Childhood maltreatment is associated with an automatic negative emotion processing bias in the amygdala

Major depression has been repeatedly associated with amygdala hyper‐responsiveness to negative (but not positive) facial expressions at early, automatic stages of emotion processing using subliminally presented stimuli. However, it is not clear whether this “limbic bias” is a correlate of depression or represents a vulnerability marker preceding the onset of the disease. Because childhood maltreatment is a potent risk factor for the development of major depression in later life, we explored whether childhood maltreatment is associated with amygdalar emotion processing bias in maltreated but healthy subjects. Amygdala responsiveness to subliminally presented sad and happy faces was measured by means of fMRI at 3 T in N = 150 healthy subjects carefully screened for psychiatric disorders. Childhood maltreatment was assessed by the 25‐item childhood trauma questionnaire (CTQ). A strong association of CTQ‐scores with amygdala responsiveness to sad, but not happy facial expressions emerged. This result was further qualified by an interaction of emotional valence and CTQ‐scores and was not confounded by trait anxiety, current depression level, age, gender, intelligence, education level, and more recent stressful life‐events. Childhood maltreatment is apparently associated with detectable changes in amygdala function during early stages of emotion processing which resemble findings described in major depression. Limbic hyper‐responsiveness to negative facial cues could be a consequence of the experience of maltreatment during childhood increasing the risk of depression in later life. Limitation: the present association of limbic bias and maltreatment was demonstrated in the absence of psychopathological abnormalities, thereby limiting strong conclusions. Hum Brain Mapp 34:2899–2909, 2013. © 2012 Wiley Periodicals, Inc.     

Oxytocin Reduces Reward-Driven Food Intake in Humans

Experiments in animals suggest that the neuropeptide oxytocin acts as an anorexigenic signal in the central nervous control of food intake. In humans, however, research has almost exclusively focused on the involvement of oxytocin in the regulation of social behavior. We investigated the effect of intranasal oxytocin on ingestion and metabolic function in healthy men. Food intake in the fasted state was examined 45 min after neuropeptide administration, followed by the assessment of olfaction and reward-driven snack intake in the absence of hunger. Energy expenditure was registered by indirect calorimetry, and blood was repeatedly sampled to determine concentrations of blood glucose and hormones. Oxytocin markedly reduced snack consumption, restraining, in particular, the intake of chocolate cookies by 25%. Oxytocin, moreover, attenuated basal and postprandial levels of adrenocorticotropic hormone and cortisol and curbed the meal-related rise in plasma glucose. Energy expenditure and hunger-driven food intake as well as olfactory function were not affected. Our results indicate that oxytocin, beyond its role in social bonding, regulates nonhomeostatic, reward-related energy intake, hypothalamic-pituitary-adrenal axis activity, and the glucoregulatory response to food intake in humans. These effects can be assumed to converge with the psychosocial function of oxytocin and imply possible applications in the treatment of metabolic disorders.The hypothalamic nonapeptide oxytocin is released into the circulation by axonal terminals in the posterior pituitary and, moreover, acts directly on central nervous receptors. Oxytocin, which has been highly preserved during mammalian evolution, regulates physiological functions related to reproduction and mother-infant interaction, such as lactation, and in recent years, has been shown to modulate affiliative behavior (1). Research in humans has almost exclusively focused on the role of oxytocin in the regulation of prosocial behavior, including trust, attachment, and sexual behavior (2–5), largely ignoring potential effects of the neuropeptide on ingestive behavior and metabolism. In fact, evidence from rodent studies indicates that the neuropeptide acts as a strong inhibitor of food intake and affects energy expenditure and glucose homeostasis (6–9). Oxytocinergic neurons in the hypothalamic paraventricular nucleus are assumed to mediate the food intake–limiting effect of leptin, an adipokine that provides the brain with negative feedback on body fat stores and sensitizes caudal brainstem nuclei to satiety factors such as cholecystokinin (10). Hypothalamic oxytocin signaling, moreover, mediates anorexigenic effects of the satiety factor nesfatin-1 in a leptin-independent manner (11). Importantly, oxytocin reduces food intake not only in normal-weight rodents but also in animals with diet-induced obesity (8,12,13), so oxytocinergic pathways might be a promising target of clinical interventions in obese patients.The direct manipulation of neuropeptidergic central nervous signaling pathways can be achieved via the intranasal administration of peptides, which is known to bypass the blood–brain barrier and result in significant cerebrospinal fluid elevations in substance levels within 40 min, without the need for systemic infusion (14,15). This approach has been validated, among others, for vasopressin, a close homolog of oxytocin (14), and intranasal oxytocin administration has been shown to reliably modulate neuropsychological functions in a series of studies (2–5) in the absence of relevant side effects (16). Surprisingly, however, the effect of intranasal oxytocin on energy metabolism, including ingestive behavior, has not been investigated in humans so far. The assessment of respective effects of intravenous oxytocin (17) is hampered because peripheral oxytocin is not readily transported across the blood–brain barrier (18).In the present experiments, we studied the contribution of oxytocin signaling to the control of ingestive behavior and energy expenditure in normal-weight, healthy men, with a particular view to endocrine regulators of metabolism, such as ghrelin and insulin, as well as hypothalamic-pituitary-adrenal (HPA) axis secretory activity. Ingestive behavior is not only regulated homeostatically (i.e., by central nervous pathways that respond to energy depletion) but also by nonhomeostatic brain circuits that process the reward-related, “hedonic” qualities of food intake (19). Therefore, we applied a twofold assessment of food intake that relied, on the one hand, on a large breakfast buffet after an overnight fast to investigate homeostatic, primarily hunger-driven energy intake (20–22), and on the other hand, on a collection of snacks of varying palatability offered after breakfast intake for the measurement of reward-driven food intake (22–24).     

