Plasma concentrations of endocannabinoids and related primary Fatty Acid amides in patients with post-traumatic stress disorder.

Endocannabinoids (ECs) and related N-acyl-ethanolamides (NAEs) play important roles in stress response regulation, anxiety and traumatic memories. In view of the evidence that circulating EC levels are elevated under acute mild stressful conditions in humans, we hypothesized that individuals with traumatic stress exposure and post-traumatic stress disorder (PTSD), an anxiety disorder characterized by the inappropriate persistence and uncontrolled retrieval of traumatic memories, show measurable alterations in plasma EC and NAE concentrations. We determined plasma concentrations of the ECs anandamide (ANA) and 2-arachidonoylglycerol (2-AG) and the NAEs palmitoylethanolamide (PEA), oleoylethanolamide (OEA), stearoylethanolamine (SEA), and N-oleoyldopamine (OLDA) by HPLC-MS-MS in patients with PTSD (n = 10), trauma-exposed individuals without evidence of PTSD (n = 9) and in healthy control subjects (n = 29). PTSD was diagnosed according to DSM-IV criteria by administering the Clinician Administered PTSD Scale (CAPS), which also assesses traumatic events. Individuals with PTSD showed significantly higher plasma concentrations of ANA (0.48±0.11 vs. 0.36±0.14 ng/ml, p = 0.01), 2-AG (8.93±3.20 vs. 6.26±2.10 ng/ml, p<0.01), OEA (5.90±2.10 vs. 3.88±1.85 ng/ml, p<0.01), SEA (2.70±3.37 vs. 0.83±0.47, ng/ml, p<0.05) and significantly lower plasma levels of OLDA (0.12±0.05 vs. 0.45±0.59 ng/ml, p<0.05) than healthy controls. Moreover, PTSD patients had higher 2-AG plasma levels (8.93±3.20 vs. 6.01±1.32 ng/ml, p = 0.03) and also higher plasma concentrations of PEA (4.06±1.87 vs. 2.63±1.34 ng/ml, p<0.05) than trauma-exposed individuals without evidence of PTSD. CAPS scores in trauma-exposed individuals with and without PTSD (n = 19) correlated positively with PEA (r = 0.55, p = 0.02) and negatively with OLDA plasma levels (r = -0.68, p<0.01). CAPS subscores for intrusions (r = -0.65, p<0.01), avoidance (r = -0.60, p<0.01) and hyperarousal (r = -0.66, p<0.01) were all negatively related to OLDA plasma concentrations. PTSD appears to be associated with changes in plasma EC/NAE concentrations. This may have pathophysiological and diagnostic consequences but will need to be reproduced in larger cohorts

Mu suppression – a good measure of the human mirror neuron system?

Mu suppression has been proposed as a signature of the activity of the human mirror neuron system. However the mu frequency band (8-13 Hz) overlaps with the alpha frequency band, which is sensitive to attentional fluctuation, and thus mu suppression could potentially be confounded by changes in attentional engagement. The specific baseline against which mu suppression is assessed may be crucial, yet there is little consistency in how this is defined. We examined mu suppression in 61 typical adults, the largest mu suppression study so far conducted. We compared different methods of baselining, and examined activity at central and occipital electrodes, to both biological (hands) and non-biological (kaleidoscope) moving stimuli, to investigate the involvement of attention and alpha activity in mu suppression. We also examined changes in beta power, another candidate index of mirror neuron system engagement. We observed strong mu suppression restricted to central electrodes when participants performed hand movements, demonstrating that mu is indeed responsive to the activity of the motor cortex. However, when we looked for a similar signature of mu suppression to passively observed stimuli, the baselining method proved to be crucial. Selective suppression for biological vs non-biological stimuli was seen at central electrodes only when we used a within-trial baseline based on a static stimulus: this method greatly reduced trial-by-trial variation in the suppression measure compared with baselines based on blank trials presented in separate blocks. Even in this optimal condition, 16-21% of participants showed no mu suppression. Changes in beta power also did not match our predicted pattern for mirror neuron system engagement, and did not seem to offer a better measure than mu. Our conclusions are in contrast to those of a recent meta-analysis, which concluded that mu suppression is a valid means to examine mirror neuron activity. We argue that mu suppression can be used to index the human mirror neuron system, but the effect is weak and unreliable and easily confounded with alpha suppression

Narrative exposure therapy for PTSD increases top-down processing of aversive stimuli - evidence from a randomized controlled treatment trial

