Variation within the serotonin (5-HT) 5-HT2C receptor system aligns with vulnerability to cocaine cue reactivity

Cocaine dependence remains a challenging public health problem with relapse cited as a major determinant in its chronicity and severity. Environmental contexts and stimuli become reliably associated with its use leading to durable conditioned responses (‘cue reactivity'') that can predict relapse as well as treatment success. Individual variation in the magnitude and influence of cue reactivity over behavior in humans and animals suggest that cue-reactive individuals may be at greater risk for the progression to addiction and/or relapse. In the present translational study, we investigated the contribution of variation in the serotonin (5-HT) 5-HT_2C receptor (5-HT_2CR) system in individual differences in cocaine cue reactivity in humans and rodents. We found that cocaine-dependent subjects carrying a single nucleotide polymorphism (SNP) in the HTR2C gene that encodes for the conversion of cysteine to serine at codon 23 (Ser23 variant) exhibited significantly higher attentional bias to cocaine cues in the cocaine-word Stroop task than those carrying the Cys23 variant. In a model of individual differences in cocaine cue reactivity in rats, we identified that high cocaine cue reactivity measured as appetitive approach behavior (lever presses reinforced by the discrete cue complex) correlated with lower 5-HT_2CR protein expression in the medial prefrontal cortex and blunted sensitivity to the suppressive effects of the selective 5-HT_2CR agonist WAY163909. Our translational findings suggest that the functional status of the 5-HT_2CR system is a mechanistic factor in the generation of vulnerability to cocaine-associated cues, an observation that opens new avenues for future development of biomarker and therapeutic approaches to suppress relapse in cocaine dependence.     

Bildgebung bei epileptischen Enzephalopathien

Epileptic encephalopathies (EE) belong to the group of epilepsies which are associated with expressed cognitive and behavioral disturbances subsequent to epileptic activity. Despite the great importance of EE in the development and psychosocial adaptation of affected children, the mechanisms of cognitive deficits in EE have so far been insufficiently investigated. This review article summarizes the various neuroimaging studies which have tried to describe specific neuronal networks in EE. The results show that although epileptic activity in EE can be generated in different brain regions, specific propagation pathways and networks exist which are very characteristic for each different form of encephalopathy. In some forms of EE the epileptic activity seems to impair the integrity of the default mode network and possibly to interfere with cognitive function through this mechanism. Furthermore, there are further mechanisms underlying EE, e.g. abnormal connectivity patterns between brain regions which participate in the control of cognitive functions and impairment of the connections and activities in the thalamocortical network.     

Short-term inhibition of DPP-4 enhances endothelial regeneration after acute arterial injury via enhanced recruitment of circulating progenitor cells

Background

Endothelial injuries regularly occur in atherosclerosis and during interventional therapies of the arterial occlusive disease. Disturbances in the endothelial integrity can lead to insufficient blood supply and bear the risk of thrombus formation and acute vascular occlusion. At present, effective therapeutics to restore endothelial integrity are barely available.We analyzed the effect of pharmacological DPP-4-inhibition by Sitagliptin on endogenous progenitor cell-based endothelial regeneration via the SDF-1α/CXCR4-axis after acute endothelial damage in a mouse model of carotid injury.

Methods and Results

Induction of a defined endothelial injury was performed in the carotid artery of C57Bl/6 mice which led to a local upregulation of SDF-1α expression. Animals were treated with placebo, Sitagliptin or Sitagliptin + AMD3100. Using mass spectrometry we could prove that Sitagliptin prevented cleavage of the chemokine SDF-1α. Accordingly, increased SDF-1α concentrations enhanced recruitment of systemically applied and endogenous circulating CXCR4 + progenitor cells to the site of vascular injury followed by a significantly accelerated reendothelialization as compared to placebo-treated animals. Improved endothelial recovery, as well as recruitment of circulating CXCR4 + progenitor cells (CD133 +, Flk1 +), was reversed by CXCR4-antagonization through AMD3100. In addition, short-term Sitagliptin treatment did not significantly promote neointimal or medial hyperplasia.

Conclusion

Sitagliptin can accelerate endothelial regeneration after acute endothelial injury. DPP-4 inhibitors prevent degradation of the chemokine SDF-1α and thus improve the recruitment of regenerative circulating CXCR4 + progenitor cells which mediate local endothelial cell proliferation without adversely affecting vessel wall architecture.     

