Chronic intracerebral prolactin attenuates neuronal stress circuitries in virgin rats

Prolactin (PRL) has been shown to promote maternal behaviour, and to regulate neuroendocrine and emotional stress responses. These effects appear more important in the peripartum period, when the brain PRL system is highly activated. Here, we studied the mechanisms that underlie the anti-stress effects of PRL. Ovariectomized, estradiol-substituted Wistar rats were implanted with an intracerebroventricular cannula and treated with ovine PRL (0.01, 0.1 or 1 microg/h; 5 days via osmotic minipumps) or vehicle, and their responses to acute restraint stress was assessed. Chronic PRL treatment exerted an anxiolytic effect on the elevated plus-maze, and attenuated the acute restraint-induced rise in plasma adrenocorticotropin, corticosterone and noradrenaline. At the neuronal level, in situ hybridization revealed PRL effects on the expression patterns of the immediate-early gene c-fos and corticotropin-releasing factor (CRF). Under basal conditions, PRL significantly reduced c-fos mRNA expression within the central amygdala. In response to restraint, the expression of both c-fos mRNA and protein and of CRF mRNA was decreased in the parvocellular part of the paraventricular nucleus (PVN) of PRL-treated compared with vehicle-treated animals. In conclusion, our data demonstrate that chronic elevation of PRL levels within the brain results in reduced neuronal activation within the hypothalamus, specifically within the PVN, in response to an acute stressor. Thus, PRL acting at various relevant brain regions exerts profound anxiolytic and anti-stress effects, and is likely to contribute to the attenuated stress responsiveness found in the peripartum period, when brain PRL levels are physiologically upregulated.     

The group home as moral laboratory: tracing the ethic of autonomy in Dutch intellectual disability care

Medicine, Health Care and Philosophy - This paper examines the prevalence of the ideal of “independence” in intellectual disability care in the Netherlands. It responds to a number of...     

Opposite effects of maternal separation on intermale and maternal aggression in C57BL/6 mice: link to hypothalamic vasopressin and oxytocin immunoreactivity

Early life stress, in particular child abuse and neglect, is an acknowledged risk factor for the development of pathological anxiety and aggression. In rodents, 3-h daily maternal separation (MS) during the first 2 weeks of life is an established animal model of early life stress and has repeatedly been shown to increase anxiety and stress responsiveness in adulthood. However, preclinical studies on the effects of postnatal stress on adult aggression are limited. The present study investigated whether MS affects intermale aggression and/or maternal aggression in C57BL/6 mice. In both adult male and virgin female mice, MS elevated anxiety-related behavior as tested on the elevated plus-maze, in the open field and during novel object exploration. The latency to attack an unknown male intruder, as assessed with the resident-intruder test, was significantly longer in MS male mice compared with control male mice. In contrast, the latency to attack a novel male intruder was significantly shorter in MS females compared with control females on days 3 and 5 of lactation. These opposite effects of MS can be explained by the fact that intermale and maternal aggression are two different forms of aggression, and hence, might be modulated by different neurobiological pathways. Indeed, in the paraventricular nucleus of the hypothalamus, MS was found to selectively increase vasopressin immunoreactivity in males, whereas MS selectively decreased oxytocin immunoreactivity in lactating females. In conclusion, MS has long-lasting and differential effects on adult intermale and maternal aggression in C57BL/6 mice. Alterations in hypothalamic vasopressin and oxytocin immunoreactivity may, in part, underlie the opposite effects of MS on intermale and maternal aggression. The MS paradigm represents a promising animal model to reveal underlying mechanisms of aggressive behavioral dysfunctions associated with early life stress.     

Elevated numbers and altered subsets of procoagulant microparticles in breast cancer patients using endocrine therapy

Introduction

Microparticles (MP) can be elevated in cancer and thromboembolic disease. We hypothesized a role for MP in the hypercoagulable state in breast cancer patients using endocrine therapy, in whom both cancer and the use of endocrine therapy are independent risk factors for the development of thrombosis.

Design and methods

Plasma samples were collected from 40 breast cancer patients using endocrine therapy (20 patients without metastases receiving adjuvant therapy and 20 patients with metastatic disease treated in a palliative setting) and from 20 female healthy controls. The endocrine therapy used was either an anti-estrogen or an aromatase inhibitor. Numbers and cellular origin of MP subsets were analyzed by flowcytometry. MP-associated procoagulant activity was measured using a thrombin generation assay using conditions that allow analysis of MP induced thrombin generation.

Results

Breast cancer patients using endocrine therapy had higher levels of MP positive for Annexin V (median 10000 vs 6500 × 10E6/l), P-selectin (330 vs 200 × 10E6/l), tissue factor (33 vs 15 × 10E6/l), and of MP derived from platelets (CD41) and leukocytes (CD45). Thrombin generation in plasma was dependent on the presence of MP and thrombin generation performed after addition of isolated MP to normal plasma showed a higher endogenous thrombin potential (1105 vs 1029 nM.min) in breast cancer patients. No differences were observed in MP levels and thrombin generation parameters between the metastatic and adjuvant group.

Conclusion

Breast cancer patients using endocrine therapy have an increased MP number and a higher MP-dependent thrombin generation, irrespective of the presence of metastatic disease. Altered MP subset characteristics in these patients, especially the higher number of (activated) platelet derived MP and leukocyte derived MP, may in part explain a heightened procoagulant state in breast cancer patients using endocrine therapy.     