Adenauer H, Catani C, Gola H, et al. Narrative exposure therapy for PTSD increases top-down processing of aversive stimuli - evidence from a randomized controlled treatment trial. BMC Neuroscience. 2011;12(1): 127.BACKGROUND: Little is known about the neurobiological foundations of psychotherapy for Posttraumatic Stress Disorder (PTSD). Prior studies have shown that PTSD is associated with altered processing of threatening and aversive stimuli. It remains unclear whether this functional abnormality can be changed by psychotherapy. This is the first randomized controlled treatment trial that examines whether narrative exposure therapy (NET) causes changes in affective stimulus processing in patients with chronic PTSD. METHODS: 34 refugees with PTSD were randomly assigned to a NET group or to a waitlist control (WLC) group. At pre-test and at four-months follow-up, the diagnostics included the assessment of clinical variables and measurements of neuromagnetic oscillatory brain activity (steady-state visual evoked fields, ssVEF) resulting from exposure to aversive pictures compared to neutral pictures. RESULTS: PTSD as well as depressive symptom severity scores declined in the NET group, whereas symptoms persisted in the WLC group. Only in the NET group, parietal and occipital activity towards threatening pictures increased significantly after therapy. CONCLUSIONS: Our results indicate that NET causes an increase of activity associated with cortical top-down regulation of attention towards aversive pictures. The increase of attention allocation to potential threat cues might allow treated patients to re-appraise the actual danger of the current situation and, thereby, reducing PTSD symptoms. REGISTRATION OF THE CLINICAL TRIAL: Number: NCT00563888Name: "Change of Neural Network Indicators Through Narrative Treatment of PTSD in Torture Victims" ULR: http://www.clinicaltrials.gov/ct2/show/NCT00563888

Worldwide comparison of survival from childhood leukaemia for 1995–2009, by subtype, age, and sex (CONCORD-2): a population-based study of individual data for 89 828 children from 198 registries in 53 countries

Background Global inequalities in access to health care are reflected in differences in cancer survival. The CONCORD programme was designed to assess worldwide differences and trends in population-based cancer survival. In this population-based study, we aimed to estimate survival inequalities globally for several subtypes of childhood leukaemia. Methods Cancer registries participating in CONCORD were asked to submit tumour registrations for all children aged 0-14 years who were diagnosed with leukaemia between Jan 1, 1995, and Dec 31, 2009, and followed up until Dec 31, 2009. Haematological malignancies were defined by morphology codes in the International Classification of Diseases for Oncology, third revision. We excluded data from registries from which the data were judged to be less reliable, or included only lymphomas, and data from countries in which data for fewer than ten children were available for analysis. We also excluded records because of a missing date of birth, diagnosis, or last known vital status. We estimated 5-year net survival (ie, the probability of surviving at least 5 years after diagnosis, after controlling for deaths from other causes [background mortality]) for children by calendar period of diagnosis (1995-99, 2000-04, and 2005-09), sex, and age at diagnosis (< 1, 1-4, 5-9, and 10-14 years, inclusive) using appropriate life tables. We estimated age-standardised net survival for international comparison of survival trends for precursor-cell acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML). Findings We analysed data from 89 828 children from 198 registries in 53 countries. During 1995-99, 5-year agestandardised net survival for all lymphoid leukaemias combined ranged from 10.6% (95% CI 3.1-18.2) in the Chinese registries to 86.8% (81.6-92.0) in Austria. International differences in 5-year survival for childhood leukaemia were still large as recently as 2005-09, when age-standardised survival for lymphoid leukaemias ranged from 52.4% (95% CI 42.8-61.9) in Cali, Colombia, to 91.6% (89.5-93.6) in the German registries, and for AML ranged from 33.3% (18.9-47.7) in Bulgaria to 78.2% (72.0-84.3) in German registries. Survival from precursor-cell ALL was very close to that of all lymphoid leukaemias combined, with similar variation. In most countries, survival from AML improved more than survival from ALL between 2000-04 and 2005-09. Survival for each type of leukaemia varied markedly with age: survival was highest for children aged 1-4 and 5-9 years, and lowest for infants (younger than 1 year). There was no systematic difference in survival between boys and girls. Interpretation Global inequalities in survival from childhood leukaemia have narrowed with time but remain very wide for both ALL and AML. These results provide useful information for health policy makers on the effectiveness of health-care systems and for cancer policy makers to reduce inequalities in childhood survival

Global surveillance of cancer survival 1995-2009: analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2)

