a competitive environment out there in the business world; you just can't quit growing and expanding. As I explained some above, it is not the destination that is the most important for leaders. It`s the journey. According to scientists and psychologists, humans are the happiest when they are striving. You would think it's when they get to the victory but no…. it's during the battle. The journey makes the victory sweet. So – get out of your comfort zone – now!!! Keep conquering new territory.
6. Success & Production. Did you ever hear the expression, 'Winners Win?' It's so easy to say you have no control over a situation or to believe there are insurmountable odds against you. When you take that position it's as sealed a deal as if you quit. And, you know you cannot quit and achieve success at the same time. Are you depressed over the situation you are in? As a leader you need to give vision to others. Don't stifle your production because a situation seems insurmountable. If you do, it disqualifies you to provide for that vision. If you're a winner, then win. It's unacceptable as a leader to quit when things get tough. Blame the situation, the weather or whatever. As soon as you believe it can't be fixed, you're done.
7. Success & Hard Work. Hard work makes a difference, yes… but doing the hard work with the right attitude is best. Working with a rotten attitude will get you rotten results no matter how hard you work. Strong leaders have strong work ethics and are willing to pay the price. They sacrifice to create sacred things. Whether it's financial freedom, family, success in sports or business – you will have to make sacrifices to create the sacred thing you are chasing.
8. Success & Personal Development. Successful people invest in themselves. When Abraham Lincoln was chopping wood for eight hours, he spent 7 hours sharpening his axe. As a leader, understand your value by investing in yourself and serving others. Increasing your value creates more territory in serving more people. An employer will pay for your professional development because it's an asset to the company. As an independent business owner or a leader, you have to be willing to do the same. I remember spending money (that I could have had a lot of fun with) on books, CDs and for travels to seminars. I invested in myself and in the long term, it created the lifestyle that I wanted.
9. Success & Perseverance. Do NOT give up when the going gets tough. To be successful, you have to think long-term! Do not let the ups and downs affect your outcome. We have had great years and some that were not so great. But, we persevered because quitting was not an option. That is how we got to harvest our crop down the road. Learn right away that you must persevere longer than your competition. Continually assault the problem; if you do long enough? You will conquer. Despite the untruths of the media, success is not instantaneous. You've got to keep the dream alive in your heart and work at it. Surround yourself with encouragers and like-minded people. Greatness is not accomplished overnight and God's delays are not His denials.
10. Success & Prioritization. Ever heard that busy people get things done? It is mostly true but as you add responsibilities to your life, you will have to prioritize. Time management is one of the most important element to your success. It's important to know what you will do and also to know what you will not do. I love hockey. I coached hockey, watched hockey and I played hockey. But I realized that watching and playing hockey was not helping me to reach my goals. I had to stop and prioritize. Putting hockey on the back burner for a bit was tough. If you give up what you really want in the future for what you can have in the moment, that is what will cause you to fail. I had to decide that watching hockey every day on TV would not build my success. Now that I've crossed to the other side, I can go see the Stanley Cup every year. Throw aside the things that won't help you to your goal.
That is great information. I know Claude & Orrin Woodward have had many years of achieving success in their personal lives and also helped many people become successful. These 10 traits aren't just theory, they are actual applied principles that have worked in their lives.
That's a wrap for today folks. Take these 10 principles and make 2013 the best year in your LIFE.
Awesome post Joce! Love the 10 traits to being successful. If anybody keeps working at these 10 they will eventually have success. The biggest thing people that strive for success have to realize is that perseverance is key because the harder it gets for them the closer they are to their success!
Awesome post Joce! I love the personal examples you used!
Merry Christmas and Happry New Year to you and Cynthia!
Great article Joce! These are such great reminders to go through, study and live by! It is so nice to see you take the time to write these great posts to help us grow and change. Keep up the great work and we can't wait to see all the great things 2013 will bring for us all!!
Awesome words to live by. I know Marie and myself are doing our best to keep momentum high. Also I'm really looking forward to our annual Christmas/new years goal setting date! 2013 is our year!
That is a great article by Claude. I absolutely love #7 and #9. Totally true that I you don't believe it can be fixed, you're done!
Merry Christmas to you & Cynthia, Kaleb & baby to be!
Merry Christmas to you & Al.
Thans for that amazing blog Joce. We feel ready to hit the new year and give it everything we can to make our business grows like crazy when we read stuff like that. You and Claude are such great leaders to follow. Can't wait to read more!
Great Blog Joce!..Thanks for sharing…We are getting ready to hit this New Year!!!! We really appreciate you guys..
Great post Joce. Just what a person needs heading into the holidays. So when they are over to run and build the business big in 2013. It is going to be a great year. Merry Christmas and look forward to seeing you again in the new year.
