Subkortikale Hirnstrukturen und Hippocampussubfelder in ihrer Assoziation zur Methylierung des Serotonintransportergens bei der depressiven Störung

Die vorliegende Studie untersuchte 49 Patienten mit Major Depressive Disorder (MDD), die sich beim psychiatrischen Gesundheitsdienst des Adelaide and Meath Hospitals und des National Children’s Hospitals in Dublin in ambulanter Behandlung befanden. Ihnen gegenübergestellt wurde eine Gruppe aus 49 gesunden Kontrollprobanden. Die 98 Studienteilnehmer erhielten eine magnetresonanztomographische zerebrale Bildgebung, anhand derer wir volumetrische Unterschiede in den subkortikalen Strukturen Thalamus, Putamen, Nucleus caudatus, Pallidum, Nucleus accumbens, Hippocampus, Amygdala und der Seitenventrikel sowie der Hippocampussubfelder CA1, CA2/3, CA4/DG, Subiculum, Präsubiculum und Fimbrien analysierten. Die volumetrischen Berechnungen wurden mit dem Segmentierungsprogramm FreeSurfer durchgeführt und mit Matlab sowie manuell überprüft. Die Volumina wurden auf signifikante Unterschiede bezüglich der Diagnose MDD, des Alters und des Geschlechtes untersucht. Das Hippocampusvolumen stellte sich bei Depressiven in beiden Hemisphären signifikant kleiner dar als bei Gesunden, die Volumina der Hippocampussubfelder CA2/3 und CA4/DG zeigten einen gleichartigen Effekt unilateral links. Diese Ergebnisse werden in anderen Studien bestätigt, die Einordnung der Volumenveränderungen in die Chronologie der Major Depressive Disorder bleibt jedoch unklar. So könnte die Depression Folge einer vorausgehenden Volumenverkleinerung in bestimmten Hirnarealen sein oder die morphologischen Veränderungen im Verlauf der Major Depressive Disorder durch krankheitsassoziierte Vorgänge geschehen. Der Hippocampus stellt einen Teil des limbischen Systems dar, der generell in zahlreichen emotionalen Vorgängen sowie in der Gedächtnisfunktion involviert ist. Bezüglich geschlechtlicher Unterschiede wurde ein beidseits signifikant größeres Pallidum- und Fimbrienvolumen bei den männlichen als bei den weiblichen Probanden verzeichnet. Den volumetrischen Veränderungen im Pallidum könnte eine generell größere Rolle in emotionalen und sexuellen Vorgängen bei Männern zugrunde liegen, die Veränderungen im Fimbrienvolumen sind angesichts der aktuellen Studienlage bezüglich dieses noch wenig erforschten Hippocampussubfelds schwer zu interpretieren. Das Alter der Probanden war signifikant mit einer beidseitigen Vergrößerung der Seitenventrikel, sowie einer signifikanten Verkleinerung der Volumina des Putamens, des Nucleus accumbens und des Pallidums assoziiert. Diese Beobachtung wird ebenfalls in zahlreichen vorausgehenden Studien belegt und ist wahrscheinlich durch eine physiologische Atrophie der Hirnsubstanz im Alter und eine fraglich reaktive Vergrößerung der Ventrikel zum intrakraniellen Volumenausgleich bedingt. Weiterhin stellte sich die Frage nach dem Zusammenhang von volumetrischen Veränderungen mit Stresserlebnissen in der Kindheit, die wir bei den Studienteilnehmern anhand des Childhood Trauma Questionnaires anamnestisch erhoben. In diesem Zusammenhang erhielten wir weder signifikante Ergebnisse in den Volumina der subkortikalen Strukturen noch in denen der Hippocampussubfelder, lediglich die Interaktion zwischen kindlichem Stress und Diagnose zeigte eine signifikante Assoziation bezüglich des Pallidumvolumens der rechten Hemisphäre auf. Patienten, die in der Kindheit keinen Missbrauch erfahren hatten, hatten durchschnittlich kleinere Pallidumvolumina, Patienten mit kindlichem Missbrauch zeigten auf der rechten Seite größere und auf der linken Seite kleinere Pallidumvolumina als die Kontrollprobanden. Innerhalb der nach Missbrauchserlebnissen aufgeteilten Probandengruppen erreichten diese Ergebnisse keine Signifikanz mehr, jedoch wird die Bedeutung des Pallidums als stresssensitive zerebrale Struktur hervorgehoben. Den zweiten großen Teil der Studie stellte die Untersuchung einer Untergruppe unserer Studienteilnehmer von insgesamt 69 Probanden (33 Patienten und 36 Kontrollprobanden) dar, die sich zu einer Blutentnahme zur Analyse epigenetischer Methylierung des Serotonintransportergens SLC6A4 in der DNA peripherer Blutzellen bereit erklärt hatten. Hier untersuchten wir die Assoziationen zwischen Methylierung und Alter, Geschlecht, Diagnose, kindlichem Missbrauch und Hippocampusvolumen. Es ergaben sich jeweils unabhängige signifikante Zusammenhänge zwischen Methylierung und Alter, kindlichem Stress und Hippocampusvolumen. Alter und Missbrauch waren positiv korreliert, ältere und Probanden, die kindlichem Missbrauch erfahren hatten, zeigten höhere Methylierungsanteile auf. Mit dem Hippocampusvolumen verhielt es sich umgekehrt, hier lag eine signifikante Assoziation zwischen kleineren Volumina und höherer Methylierung vor. Auch diese Ergebnisse werden durch andere Arbeiten bestätigt und lassen vermuten, dass das Volumen des Hippocampus als hochgradig glukokortikoid- und damit stressempfindliche Region mit der Methylierung des Serotonintransportergens zusammenhängt, die als eventuelle Möglichkeit der Einflussnahme auf die Genetik des Menschen durch äußere Einflüsse wie beispielsweise Stresserlebnisse gehandelt wird. Kindlicher Missbrauch ließ für sich keine signifikante Assoziation mit dem Hippocampusvolumen verzeichnen, was den Mechanismus der Epigenetik als Mittel zur Beeinflussung physiologischer Vorgänge plausibel erscheinen lässt. Zudem untersuchten wir die Methylierung der beiden speziellen Genloki CpG 5_6 und CpG 11_12, die auf dem Gesamtgenabschnitt CpG 5 bis 15 des SLC6A4-Gens liegen und als besonders mit der Serotoninsynthese assoziierte Genabschnitte identifiziert wurden. Hier stellten wir generell einen besonders hohen Methylierungsanteil an CpG 5_6 fest, CpG 11_12 war deutlich weniger häufig signifikant hoch methyliert. Die spezifischen Funktionen der einzelnen Genloki des SLC6A4 sind noch unklar. Die Zusammenschau der vielfältigen Untersuchungen und Ergebnisse unserer Studie zeigen diverse signifikante Zusammenhänge zwischen Depression, kindlichem Stress, Methylierung und volumetrischen Veränderungen zerebraler Strukturen, insbesondere der Hippocampusregion und ihrer Subfelder, auf. Multiple Fragestellungen, insbesondere zur chronologischen Einordnung der volumetrischen und epigenetischen Veränderungen, liegen außerhalb unserer Studie und lassen Spielraum für eventuell darauf aufbauende weitere Studien zum Thema Depression, Missbrauchsereignisse in der Kindheit und Epigenetik

