Denial of Reward in the Neonate Shapes Sociability and Serotonergic Activity in the Adult Rat

BACKGROUND: Manipulations of the early environment are linked to long-lasting alterations of emotionality and social capabilities. Denial of rewarding mother-pup interactions in early life of rats could serve as model for child neglect. Negative consequences for social competence in later life, accompanied by changes in the serotonergic system would be expected. In contrast, rewarding mother-pup contact should promote adequate social abilities. METHODOLOGY/PRINCIPAL FINDINGS: Male Wistar rats trained in a T-maze during postnatal days 10-13 under denial (DER) or permission (RER) of maternal contact were tested for play behavior in adolescence and for coping with defeat in adulthood. We estimated serotonin (5-HT) levels in the brain under basal conditions and following defeat, as well as serotonin receptor 1A (5-HT1A) and serotonin transporter (SERT) expression. DER rats exhibited increased aggressive-like play behavior in adolescence (i.e. increased nape attacks, p<0.0001) and selected a proactive coping style during defeat in adulthood (higher sum of proactive behaviors: number of attacks, flights, rearings and defensive upright posture; p = 0.011, p<0.05 vs RER, non-handled-NH). In adulthood, they had lower 5-HT levels in both the prefrontal cortex (p<0.05 vs RER) and the amygdala (p<0.05 vs NH), increased 5-HT levels following defeat (PFC p<0.0001) and decreased serotonin turnover (amygdala p = 0.008). The number of 5-HT1A immunopositive cells in the CA1 hippocampal area was increased (p<0.05 DER, vs RER, NH); SERT levels in the amygdala were elevated (p<0.05 vs RER, NH), but were lower in the prefrontal cortex (p<0.05 vs NH). CONCLUSIONS/SIGNIFICANCE: Denial of expected maternal reward early in life negatively affects sociability and the serotonergic system in a complex manner. We propose that our animal model could contribute to the identification of the neurobiological correlates of early neglect effects on social behavior and coping with challenges, but also in parallel with the effects of a rewarding early-life environment

The effect of parity and environmental restriction on behavioural and physiological responses of pre-parturient pigs

There is increasing evidence that restriction of pre-parturient behaviour in pigs is stress-inducing, characterised by an elevation in hypothalamic-pituitary-adrenal (HPA) activity in gilts. To determine whether pigs adapt to behavioural restriction, through modification of nest-building behaviour, we studied pre-parturient pigs in either farrowing crates (no bedding, n = 7) or straw-bedded pens (n = 7) in their first (gilts) and second (sows) parity. with physiological measurements being taken in the second parity. Observations and blood sampling were carried out during the preparturient phase. Crated pigs changed posture more often than penned pigs (F-1,F-12 = 7.06, P <0.05), with the number of posture changes reducing across parities in both environments. The reduction in posture changing was more apparent in the crated sows which may indicate that attempted nest-building behaviour of sows with prior experience of farrowing crates is less fragmented. The crated pigs spent a greater proportion of time sitting across both parities (F-1,F-12 = 9.4, P <0.01), and spent less time manipulating available substrates (F-1,F-12 = 10.67, P <0.05). There was a tendency for penned pigs to spend a greater proportion of time standing (F-1,F-12 = 3.77, P = 0.076) with peak nesting behaviour occurring earlier in relation to parturition than in crated pigs. In addition penned sows performed more floor-directed behaviour than penned gilts, and at an earlier stage in relation to parturition. However, crated sows also performed peak nest-building earlier than crated gilts. Plasma cortisol profiles indicated elevated HPA activity in crated sows during the pre-parturient period (F-42,F-303 = 1.43, P <0.05) suggesting increased physiological stress, however, the difference between crated and penned sows was less than that previously seen in gilts. The increased range of pre-parturient behaviours seen in the penned sows suggests that experience may result in an 'improvement' in their nest-building behaviour: earlier preparation of the nest site and then subsequent manipulation of substrates. The crated sows appeared to show some behavioural adaptation to the crate environment; earlier peak in floor directed behaviour and total substrate directed behaviour, reduced posture changing. In conclusion the nest-building behaviour of pigs is modified over parities with adaptation to the behavioural restrictions imposed by the farrowing crate. However, this adaptation, through prior experience, does not completely reduce the elevation in HPA activity previously reported in pre-parturient crated gilts. (C) 2001 Elsevier Science B.V. All rights reserved