Awesome post! With the New Year just around the corner, the timing couldn't be better! I look forward to applying these principles in the upcoming year. 2013 will be an amazing year!!!
Thanks for sharing this great post with. With 2013 under way,I look forward to putting these in practice. Happy New Years!
choose?.I am trying to find issues to improve my web site!


text:
Gary's Blog: This & That
By Gary Dickman.
I wrote last week how starting this week we have football every week until mid-February. And that's a great thing. We still have a lot to look forward to with other sports as well.
This weekend will mark the end of the 2020 Tokyo Olympics. I've enjoyed most of what I've watched. The problem with the Olympics is that I never know what's on at what time, what channel an event is on, and if it's live or not. I know NBC is getting a lot of criticism with this, I'm not the only one. I don't think it's anyone's fault, though. Back in the day, the Olympics were only shown on one channel. NBC would have about 12-14 hours a day of coverage. Back then, I would have loved to have these extra channels, it would have been great to have a choice of what to watch.
With the time difference, Tokyo is 19 hours ahead of Hawaii, it's made things difficult as well. I read two days ago that Simone Biles was going to compete on Tuesday in her last event, the balance beam. I didn't know what time, and just before I started writing this, she won a bronze medal. I didn't think she'd be competing at 1:00 a.m., Hawaii time. Same with team USA men's basketball. A big game vs Spain on Tuesday, what time, I didn't know. But at 11 p.m. on Monday night, the game was already over. At least Team USA won. So even though there's so much more to watch these days, it's hard to know what's live, and when and where I can see it.
Back to Simone Biles. A week ago we read she had an injury, and was unable to compete. In the days to follow, we heard about a new sports term, "The Twisties." It's a phenomenon that means when an athlete loses their sense of where they are in space. Wow. I said last week that gymnastics were one of the events I look forward to the most in the Olympics. To see the best in the world doing things that you'll see in a movie with stunt performers and magical cameras. Gymnastics isn't like a movie, it's real. But some of these great athletes make it look fake with their amazing, seemingly impossible performances. And now to know about the Twisties.
Bob Costas has a new show on HBO, "Back on the Record," and one of his guests this week was Aly Raisman, a former gold medal winner for Team USA. She said that the Twisties is actually very common, and that she and Simone have talked at length about it in the past. Having that feeling can easily result in a very serious injury, or getting paralyzed or worse. I'm surprised we haven't heard about this before. To me, it gives me an even greater appreciation of these world-class athletes. And to think, there are some that have criticized Biles for being a quitter and for failing her country and sport. Those morons just don't get it. How ignorant can you be? Charles Barkley was on the same show with Bob Costas and described these types of fans. I won't write the word, you'll have to watch the show. I couldn't agree more with Barkley in how he described some fans.
I know football is starting this week, but it seems like the NBA is becoming more like the NFL in that there's really no off season. The Finals are done, then we had the draft, this week it's free agency time, next week it's the summer league in Las Vegas. And next month training camp starts. The last five or six days have been exciting with all the player movement. And it really started when the Lakers traded for Russell Westbrook. My initial reaction was now the Lakers are the team to beat. After thinking about it the last few days, however, I'm not so sure. On paper, the Lakers Big 3 are as good as any other in the league, including Brooklyn's. But it's also about the fit, the chemistry, how these stars will play as a team. As great as the LA 3 are, I think it'll be a major challenge to make it work.
Russell Westbrook is a triple-double waiting to happen every night. That's mostly based on him having the ball in his hands the majority of the time. There's that LeBron guy too, and he's used to having the ball the majority of the time. With both guys probably having to give up the ball now, it takes away from how effective they'll be. I'm not talking about stats, I'm talking about their ability to take over games with the ball in their hands. If Westbrook has the ball, he's not giving it up with 15 seconds left on the shot clock. Unless a guy is immediately wide open, he'll try and create an opening by his creativity and finding an open teammate, often with less than 10 seconds on the shot clock. That's what LeBron does so well, too, that's just an example on how these stars might offset each other a little. Now it may work out well, and they could win a title next year. I think they'll go through some growing pains though.
Now I said back in 2010 when LBJ joined the Heat that it'll be hard to win, too many All-Stars on one team, and he and Dwyane Wade will have to really adjust for it to work. And it obviously did. The Heat went to four straight Finals , winning two of them. Some might say that only winning two was a failure. But those would be the same type of fans that criticize Simone Biles. The ones Charles Barkley described using the word I can't write here.