The care receivers perspective: How care‐dependent people struggle with accepting help from family members,friends and neighbours

In many countries in north‐western Europe, the welfare state is changing, and governments expect a great deal of informal care. In the Netherlands, citizens are also increasingly expected to rely on informal instead of professional care. In this study, we aim to determine to what extent Dutch care‐dependent people want to rely on social network members and what reasons they raise for accepting or refusing informal care. To answer this question, we observed 65 so‐called ‘kitchen table talks’, in which social workers assess citizens’ care needs and examine to what extent relatives, friends and/or neighbours can provide help and care. We also interviewed 50 professionals and 30 people in need of care. Our findings show that a great deal of informal care is already given (in 46 out of 65 cases), especially between people who have a close emotional bond. For this reason, people in need of care often find it difficult to ask their family members, friends or neighbours for extra assistance. People are afraid to overburden their family members, friends or neighbours. Another reason people in need of care raise against informal care is that they feel ashamed of becoming dependent. Although the government wants to change the meaning of autonomy by emphasising that people are autonomous when they rely on social network members, people who grew up in the heyday of the welfare state feel embarrassed and ashamed when they are not able to reciprocate. Our findings imply that policymakers and social professionals need to reconsider the idea that resources of informal care are inexhaustible and that citizens can look after each other much more than they already do. It is important that social policymakers approach the codes and norms underlying social relations more cautiously because pressure on these relations can have negative effects.     

Early life stress impairs social recognition due to a blunted response of vasopressin release within the septum of adult male rats

Early life stress poses a risk for the development of psychopathologies characterized by disturbed emotional, social, and cognitive performance. We used maternal separation (MS, 3h daily, postnatal days 1-14) to test whether early life stress impairs social recognition performance in juvenile (5-week-old) and adult (16-week-old) male Wistar rats. Social recognition was tested in the social discrimination test and defined by increased investigation by the experimental rat towards a novel rat compared with a previously encountered rat. Juvenile control and MS rats demonstrated successful social recognition at inter-exposure intervals of 30 and 60 min. However, unlike adult control rats, adult MS rats failed to discriminate between a previously encountered and a novel rat after 60 min. The social recognition impairment of adult MS rats was accompanied by a lack of a rise in arginine vasopressin (AVP) release within the lateral septum seen during social memory acquisition in adult control rats. This blunted response of septal AVP release was social stimulus-specific because forced swimming induced a rise in septal AVP release in both control and MS rats. Retrodialysis of AVP (1 μg/ml, 3.3 μl/min, 30 min) into the lateral septum during social memory acquisition restored social recognition in adult MS rats at the 60-min interval. These studies demonstrate that MS impairs social recognition performance in adult rats, which is likely caused by blunted septal AVP activation. Impaired social recognition may be linked to MS-induced changes in other social behaviors like aggression as shown previously.     

Recurrence of Clostridium difficile-associated diarrhoea prevented by the administration of a whey concentrate from specifically immunised cows; prospective study

OBJECTIVE: To try to prevent recurrences of Clostridium difficile-associated diarrhoea (CDAD) by treatment with a specific neutralising secretory IgA-enriched whey-protein concentrate (40%) made from the milk of cows immunised with C. difficile and its toxins. DESIGN: Prospective, non-blinded, clinical cohort study. METHOD: In 2005-2006, 100 consecutive patients with CDAD received the whey concentrate for 2 weeks after completion of standard antibiotic therapy. For a period of 60 days after the start of the administration, the safety and preliminary efficacy of the whey concentrate were evaluated by means of a diary, blood determinations, active surveillance for adverse events, and the recurrence of CDAD. RESULTS: The whey concentrate was well tolerated and no safety issues were raised. Eleven out of 109 episodes (10%) were followed by a recurrence. After completion of the whey concentrate therapy, a positive test for faecal toxins or culture of C. difficile was predictive for the recurrence of CDAD (relative risk: 8.2 (95% CI: 1.04-64), and 4.7 (95% CI: 0.5-47), respectively). A positive faeces toxin during administration of the whey concentrate was also associated with an early recurrence of CDAD. CONCLUSION: Compared to historical and contemporary findings in control groups, the whey concentrate appeared to reduce the recurrence of CDAD by about 50%. However, the standard dose of the whey concentrate was probably not sufficient to fully neutralise the C. difficile toxins in faeces in all episodes.     

Prenatal stress increases HPA axis activity and impairs maternal care in lactating female offspring: implications for postpartum mood disorder

Early life stress is believed to constitute a risk factor for the development of mood disorders later in life. In the present study, we hypothesized that prenatal stress (PS) exerts long-lasting effects in female rat offspring, resulting in impaired adaptations to stress during lactation and, as such, may be a contributory factor to postpartum mood disorders. PS increased anxiety in adult virgin females compared with controls. During lactation, PS dams nursed significantly less and spent less time with pups compared with controls, whereas dams did not differ in pup retrieval or maternal aggression. HPA axis reactivity was elevated in response to a mild stressor in PS dams compared to their controls, but not in virgins, with the delta corticosterone response returning to the higher level seen in virgins. Moreover, corticotropin-releasing hormone (CRH) mRNA expression within the parvocellular region of the paraventricular nucleus (PVN) was increased in both virgins and dams exposed to PS compared with the relative controls, while the attenuation in expression in lactating controls was abolished following PS. In addition, arginine vasopressin (AVP) mRNA was increased in the parvocellular, but not magnocellular part of the PVN, in both PS-exposed virgins and lactating dams compared with their relative controls; although expression was also higher in controls during lactation compared with virgins. Thus, the present study demonstrates that exposure to PS results in long-lasting behavioural and neuroendocrine alterations in the female offspring, which are manifested during the lactation period. Furthermore, it implicates PS as a potential risk factor for the development of postpartum mood disorders, and that alterations in the HPA axis reactivity, at least partially, are involved.