The ultrasound frequency determines the degree of intrinsic coagulation activation

Diagnostic ultrasound activates intrinsic coagulation. The aim of the present work was to quantify the action of different ultrasound frequencies on the contact phase of human blood coagulation. Pooled normal citrated platelet-poor plasma in 2 ml aliquots in polypropylene monovettes was exposed to diagnostic ultrasound, changing the ultrasound frequency from 17 to 15 to 12 to 8 to 7 MHz (at an intensity of 1.1 MI). After 0-2 min (23°C), 400 μl samples were withdrawn and placed into polypropylene Eppendorf cups. Forty microliters of plasma sample was pipetted into U-wells polystyrene microtiter plates of high purity (Brand781600). Immediately thereafter, the recalcified coagulation activity assay (RECA) was performed. Seventeen megahertz ultrasound exposure was the weakest activator of intrinsic coagulation of all frequencies tested: even 2 min of exposure at 23°C enhanced F2a generation by only about three-fold. The shorter the ultrasound exposure, the better the action against intrinsic hemostasis: 0.5 min of ultrasound exposure at 23°C induced less than two-fold thrombin generation in all frequencies tested. One minute ultrasound exposure (23°C) triggered intrinsic coagulation strongest at 8 MHz, showing an approximately four-fold increase in F2a generation. A 1.5 min of ultrasound exposure (23°C) triggered coagulation strongest at 7 MHz, showing an approximately 14-fold increase in F2a generation. Two minute of ultrasound exposure (23°C) triggered coagulation strongest at 15 MHz, showing an approximately 18-fold increase in F2a generation. Ultrasound has to be considered as a potential inducer of pathologic systemic coagulation. Patients at risk for increased coagulation activation and/or liver insufficiency should be protected with low molecular weight heparin, if a prolonged ultrasound diagnostic is planned. Ultrasound frequencies of about 17 MHz are the weakest activators of intrinsic coagulation. Ultrasound frequencies of about 7 MHz might be used for therapeutic induction of coagulation activation, such as in patients with severe cerebral or hepatic hemorrhages.     

Outcome of surgery for ileojejunal neuroendocrine tumors

Purpose

Neuroendocrine tumors (NET) of the ileum/jejunum are rare and may require different treatment options to provide long-term survival. The purpose of the study was to evaluate the outcome of surgery for ileojejunal NET.

Methods

A database of patients that underwent surgery for ileojejunal NETs between 1999 and 2010 was retrospectively analyzed regarding the clinical characteristics, surgical therapy, survival and prognostic factors.

Results

Only six of 97 patients with ileojejunal NET who underwent surgery had localized tumors (stage I/II), 29 had lymph node involvement (stage III) and 62 had distant metastases (stage IV) at the initial presentation. All stage I/II tumors were cured, in comparison to 69 % of stage III and 0 % of stage IV tumors (p = 0.01). Palliative surgery in combination with sequential multimodal treatment regimens resulted in a 5-year survival rate of 63 % in patients with stage IV tumors. A multivariate analysis showed that incomplete resection (HR 2.87; CI 1.18–6.98; p = 0.04) and distant metastases (HR 5.39; 95 % CI 1.23–23.57; p = 0.02) were associated with worse disease-specific survival.

Conclusions

Localized and regionally restricted ileojejunal NETs have an excellent prognosis after surgical treatment. Although stage IV tumors cannot be cured, an aggressive surgical approach in combination with medical or interventional treatment can provide long-term survival.