text:
Real Estate Strategy Track Record Commercial Real Estate Residential Real Estate Team Investor Contact Real Estate News
Shipping Strategy Track Record Maritime Investments Team Investor Contact Shipping News
Infrastructure Strategy Renewable Energies Industrial Opportunities Team Investor Contact Infrastructure News
Equity Story Highlights Strategy Corporate Profile Key Financial Figures
Publications Press and IR Releases Financial Reports Company Presentations
Share & Research Basic Information Share Performance Shareholder Structure Analysts
Annual General Meeting Actual /Recent Archive
Corporate Governance Basic Principles Management Board Supervisory Board Directors' Dealings
Contact & Calendar Contact Mailing List Financial Calendar
Palmaille 71
+49 (0) 40 - 380 22 - 4200
contact@mpc-capital.com
About us History Management Corporate Social Responsibility
Real Estate Shipping Infrastructure
Equity Story Publications Share & Research Annual General Meeting Corporate Governance Contact & Calendar
Press Releases Downloads Newsletter Contact
MPC Capital AG reports double-digit earnings growth in financial year 2017
- Initial portfolio of three medical centres in the Netherlands
- Pipeline for further growth with committed capital and further assets in the pipeline
Hamburg/Amsterdam, 13 March 2019 - MPC Capital AG (Deutsche Börse Scale, ISIN DE000A1TNWJ4) has launched a new healthcare strategy within its Real Estate asset unit. The new strategy, which has been implemented by MPC Capital's Dutch subsidiary Cairn Real Estate, has most recently reached the financial close of a capital raising, having secured a total of EUR 30 million in equity. Cairn Real Estate is set to leverage this capital to further grow the portfolio with the aim of reaching a total of circa EUR 70 million.
The initial investment and development portfolio consists of three medical centres across the Netherlands. In addition to these, the company has also initiated the development of a primary care medical centre in Alphen ad Rijn and the construction of a new private nursing home in Bodegraven.
Pieter Akkerman, Managing Director at Cairn Real Estate: "We are excited to have launched a new strategy that centres around the healthcare sector. It presents us with the opportunity to invest into a market which is experiencing increased opportunities that are still attractively priced. Throughout the Netherlands, we are seeing a rise in the demand for health services with a growing and ageing population that is suffering from a greater incidence of chronic diseases. In addition, there is a shift towards primary care from expensive inflexible hospitals and an increasing demand for smaller nursing homes rather than the large traditional nursing homes. This is fuelling the need for further healthcare assets in the country."
Together with international institutional investors, MPC Capital plans to purchase additional healthcare development and portfolio projects in the Netherlands.
About MPC Capital AG
MPC Capital AG is an internationally active asset and investment manager specialising in real asset investments. Together with its subsidiaries, the company develops and manages investment products for international institutional investors, family offices and professional investors. Its focus is on the asset categories Real Estate, Shipping and Infrastructure. MPC Capital AG has been quoted on the stock exchange since 2000 and has around 300 employees group-wide.
Hamburg, 15 February 2019 - Hamburg-based Asset and Investment Manager MPC Capital AG (Deutsche Börse, Scale, ISIN DE000A1TNWJ4) today releases its 2018 Annual Report. Preliminary figures announced on 1 February 2019 are hereby confirmed.
Earnings before taxes (EBT) rise by 11% to EUR 17.4 million
Consolidated net profit improved by 29% to EUR 13.2 million
EUR 1.1 billion in new assets added in 2017
Hamburg, 26 January 2018 - The Hamburg-based asset and investment manager MPC Capital AG (Deutsche Börse SCALE, ISIN DE000A1TNWJ4) continued to develop positively in the financial year 2017. According to preliminary figures pre-tax earnings (EBT) of the MPC Capital Group improved by 11% from EUR 15.7 million in the previous year to EUR 17.4 million in the financial year 2017. Net profit for 2017 rose by 29% to EUR 13.2 million (2016: EUR 10.2 million).
While consolidated sales of EUR 47.3 million were lower than in the previous year (EUR 53.8 million), additional EUR 12.3 million resulted from a transaction which, due to its structure, was not classified as sales but as other operating income. Taking into account this transaction, growth in the financial year 2017 was 11% compared to the previous year.
In 2017, MPC Capital was a co-investor in various investment projects with around EUR 30 million and thus tied up new assets in the areas of real estate, shipping and infrastructure worth around EUR 1.1 billion. The total transaction volume from acquisitions and sales amounted to EUR 2.6 billion. As of 31 December 2017, the Assets under Management (AuM) of the MPC Capital Group amounted to EUR 5.1 billion.
The financial assets of the Group increased to EUR 54.5 million as of 31 December 2017 (31 December 2016: EUR 29.3 million). A large part of the funds raised from two capital increases in 2016 could thus be successfully invested within approximately one and a half years. As a result, cash and cash equivalents as of 31 December 2017 decreased to EUR 28.9 million (31 December 2016: EUR 65.6 million). At 76%, the equity ratio remained at a high level as of the 2017 balance sheet date (31 December 2016: 70%).