The failing heart stimulates tumor growth by circulating factors

Background—Heart failure (HF) survival has improved and nowadays many patients with HF die from non-cardiac causes, including cancer. Our aim was to investigate whether a causal relationship exists between HF and the development of cancer. Methods—HF was induced by inflicting large anterior myocardial infarction (MI) in APCmin mice, which are prone to develop precancerous intestinal tumors, and tumor growth was measured. In addition, to rule out hemodynamic impairment, a heterotopic heart transplantation model was employed, where an infarcted or sham-operated heart was transplanted into a recipient mouse, while the native heart was left in situ. After 6 weeks, tumor number, volume, and proliferation were quantified. Candidate secreted proteins were selected because they were previously associated both with (colon) tumor growth and with myocardial production in post-MI proteomic studies. Myocardial gene expression levels of these selected candidates were analyzed, as well as their proliferative effects on HT-29 (colon cancer) cells. We validated these candidates by measuring them in plasma of healthy subjects and HF patients. Finally, we associated the relation between cardiac specific and inflammatory biomarkers and new-onset cancer in a large prospective general population cohort. Results—The presence of failing hearts, both native and heterotopically transplanted, resulted in significantly increased intestinal tumor load of 2.4fold in APCmin mice (all P<0.0001). The severity of left ventricular (LV) dysfunction and fibrotic scar strongly correlated with tumor growth (P=0.002 and P=0.016, respectively). We identified several proteins (including serpinA3 and A1, fibronectin, ceruloplasmin, and PON1) that were elevated in human patients with chronic HF (N=101) compared to healthy subjects (N=180, P<0.001). Functionally, serpinA3 resulted in marked proliferation effects in human colon cancer (HT-29) cells, associated with Akt-S6 phosphorylation. Finally, elevated cardiac and inflammation biomarkers in apparently healthy humans (N=8319), were predictive for new-onset cancer (N=1124), independent from risk factors for cancer (age, smoking status and body mass index). Conclusions—We demonstrate that the presence of HF is associated with enhanced tumor growth and this is independent from hemodynamic impairment and could be due cardiac excreted factors. A diagnosis of HF may therefore be considered a risk factor for incident cancer

Axillary recurrence after a tumor-positive sentinel lymph node biopsy without axillary treatment: a review of the literature

Item does not contain fulltextBACKGROUND: Sentinel lymph node biopsy (SLNB) has become standard of care as a staging procedure in patients with invasive breast cancer. A positive SLNB allows completion axillary lymph node dissection (cALND) to be performed. The axillary recurrence rate (ARR) after cALND in patients with positive SLNB is low. Recently, several studies have reported a similar low ARR when cALND is not performed. This review aims to determine the ARR when cALND is omitted in SLNB-positive patients. METHODS: A literature search was performed in the PubMed database with the search terms "breast cancer," "sentinel lymph node biopsy," "axillary" and "recurrence." Articles with data regarding follow-up of patients with SLNB-positive breast cancer were identified. To be eligible, patients should not have received cALND and ARR should be reported. RESULTS: Thirty articles were analyzed. This resulted in 7,151 patients with SLNB-positive breast cancer in whom a cALND was omitted (median follow-up of 45 months, range 1-142 months). Overall, 41 patients developed an axillary recurrence. 27 studies described 3,468 patients with micrometastases in the SLNB, of whom 10 (0.3 %) developed an axillary recurrence. ARR varied between 0 and 3.7 %. Sixteen studies described 3,268 patients with macrometastases, 24 (0.7 %) axillary recurrences were seen. ARR varied between 0 and 7.1 %. Details regarding type of surgery and adjuvant treatment were lacking in the majority of studies. CONCLUSIONS: ARR appears to be low in SLNB-positive patients even when a cALND is not performed. Withholding cALND may be safe in breast cancer selected patients such as those with isolated tumor cells or micrometastatic disease

Safety of avoiding routine use of axillary dissection in early stage breast cancer: a systematic review

Item does not contain fulltextPhysicians are moving away from routine axillary lymph node dissection (ALND) in clinically node-negative breast cancer. We conducted a systemic review on the safety of this policy. Pubmed and Cochrane library were searched for. Sixty-eight studies were included: studies of clinically node-negative patients in the pre-sentinel node (SN) era; observational studies of SN-negative patients, without ALND; comparative studies of SN-negative patients, with a non-ALND and an ALND group; SN-positive studies, of patients without ALND. Primary endpoint was the pooled axillary recurrence rate (ARR) of each category; secondary endpoint was overall survival (OS) rate. In pre-SN studies, with larger tumors and less systemic therapy, ARR without ALND after 5-10 years follow-up was 12-18%, with 5% reduced OS. In the observational SN-negative studies, with median follow-up of 36 months, the pooled ARR was 0.6% (95% CI 0.6-0.8). In the comparative SN-negative studies, pooled ARR was 0.4% (95% CI 0.2-0.6) without ALND versus 0.3% (95% CI 0.1-0.6) with ALND at 31 and 47 months, respectively, and no survival disadvantage. In SN-positive studies, ARR was up to 1.7% (95% CI 1.0-2.7) at 30 months. For patients with an H&E positive SN the ARR without ALND was 5% after 23 months, which may imply rates as high as 13 and 18% after 5 and 8 years. In conclusion, this systematic review confirms the safety of omitting ALND in SN-negative patients. There is a potential role for avoiding ALND in selected SN-positive patients, but eligibility criteria and the role of systemic therapy need further to be elucidated