BACKGROUND: Worldwide data for cancer survival are scarce. We aimed to initiate worldwide surveillance of cancer survival by central analysis of population-based registry data, as a metric of the effectiveness of health systems, and to inform global policy on cancer control. METHODS: Individual tumour records were submitted by 279 population-based cancer registries in 67 countries for 25·7 million adults (age 15-99 years) and 75,000 children (age 0-14 years) diagnosed with cancer during 1995-2009 and followed up to Dec 31, 2009, or later. We looked at cancers of the stomach, colon, rectum, liver, lung, breast (women), cervix, ovary, and prostate in adults, and adult and childhood leukaemia. Standardised quality control procedures were applied; errors were corrected by the registry concerned. We estimated 5-year net survival, adjusted for background mortality in every country or region by age (single year), sex, and calendar year, and by race or ethnic origin in some countries. Estimates were age-standardised with the International Cancer Survival Standard weights. FINDINGS: 5-year survival from colon, rectal, and breast cancers has increased steadily in most developed countries. For patients diagnosed during 2005-09, survival for colon and rectal cancer reached 60% or more in 22 countries around the world; for breast cancer, 5-year survival rose to 85% or higher in 17 countries worldwide. Liver and lung cancer remain lethal in all nations: for both cancers, 5-year survival is below 20% everywhere in Europe, in the range 15-19% in North America, and as low as 7-9% in Mongolia and Thailand. Striking rises in 5-year survival from prostate cancer have occurred in many countries: survival rose by 10-20% between 1995-99 and 2005-09 in 22 countries in South America, Asia, and Europe, but survival still varies widely around the world, from less than 60% in Bulgaria and Thailand to 95% or more in Brazil, Puerto Rico, and the USA. For cervical cancer, national estimates of 5-year survival range from less than 50% to more than 70%; regional variations are much wider, and improvements between 1995-99 and 2005-09 have generally been slight. For women diagnosed with ovarian cancer in 2005-09, 5-year survival was 40% or higher only in Ecuador, the USA, and 17 countries in Asia and Europe. 5-year survival for stomach cancer in 2005-09 was high (54-58%) in Japan and South Korea, compared with less than 40% in other countries. By contrast, 5-year survival from adult leukaemia in Japan and South Korea (18-23%) is lower than in most other countries. 5-year survival from childhood acute lymphoblastic leukaemia is less than 60% in several countries, but as high as 90% in Canada and four European countries, which suggests major deficiencies in the management of a largely curable disease. INTERPRETATION: International comparison of survival trends reveals very wide differences that are likely to be attributable to differences in access to early diagnosis and optimum treatment. Continuous worldwide surveillance of cancer survival should become an indispensable source of information for cancer patients and researchers and a stimulus for politicians to improve health policy and health-care systems

The histology of ovarian cancer: worldwide distribution and implications for international survival comparisons (CONCORD-2)

Objective Ovarian cancers comprise several histologically distinct tumour groups with widely different prognosis. We aimed to describe the worldwide distribution of ovarian cancer histology and to understand what role this may play in international variation in survival. Methods The CONCORD programme is the largest population-based study of global trends in cancer survival. Data on 681,759 women diagnosed during 1995â\u80\u932009 with cancer of the ovary, fallopian tube, peritoneum and retroperitonum in 51 countries were included. We categorised ovarian tumours into six histological groups, and explored the worldwide distribution of histology. Results During 2005â\u80\u932009, type II epithelial tumours were the most common. The proportion was much higher in Oceania (73.1%), North America (73.0%) and Europe (72.6%) than in Central and South America (65.7%) and Asia (56.1%). By contrast, type I epithelial tumours were more common in Asia (32.5%), compared with only 19.4% in North America. From 1995 to 2009, the proportion of type II epithelial tumours increased from 68.6% to 71.1%, while the proportion of type I epithelial tumours fell from 23.8% to 21.2%. The proportions of germ cell tumours, sex cord-stromal tumours, other specific non-epithelial tumours and tumours of non-specific morphology all remained stable over time. Conclusions The distribution of ovarian cancer histology varies widely worldwide. Type I epithelial, germ cell and sex cord-stromal tumours are generally associated with higher survival than type II tumours, so the proportion of these tumours may influence survival estimates for all ovarian cancers combined. The distribution of histological groups should be considered when comparing survival between countries and regions