While the 2017 financial year was marked by a number of significant exits, the focus in 2018 will be on linking up with new projects. On the basis of the envisaged growth in AuM, the Management Board expects a revenue growth of at least 10% and a disproportional rise in EBT.
Due to the promising development of the company, MPC Capital is evaluating various financing alternatives, including capital market options, in order to tap further growth opportunities. This can increase the attractiveness of MPC Capital shares and would support the financing of the further profitable growth of MPC Capital.
Note: The complete Annual Report 2017 of MPC Capital AG is expected to be published on 15 February 2018.
www.mpc-capital.com
Stefan Zenker
Head of Investor & Public Relations
+49 (40) 380 22 - 4347
s.zenker@mpc-capital.com
2019 © MPC Münchmeyer Petersen Capital AG


Applications are invited for a 10 PA post in Paediatric Neurosurgery based at the Royal Manchester Children's Hospital. The successful candidate will join a dynamic paediatric neurosurgery department composed of 5 Consultant Paediatric Neurosurgeons.
The Manchester Paediatric Neurosurgery Service provides tertiary level care for children with neurosurgical disorders throughout the North West of England. This is achieved through a region-wide PICU retrieval service for acute emergencies, a dedicated paediatric neuroscience inpatient facility on ward 78 and outpatient services provided at RMCH and through a network of outreach clinics across the region.
The team deliver a wide range of highly specialised and complex neurosurgical services, for example Neuro-oncology including neurosurgical support for the National Proton Therapy Service, Children's Epilepsy Surgical Service, Complex Spine, Paediatric Neurovascular, Foetal Management, Craniofacial and Trauma services.
In addition to the challenges of the role, we can offer you a commitment to teaching, education, research and audit. The post-holder will have experience in all areas of paediatric neurosurgery but will have a keen interest in developing a sub-speciality interest in neuro-oncology. The successful candidate will be on, or eligible to join, the Specialist Register for Neurosurgery, within 6 months of the Appointments Committee.
From 1st October 2017, Central Manchester University Hospitals NHS Foundation Trust (CMFT) and the University Hospital of South Manchester NHS Foundation Trust (UHSM) has joined together to create a new Foundation Trust which has been named Manchester University NHS Foundation Trust.
Our new organisation will provide a single hospital service across the city of Manchester and in 12- 18 months will also include the services currently provided by North Manchester General Hospital. These changes will make a real difference to the health outcomes and quality of life for the people of Manchester. That's why this really is an extremely exciting and challenging period in the delivery of health and social care in Greater Manchester and one that provides a wealth career opportunities for great people right across our Group.
Central Manchester University Hospitals NHS Foundation Trust (CMFT) and the University Hospital of South Manchester NHS Foundation Trust (UHSM) have joined together to create a new Foundation Trust, Manchester University NHS Foundation Trust (MFT). As a result, it's an extremely exciting and challenging period in the delivery of health and social care in Greater Manchester and one that provides a wealth of opportunity. Our new organisation will provide a single hospital service across the city of Manchester, where these changes will make a real difference to the health outcomes and quality of life for the communities we serve.


text:
180 years ago today - Jan 7, 1843
While riding from Springfield to Nauvoo after the end of Joseph Smith's extradition trial William Law sings a song he has written for the occasion: "And are you sure the news is true?/And are you sure he's free?/Then let us join with one accord,/And have a Jubilee/We'll have a Jubilee, My Friend/We'll have a Jubilee/With heart and voice we'll all rejoice/In that our Prophet's free." The song has 14 verses.
15 years ago today - Jan 27, 2008
125 years ago today - Jan 27, 1898; Thursday
135 years ago today - Jan 27, 1888 • Friday
155 years ago today - Jan 27, 1868
120 years ago today - Jan 26, 1903 (Monday)
135 years ago today - Jan 26, 1888 • Thursday
150 years ago today - Jan 25, 1873 (Afternoon)
170 years ago today - Jan 25, 1853. Tuesday.
170 years ago today - Jan 25, 1853 • Tuesday
125 years ago today - Sunday, Jan 23, 1898
120 years ago today - Thursday, Jan 22, 1903
190 years ago today - Jan. 22-23, 1833
180 years ago today - Jan 20, 1843 - Friday
95 years ago today - Jan 19-20,1928
125 years ago today - Jan 19, 1898; Wednesday
180 years ago today - Jan 18, 1843, Wednesday
50 years ago today - Jan. 16-25, 1973
135 years ago today - Jan 16, 1888 • Monday
5 years ago today - Jan 15, 2018
190 years ago today - Jan 13, 1833-14