How Does Ionizing Irradiation Contribute to the Induction of Anti-Tumor Immunity?

Radiotherapy (RT) with ionizing irradiation is commonly used to locally attack tumors. It induces a stop of cancer cell proliferation and finally leads to tumor cell death. During the last years it has become more and more evident that besides a timely and locally restricted radiation-induced immune suppression, a specific immune activation against the tumor and its metastases is achievable by rendering the tumor cells visible for immune attack. The immune system is involved in tumor control and we here outline how RT induces anti-inflammation when applied in low doses and contributes in higher doses to the induction of anti-tumor immunity. We especially focus on how local irradiation induces abscopal effects. The latter are partly mediated by a systemic activation of the immune system against the individual tumor cells. Dendritic cells are the key players in the initiation and regulation of adaptive anti-tumor immune responses. They have to take up tumor antigens and consecutively present tumor peptides in the presence of appropriate co-stimulation. We review how combinations of RT with further immune stimulators such as AnnexinA5 and hyperthermia foster the dendritic cell-mediated induction of anti-tumor immune responses and present reasonable combination schemes of standard tumor therapies with immune therapies. It can be concluded that RT leads to targeted killing of the tumor cells and additionally induces non-targeted systemic immune effects. Multimodal tumor treatments should therefore tend to induce immunogenic tumor cell death forms within a tumor microenvironment that stimulates immune cells

Tumor Cell-Based Vaccine Generated With High Hydrostatic Pressure Synergizes With Radiotherapy by Generating a Favorable Anti-tumor Immune Microenvironment