Improved survival for adolescents and young adults with Hodgkin lymphoma and continued high survival for children in the Netherlands: a population-based study during 1990–2015

Population-based studies that assess long-term patterns of incidence, major aspects of treatment and survival are virtually lacking for Hodgkin lymphoma (HL) at a younger age. This study assessed the progress made for young patients with HL (<25 years at diagnosis) in the Netherlands during 1990–2015. Patient and tumour characteristics were extracted from the population-based Netherlands Cancer Registry. Time trends in incidence and mortality rates were evaluated with average annual percentage change (AAPC) analyses. Stage at diagnosis, initial treatments and site of treatment were studied in relation to observed overall survival (OS). A total of 2619 patients with HL were diagnosed between 1990 and 2015. Incidence rates increased for 18–24-year-old patients (AAPC + 1%, P = 0·01) only. Treatment regimens changed into less radiotherapy and more ‘chemotherapy only’, different for age group and stage. Patients aged 15–17 years were increasingly treated at a paediatric oncology centre. The 5-year OS for children was already high in the early 1990s (93%). For patients aged 15–17 and 18–24 years the 5-year OS improved from 84% and 90% in 1990–1994 to 96% and 97% in 2010–2015, respectively. Survival for patients aged 15–17 years was not affected by site of treatment. Our present data demonstrate that significant progress in HL treatment has been made in the Netherlands since 1990.     

Rapid changes in the gut microbiome during human evolution

Humans are ecosystems containing trillions of microorganisms, but the evolutionary history of this microbiome is obscured by a lack of knowledge about microbiomes of African apes. We sequenced the gut communities of hundreds of chimpanzees, bonobos, and gorillas and developed a phylogenetic approach to reconstruct how present-day human microbiomes have diverged from those of ancestral populations. Compositional change in the microbiome was slow and clock-like during African ape diversification, but human microbiomes have deviated from the ancestral state at an accelerated rate. Relative to the microbiomes of wild apes, human microbiomes have lost ancestral microbial diversity while becoming specialized for animal-based diets. Individual wild apes cultivate more phyla, classes, orders, families, genera, and species of bacteria than do individual humans across a range of societies. These results indicate that humanity has experienced a depletion of the gut flora since diverging from Pan.The human microbiome is shaped by host genetics, environment, and lifestyle (1–3); thus, humanity''s unique evolutionary and cultural histories must have altered our associations with microorganisms (4). Despite intensive investigation of the microbiomes of humans spanning a range of geographic locations and cultures (5–7), how the composition of the microbiome has changed since humans diverged from other species, and since human populations diverged from one another, remains unclear, owing to a lack of knowledge about the microbiomes of ancestral hominid populations.Understanding how the composition of the human microbiome has changed over evolutionary time requires the inclusion of the microbiomes of phylogenetic outgroups (i.e., the African apes) into analyses of human microbiomes. Previous comparisons of the gut microbiomes of humans and the African apes have been restricted to just a few individuals per host species (8), precluding detection of the precise compositional differences that distinguish the microbiomes of the host species. Comparing the microbiomes of populations of chimpanzees, bonobos, gorillas, and humans while considering the phylogenetic relatedness among the hosts can reveal how the composition of the microbiome has changed since the host species diversified.Here we used a phylogenetic approach to identify the shifts in the composition of the microbiome that occurred along the lineages leading to the extant species of Homo and Pan. This analysis shows that humans across a range of cultures and geographies harbor microbiomes that are disproportionately divergent from those within wild apes. In particular, among the living hominid species, humans harbor uncharacteristically low levels of microbial diversity within their gut microbiomes.     

The PML domain of PML–RARα blocks senescence to promote leukemia

In most acute promyelocytic leukemia (APL) cases, translocons produce a promyelocytic leukemia protein–retinoic acid receptor α (PML–RARα) fusion gene. Although expression of the human PML fusion in mice promotes leukemia, its efficiency is rather low. Unexpectedly, we find that simply replacing the human PML fusion with its mouse counterpart results in a murine PML–RARα (mPR) hybrid protein that is transformed into a significantly more leukemogenic oncoprotein. Using this more potent isoform, we show that mPR promotes immortalization by preventing cellular senescence, impeding up-regulation of both the p21 and p19^ARF cell-cycle regulators. This induction coincides with a loss of the cancer-associated ATRX/Daxx–histone H3.3 predisposition complex and suggests inhibition of senescence as a targetable mechanism in APL therapy.Acute promyelocytic leukemia (APL) is characterized by chromosomal translocations involving retinoic acid receptor alpha (RARα) with a limited number of translocation partners. A common feature of APL-promoting fusion proteins is their ability to self-associate. Indeed, previous studies have shown that fusion of RARα with self-associating domains is sufficient to render RARα leukemogenic (1). In APL patients, the predominant leukemogenic protein found in 95–99% of cases is the result of the fusion of promyelocytic leukemia protein (PML) with RARα (human PML–RARα; hPR) (2, 3). RARα and PML are regulatory proteins implicated in multiple aspects of differentiation and development (4) and apoptosis and cellular senescence (5, 6), respectively. Despite speculation, the relevance of senescence in APL is not fully understood (7, 8).Current mouse models recapitulate many key features of the human disease, including a malignant promyelocytic phenotype and sensitivity to all-trans retinoic acid (ATRA), but suffer from incomplete penetrance and long latency until disease presentation (1, 9, 10). We reasoned that the relatively low leukemogenic activity of hPR in mice might be due to modest sequence identity between human and mouse PML (PML: 63% identity; RARα: 98% identity). Consistent with this notion, we have designed an “experimental oncoprotein” corresponding to the fusion of mouse PML with RARα (mPR), which produced myelocytic leukemia similar to hPR-induced murine APL (10) but with higher penetrance and shorter latency periods. Notably, expression of mPR disrupted PML nuclear bodies (PML-NBs), phenocopying hPR-induced APL (11, 12). We show here that senescence-related up-regulation of p21 and p19 is completely lost in primary murine bone marrow cells upon expression of mPR. Furthermore, we find that the assembly of the death domain associated protein (Daxx)–alpha thalassemia/mental retardation syndrome X-linked (ATRX) complex at PML-NBs is disrupted by mPR expression, implicating this PML–ATRX–Daxx (PAX) complex in cellular senescence and tumor suppressor activity for PML (13). This study provides experimental evidence for the relevance of PML-NB disruption in APL genesis.     