Lancet

BACKGROUND: In 2015, the second cycle of the CONCORD programme established global surveillance of cancer survival as a metric of the effectiveness of health systems and to inform global policy on cancer control. CONCORD-3 updates the worldwide surveillance of cancer survival to 2014. METHODS: CONCORD-3 includes individual records for 37.5 million patients diagnosed with cancer during the 15-year period 2000-14. Data were provided by 322 population-based cancer registries in 71 countries and territories, 47 of which provided data with 100% population coverage. The study includes 18 cancers or groups of cancers: oesophagus, stomach, colon, rectum, liver, pancreas, lung, breast (women), cervix, ovary, prostate, and melanoma of the skin in adults, and brain tumours, leukaemias, and lymphomas in both adults and children. Standardised quality control procedures were applied; errors were rectified by the registry concerned. We estimated 5-year net survival. Estimates were age-standardised with the International Cancer Survival Standard weights. FINDINGS: For most cancers, 5-year net survival remains among the highest in the world in the USA and Canada, in Australia and New Zealand, and in Finland, Iceland, Norway, and Sweden. For many cancers, Denmark is closing the survival gap with the other Nordic countries. Survival trends are generally increasing, even for some of the more lethal cancers: in some countries, survival has increased by up to 5% for cancers of the liver, pancreas, and lung. For women diagnosed during 2010-14, 5-year survival for breast cancer is now 89.5% in Australia and 90.2% in the USA, but international differences remain very wide, with levels as low as 66.1% in India. For gastrointestinal cancers, the highest levels of 5-year survival are seen in southeast Asia: in South Korea for cancers of the stomach (68.9%), colon (71.8%), and rectum (71.1%); in Japan for oesophageal cancer (36.0%); and in Taiwan for liver cancer (27.9%). By contrast, in the same world region, survival is generally lower than elsewhere for melanoma of the skin (59.9% in South Korea, 52.1% in Taiwan, and 49.6% in China), and for both lymphoid malignancies (52.5%, 50.5%, and 38.3%) and myeloid malignancies (45.9%, 33.4%, and 24.8%). For children diagnosed during 2010-14, 5-year survival for acute lymphoblastic leukaemia ranged from 49.8% in Ecuador to 95.2% in Finland. 5-year survival from brain tumours in children is higher than for adults but the global range is very wide (from 28.9% in Brazil to nearly 80% in Sweden and Denmark). INTERPRETATION: The CONCORD programme enables timely comparisons of the overall effectiveness of health systems in providing care for 18 cancers that collectively represent 75% of all cancers diagnosed worldwide every year. It contributes to the evidence base for global policy on cancer control. Since 2017, the Organisation for Economic Co-operation and Development has used findings from the CONCORD programme as the official benchmark of cancer survival, among their indicators of the quality of health care in 48 countries worldwide. Governments must recognise population-based cancer registries as key policy tools that can be used to evaluate both the impact of cancer prevention strategies and the effectiveness of health systems for all patients diagnosed with cancer. FUNDING: American Cancer Society; Centers for Disease Control and Prevention; Swiss Re; Swiss Cancer Research foundation; Swiss Cancer League; Institut National du Cancer; La Ligue Contre le Cancer; Rossy Family Foundation; US National Cancer Institute; and the Susan G Komen Foundation

Immunological and Endocrine Alterations in Posttraumatic Stress Disorder

Posttraumatic stress disorder (PTSD) is associated with an enhanced susceptibility to various somatic diseases. However, the exact mechanisms linking traumatic stress to subsequent physical health problems have remained unclear, with recent research discussing stress-related alterations in the endocrine and immune system as potential mediators. The present thesis is composed of three studies, investigating basal immune alterations as well as acute changes in immune and endocrine parameters in response to trauma reminders in patients with PTSD due to war and torture experiences. Study A investigated the influence of chronic stress associated with PTSD on alterations in T lymphocyte differentiation subsets. Results show a profoundly altered composition of the peripheral T cell compartment in PTSD patients, as evidenced by a substantial reduction in the proportion of regulatory T cells as well as a significantly reduced proportion of naïve cytotoxic T lymphocytes and enhanced proportions of memory T lymphocytes in individuals with PTSD compared to control subjects. Study B examined plasma cytokine levels as well as spontaneous and lipopolysaccharide (LPS)-stimulated cytokine production by peripheral blood mononuclear cells (PBMCs). Moreover, acute changes in plasma cytokines in response to the confrontation with trauma reminders were studied. Results demonstrate, that the spontaneous production of the pro-inflammatory cytokines Interleukin (IL) 1β, IL-6 and Tumor Necrosis Factor (TNF-α) by PBMCs was significantly higher in the PTSD compared to the control group. Moreover, in the PTSD patient group we found a positive association between PTSD symptom severity and plasma TNF-α levels following the confrontation with trauma reminders. Study C investigated the effect of trauma type (rape vs. other trauma types) on salivary and plasma cortisol responses of PTSD patients after being confronted with trauma reminders. Results demonstrate differential salivary cortisol responses in PTSD patients who had been raped compared to those who had not been raped. Whereas those PTSD patients with a past experience of rape showed a significant salivary cortisol increase when reminded of their traumatic events, salivary cortisol levels decreased in the course of the measurement period for the group who had not been raped. In sum, these findings might constitute a key factor in the enhanced susceptibility of persons with PTSD to a range of physical diseases. Moreover results support subtyping in relation to the type of traumatic stressors experienced. The nearness of the perpetrator during a traumatic event might modulate peritraumatic physiologic responses, as well as later physiological responses to trauma reminders