Dendritic cell (DC)-based vaccines pulsed with high hydrostatic pressure (HHP)-inactivated tumor cells have been demonstrated to be a promising immunotherapy for solid tumors. We focused on sole injection of tumor cells that were inactivated by HHP and their combination with local radiotherapy (RTx) for in vivo induction of anti-tumor immune responses. HHP-treatment of tumor cells resulted in pre-dominantly necrotic cells with degraded DNA. We confirmed that treatments at 200 MPa or higher completely inhibited the formation of tumor cell colonies in vitro. No tumor growth was seen in vivo after injection of HHP-treated tumor cells. Single vaccination with HHP-killed tumor cells combined with local RTx significantly retarded tumor growth and improved the survival as shown in B16-F10 and CT26 tumor models. In B16-F10 tumors that were irradiated with 2 × 5Gy and vaccinated once with HHP-killed tumor cells, the amount of natural killer (NK) cells, monocytes/macrophages, CD4+ T cells and NKT cells was significantly increased, while the amount of B cells was significantly decreased. In both models, a trend of increased CD8+ T cell infiltration was observed. Generally, in irradiated tumors high amounts of CD4+ and CD8+ T cells expressing PD-1 were found. We conclude that HHP generates inactivated tumor cells that can be used as a tumor vaccine. Moreover, we show for the first time that tumor cell-based vaccine acts synergistically with RTx to significantly retard tumor growth by generating a favorable anti-tumor immune microenvironment

Expression of glucocorticoid inducible genes is associated with reductions in cornu ammonis and dentate gyrus volumes in patients with major depressive disorder

Alterations of the glucocorticoid system and of hippocampal volumes have consistently been reported in patients with major depressive disorders (MDD). The aim of the present study was to investigate whether the messenger RNA (mRNA) expression of glucocorticoid inducible genes is associated with changes in the cornu ammonis (CA) and dentate gyrus subfields. Forty-three patients with MDD and 43 healthy controls were recruited and investigated with high resolution magnetic resonance imaging. Hippocampal subfields were measured using freesurfer. Measurement of whole blood mRNA expression of glucocorticoid inducible genes serum and glucocorticoid-regulated kinase 1 (SGK1), FK506 binding protein 5 (FKBP5), and glucocorticoid induced leucine zipper (GILZ) was performed. Patients with MDD had significantly smaller volumes of CA1, CA2/3, CA4/DG, and subiculum compared to healthy controls. In the regression analysis, the factor diagnosis had a significant moderating effect on the association of SGK1 and hippocampal volumes. Patients with low expression of SGK1 had significantly smaller CA2/3 and CA4/DG volumes compared to patients with high expression of SGK1 mRNA and to healthy controls with low/high expression of SGK1, respectively. Therefore, a lack of mRNA expression of glucocorticoid inducible genes in patients with MDD that seems to correspond to a blunted cortisol response is associated with smaller hippocampal CA and dentate gyrus volumes. SGK1 seems to be particularly relevant for stress-related mental disorders

The PanCareSurFup consortium:research and guidelines to improve lives for survivors of childhood cancer

Background: Second malignant neoplasms and cardiotoxicity are among the most serious and frequent adverse health outcomes experienced by childhood and adolescent cancer survivors (CCSs) and contribute significantly to their increased risk of premature mortality. Owing to differences in health-care systems, language and culture across the continent, Europe has had limited success in establishing multi-country collaborations needed to assemble the numbers of survivors required to clarify the health issues arising after successful cancer treatment. PanCareSurFup (PCSF) is the first pan-European project to evaluate some of the serious long-term health risks faced by survivors. This article sets out the overall rationale, methods and preliminary results of PCSF. Methods: The PCSF consortium pooled data from 13 cancer registries and hospitals in 12 European countries to evaluate subsequent primary malignancies, cardiac disease and late mortality in survivors diagnosed between ages 0 and 20 years. In addition, PCSF integrated radiation dosimetry to sites of second malignancies and to the heart, developed evidence-based guidelines for long-term care and for transition services, and disseminated results to survivors and the public. Results: We identified 115,596 individuals diagnosed with cancer, of whom 83,333 were 5-year survivors and diagnosed from 1940 to 2011. This single data set forms the basis for cohort analyses of subsequent malignancies, cardiac disease and late mortality and case–control studies of subsequent malignancies and cardiac disease in 5-year survivors. Conclusions: PCSF delivered specific estimates of risk and comprehensive guidelines to help survivors and care-givers. The expected benefit is to provide every European CCS with improved access to care and better long-term health

Perception of Thermal Pain and the Thermal Grill Illusion Is Associated with Polymorphisms in the Serotonin Transporter Gene