Stochastic dynamic causal modeling of working memory connections in cocaine dependence

Although reduced working memory brain activation has been reported in several brain regions of cocaine‐dependent subjects compared with controls, very little is known about whether there is altered connectivity of working memory pathways in cocaine dependence. This study addresses this issue by using functional magnetic resonance imaging‐based stochastic dynamic causal modeling (DCM) analysis to study the effective connectivity of 19 cocaine‐dependent subjects and 14 healthy controls while performing a working memory task. Stochastic DCM is an advanced method that has recently been implemented in SPM8 that can obtain improved estimates, relative to deterministic DCM, of hidden neuronal causes before convolution with the hemodynamic response. Thus, stochastic DCM may be less influenced by the confounding effects of variations in blood oxygen level‐dependent response caused by disease or drugs. Based on the significant regional activation common to both groups and consistent with previous working memory activation studies, seven regions of interest were chosen as nodes for DCM analyses. Bayesian family level inference, Bayesian model selection analyses, and Bayesian model averaging (BMA) were conducted. BMA showed that the cocaine‐dependent subjects had large differences compared with the control subjects in the strengths of prefrontal–striatal modulatory (B matrix) DCM parameters. These findings are consistent with altered cortical–striatal networks that may be related to reduced dopamine function in cocaine dependence. As far as we are aware, this is the first between‐group DCM study using stochastic methodology. Hum Brain Mapp 35:760–778, 2014. © 2012 Wiley Periodicals, Inc.     

Impact of gender and age on risk factor distribution and health perception: evaluation in a prospective population with heart disease

Aim

Several large surveys have highlighted the inadequate risk factor control in populations at elevated cardiovascular risk. These populations would substantially benefit from risk reduction and could demonstrate increased awareness for risk factor control. Risk factor segregation by gender has been previously described, yet its analysis in the medical field frequently omits sociodemographic variables, which could act as potential confounders.

Subject and methods

We analyzed risk factor prevalence in a population of 1,559 patients with severe coronary heart disease prior to a coronary bypass graft (CABG) surgery. Univariate correlations between risk factor type and frequency and gender were explored. Following, multivariable models were fitted to account for sociodemographic aspects associated with gender. Interaction terms were incorporated as fit. Lastly, the correlation between gender-specific risk factor profiles and their association with self-perceived health status was assessed.

Results

Our study identified gender as the main segregating variable for risk factors after multiple adjustments and inclusion of interaction terms. Obesity and hypertension displayed a significant association with the female population (OR?=?1.598, p?=?0.047 and OR?=?3.737, p?=?0.006, respectively), while smoking and elevated alcohol consumption prevailed in males (OR?=?1.77, p?=?0.038 and OR?=?2.768, p?=?0.013, respectively). Additionally, gender-specific analysis of health perception according to risk factor loads revealed that male patients rate their health in overall better terms regardless of their risk profile.

Conclusions

Our study confirmed the role of gender as the primary risk profile segregator after multiple adjustments for potential sociodemographic confounders, even in a population at elevated cardiovascular risk. Subjective health perception, which displayed marked gender differences, should be further investigated as a potential adherence and outcome modulator.     

The mindful attention and awareness scale is associated with lower levels of high-frequency heart rate variability in a laboratory context

Trait mindfulness has been associated with well-being. A key component of trait mindfulness is intentional attention and awareness which is most commonly measured by the Mindful Attention and Awareness Scale (MAAS). This study investigated the relationship between the MAAS and cardiovascular (HF-HRV, heart rate) reactivity to two laboratory stressors that evoked different patterns of change in heart rate (HR). One stressor (viewing a video of a surgery) evoked HR deceleration while the other stressor (mental arithmetic) evoked HR acceleration. Undergraduate students completed the MAAS and were then exposed to the two stressors while ECG (electrocardiography) was recorded. Findings support the reliability of the stressors to induce expected differential cardiovascular responses and explicate the role of parasympathetic activation. Further, a main effect for MAAS was observed indicating that across laboratory conditions, persons scoring higher on the MAAS had lower HF-HRV relative to persons scoring lower on the MAAS. These findings suggest that higher levels of intentional attention and awareness in a laboratory context might promote parasympathetic withdrawal because these participants were more vigilant, experienced higher cognitive load, and detected more threat cues. Implications for the MAAS and cardiovascular responses to stress are discussed.