Early Processing of Threat Cues in Posttraumatic Stress Disorder-Evidence for a Cortical Vigilance-Avoidance Reaction

Adenauer H, Pinoesch S, Catani C, et al. Early Processing of Threat Cues in Posttraumatic Stress Disorder-Evidence for a Cortical Vigilance-Avoidance Reaction. Biological Psychiatry. 2010;68(5):451-458.Background: The present study investigated the influence of posttraumatic stress disorder (PTSD) on early visual processing of affective stimuli in survivors of war and torture. Methods: Trauma-exposed refugees with (n = 36) and without (n = 21) PTSD as well as unexposed control subjects (n = 16) participated in a magnetoencephalography study with pictures that varied in emotional content. Results: We found evidence for a biphasic cortical response in patients with PTSD in comparison with the two control groups. In response to aversive (relative to neutral or positive) pictures, PTSD patients showed elevated cortical activity over right prefrontal areas as early as 130-160 msec after stimulus onset followed by a decrease of the affect-related response in the parieto-occipital cortex at 206-256 msec. Conclusions: The increased early activity in the right prefrontal cortex most likely represents an enhanced alarm response or the fear network toward aversive stimuli in PTSD, whereas the subsequent decreased activation in right parieto-occipital areas in response to aversive pictures seems to reflect the tendency to disengage from emotional content. This finding is consistent with the hypothesis of a vigilance-avoidance reaction pattern to threat in anxiety disorders and helps to reconcile contradicting results of over- and under-responsiveness in the sensory processing of threatening stimuli in PTSD

Comparative Genome Analysis of Spiroplasma Melliferum IPMB4A, a Honeybee-Associated Bacterium

Background: The genus Spiroplasma contains a group of helical, motile, and wall-less bacteria in the classMollicutes. Similar to other members of this class, such as the animal-pathogenic Mycoplasma and theplant-pathogenic ‘Candidatus Phytoplasma’, all characterized Spiroplasma species were found to be associated witheukaryotic hosts. While most of the Spiroplasma species appeared to be harmless commensals of insects, a smallnumber of species have evolved pathogenicity toward various arthropods and plants. In this study, we isolated anovel strain of honeybee-associated S. melliferum and investigated its genetic composition and evolutionary historyby whole-genome shotgun sequencing and comparative analysis with other Mollicutes genomes.Results: The whole-genome shotgun sequencing of S. melliferum IPMB4A produced a draft assembly that was ~1.1Mb in size and covered ~80% of the chromosome. Similar to other Spiroplasma genomes that have been studiedto date, we found that this genome contains abundant repetitive sequences that originated from plectrovirusinsertions. These phage fragments represented a major obstacle in obtaining a complete genome sequence ofSpiroplasma with the current sequencing technology. Comparative analysis of S. melliferum IPMB4A with otherSpiroplasma genomes revealed that these phages may have facilitated extensive genome rearrangements in thesebacteria and contributed to horizontal gene transfers that led to species-specific adaptation to different eukaryotichosts. In addition, comparison of gene content with other Mollicutes suggested that the common ancestor of theSEM (Spiroplasma, Entomoplasma, and Mycoplasma) clade may have had a relatively large genome and flexiblemetabolic capacity; the extremely reduced genomes of present day Mycoplasma and ‘Candidatus Phytoplasma’species are likely to be the result of independent gene losses in these lineages.Conclusions: The findings in this study highlighted the significance of phage insertions and horizontal genetransfer in the evolution of bacterial genomes and acquisition of pathogenicity. Furthermore, the inclusion ofSpiroplasma in comparative analysis has improved our understanding of genome evolution in Mollicutes. Futureimprovements in the taxon sampling of available genome sequences in this group are required to provide furtherinsights into the evolution of these important pathogens of humans, animals, and plants