AIM: The main aim of this study was to assess if the perception of thermal pain thresholds is associated with genetically inferred levels of expression of the 5-HT transporter (5-HTT). Additionally, the perception of the so-called thermal grill illusion (TGI) was assessed. Forty-four healthy individuals (27 females, 17 males) were selected a-priori based on their 5-HTTLPR/rs25531 ('tri-allelic 5-HTTLPR') genotype, with inferred high or low 5-HTT expression. Thresholds for heat- and cold-pain were determined along with the sensory and affective dimensions of the TGI. RESULTS: Thresholds to heat- and cold-pain correlated strongly (rho  = -0.58, p<0.001). Individuals in the low 5-HTT-expressing group were significantly less sensitive to heat-pain (p = 0.02) and cold-pain (p = 0.03), compared to the high-expressing group. A significant gender-by-genotype interaction also emerged for cold-pain perception (p = 0.02); low 5-HTT-expressing females were less sensitive. The TGI was rated as significantly more unpleasant (affective-motivational dimension) than painful (sensory-discriminatory dimension), (p<0.001). Females in the low 5-HTT expressing group rated the TGI as significantly less unpleasant than high 5-HTT expressing females (p<0.05), with no such differences among men. CONCLUSION/SIGNIFICANCE: We demonstrate an association between inferred low 5-HTT expression and elevated thresholds to thermal pain in healthy non-depressed individuals. Despite the fact that reduced 5-HTT expression is a risk factor for chronic pain we found it to be related to hypoalgesia for threshold thermal pain. Low 5-HTT expression is, however, also a risk factor for depression where thermal insensitivity is often seen. Our results may thus contribute to a better understanding of the molecular underpinnings of such paradoxical hypoalgesia. The results point to a differential regulation of thermoafferent-information along the neuraxis on the basis of 5-HTT expression and gender. The TGI, suggested to rely on the central integration of thermoafferent-information, may prove a valuable tool in probing the affective-motivational dimension of these putative mechanisms

Rare and low-frequency coding variants alter human adult height

Height is a highly heritable, classic polygenic trait with ~700 common associated variants identified so far through genome - wide association studies . Here , we report 83 height - associated coding variants with lower minor allele frequenc ies ( range of 0.1 - 4.8% ) and effects of up to 2 16 cm /allele ( e.g. in IHH , STC2 , AR and CRISPLD2 ) , >10 times the average effect of common variants . In functional follow - up studies, rare height - increasing alleles of STC2 (+1 - 2 cm/allele) compromise d proteolytic inhibition of PAPP - A and increased cleavage of IGFBP - 4 in vitro , resulting in higher bioavailability of insulin - like growth factors . The se 83 height - associated variants overlap genes mutated in monogenic growth disorders and highlight new biological candidates ( e.g. ADAMTS3, IL11RA, NOX4 ) and pathways ( e.g . proteoglycan/ glycosaminoglycan synthesis ) involved in growth . Our results demonstrate that sufficiently large sample sizes can uncover rare and low - frequency variants of moderate to large effect associated with polygenic human phenotypes , and that these variants implicate relevant genes and pathways

Early-life respiratory tract infections and the risk of school-age lower lung function and asthma: A meta-analysis of 150 000 European children

BACKGROUND: Early-life respiratory tract infections might affect chronic obstructive respiratory diseases, but conclusive studies from general populations are lacking. Our objective was to examine if children with early-life respiratory tract infections had increased risks of lower lung function and asthma at school age. METHODS: We used individual participant data of 150 090 children primarily from the EU Child Cohort Network to examine the associations of upper and lower respiratory tract infections from age 6 months to 5 years with forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC, forced expiratory flow at 75% of FVC (FEF75%) and asthma at a median (range) age of 7 (4-15) years. RESULTS: Children with early-life lower, not upper, respiratory tract infections had a lower school-age FEV1, FEV1/FVC and FEF75% (z-score range: -0.09 (95% CI -0.14- -0.04) to -0.30 (95% CI -0.36- -0.24)). Children with early-life lower respiratory tract infections had a higher increased risk of school-age asthma than those with upper respiratory tract infections (OR range: 2.10 (95% CI 1.98-2.22) to 6.30 (95% CI 5.64-7.04) and 1.25 (95% CI 1.18-1.32) to 1.55 (95% CI 1.47-1.65), respectively). Adjustment for preceding respiratory tract infections slightly decreased the strength of the effects. Observed associations were similar for those with and without early-life wheezing as a proxy for early-life asthma. CONCLUSIONS: Our findings suggest that early-life respiratory tract infections affect development of chronic obstructive respiratory diseases in later life, with the strongest effects for lower respiratory tract infections