Under anthropogenic climate change, emerging diseases and pathogens are increasingly prevalent in high latitude and altitude regions that were previously protected by cold winter temperatures. Ongoing island-wide dieback of a foundation species, the cushion plant Azorella macquariensis, on World Heritage listed Macquarie Island provides the first sub-Antarctic example. To better understand the island-wide progression of cushion dieback and its drivers, we established and quantified plant condition classes and measured microclimate across 62 sites. We then tested whether the drivers of cushion dieback were associated with (i) water stress: represented by vapour pressure deficit, wind exposure and gravel content, (ii) pathogen virulence: using freezing days and extreme humidity as empirically supported surrogates, or (iii) both. There was a strong north-south progression in cushion condition, with dieback most active in the centre of the island and advanced in the north. Dieback was most extensive at sites with fewer freezing days and high humidity. Natural southern refugia were explained by the significantly colder temperatures, associated with a north-south temperature gradient. It is expected that under current climate change trajectories, where Macquarie is likely to continue to become warmer and wetter, cushion dieback will remain pervasive, expanding most slowly in the south and potentially outpacing recovery. We emphasise the need for increased awareness to prevent the establishment of pathogens into and across the landscapes of newly susceptible high latitude and altitude regions. Areas of high conservation significance need to be prioritised for management, to prevent further landscape-scale change under current climate trajectories.

INTRODUCTION: Mother-infant bonding describes the early emotional connectedness between a mother and her infant. The quality of the mother-infant bond early in life is related to the subsequent quality of the child's attachment, the quality of further mother-infant interactions, and various other social outcomes across the child's life span. The Recorded Interaction Task (RIT) was developed to assess mother-infant bonding using observational methods in a naturalistic but standardized setting, thus addressing shortcomings of previous self-report tools. The RIT focusses on the common interaction between mother and infant (aged 2 to 5 months old), during a diaper (nappy) change. The interaction is video recorded and later assessed. The RIT must be validated before it can be used to assess mother-infant bonding in future research or in clinical practice. METHODS: Face and content validity of the RIT were assessed by a panel of 6 experts in bonding and assessment of maternal and infant behavior. The RIT and self-reported Postpartum Bonding Questionnaire (PBQ) were administered to 15 mother-infant dyads with the correlation between their scores used to assess convergent validity. RESULTS: Acceptable face and content validity of the RIT was demonstrated. A weak correlation between the RIT and PBQ (r = -0.13) and their subscales (r = -0.22) were observed. A strong correlation between the RIT maternal behavior and infant behavior subscales was recorded (r = 0.69). DISCUSSION: The RIT appears to be a viable tool for the observational assessment of mother-infant bonding. Reliability testing and piloting will be required before the RIT can be used in future research or clinical practice.

BACKGROUND: Preliminary experimental studies have suggested that the in situ destruction of tumor tissue by local laser ablation (LA) may also stimulate host immunity against cancer. We investigated local and systemic induction of immune responses after laser ablation in the setting of residual tumor. METHODS: A murine colorectal cancer (CRC) liver metastasis model was used. Selected tumors of liver CRC bearing mice and livers of mice without tumor induction were treated with LA. Liver and tumor tissues from the ablation sites and from distant sites were collected at various time points following LA and changes in CD3+ T cells and Kupffer cells (F4/80 marker) infiltration and the expression of interferon gamma (IFNγ) were investigated by immunohistochemistry and ELISpot. Base line levels of CD3+ T cells and Kupffer cells were established in untreated mice. RESULTS: The presence of tumor induced significant accumulation of CD3+ T cells and Kupffer cells at the tumor-host interface, within the tumor vascular lakes and increased their baseline concentration within the liver parenchyma. LA of the liver induced accumulation of CD3+ T-cells and Kupffer cells at the site of injury and systemic induction of immune responses as discerned by the presence of IFNγ secreting splenocytes. LA of liver tumors induced significant increase of CD3+ T-cells at site of injury, within normal liver parenchyma, and the tumor-host interface of both ablated and distant tumors. In contrast Kupffer cells only accumulated in ablated tumors and the liver parenchyma but not in distant tumors. IFNγ expression increased significantly in ablated tumors and showed an increasing trend in distant tumors. CONCLUSION: Laser ablation in addition to local tumor destruction induces local and systemic Th1 type immune responses which may play a significant role in inhibiting tumor recurrence from residual micrometastases or circulating tumor cells.

Epithelial to mesenchymal transition (EMT) is considered an important mechanism in tumor resistance to drug treatments; however, in vivo observation of this process has been limited. In this study we demonstrated an immediate and widespread EMT involving all surviving tumor cells following treatment of a mouse model of colorectal liver metastases with the vascular disruptive agent OXi4503. EMT was characterized by significant downregulation of E-cadherin, relocation and nuclear accumulation of β-catenin as well as significant upregulation of ZEB1 and vimentin. Concomitantly, significant temporal upregulation in hypoxia and the pro-angiogenic growth factors hypoxia-inducible factor 1-alpha, hepatocyte growth factor, vascular endothelial growth factor and transforming growth factor-beta were seen within the surviving tumor. The process of EMT was transient and by 5 days after treatment tumor cell reversion to epithelial morphology was evident. This reversal, termed mesenchymal to epithelial transition (MET) is a process implicated in the development of new metastases but has not been observed in vivo histologically. Similar EMT changes were observed in response to other antitumor treatments including chemotherapy, thermal ablation, and antiangiogenic treatments in our mouse colorectal metastasis model and in a murine orthotopic breast cancer model after OXi4503 treatment. These results suggest that EMT may be an early mechanism adopted by tumors in response to injury and hypoxic stress, such that inhibition of EMT in combination with other therapies could play a significant role in future cancer therapy.

Targeted therapies require information on specific defective signaling pathways or mutations. Advances in genomic technologies and cell biology have led to identification of new therapeutic targets associated with signal-transduction pathways. Survival times of patients with colorectal cancer (CRC) can be extended with combinations of conventional cytotoxic agents and targeted therapies. Targeting EGFR- and VEGFR-signaling systems has been the major focus for treatment of metastatic CRC. However, there are still limitations in their clinical application, and new and better drug combinations are needed. This review provides information on EGFR and VEGF inhibitors, new therapeutic agents in the pipeline targeting EGFR and VEGFR pathways, and those targeting other signal-transduction pathways, such as MET, IGF1R, MEK, PI3K, Wnt, Notch, Hedgehog, and death-receptor signaling pathways for treatment of metastatic CRC. Additionally, multitargeted approaches in combination therapies targeting negative-feedback loops, compensatory networks, and cross talk between pathways are highlighted. Then, immunobased strategies to enhance antitumor immunity using specific monoclonal antibodies, such as the immune-checkpoint inhibitors anti-CTLA4 and anti-PD1, as well as the challenges that need to be overcome for increased efficacy of targeted therapies, including drug resistance, predictive markers of response, tumor subtypes, and cancer stem cells, are covered. The review concludes with a brief insight into the applications of next-generation sequencing, expression profiling for tumor subtyping, and the exciting progress made in in silico predictive analysis in the development of a prescription strategy for cancer therapy.

OBJECTIVE: Neurosurgical training poses particular challenges in Australia and New Zealand, given the large landmass, small population, and widely separated, often small, neurosurgical units. Such factors have necessitated a move away from autonomous, single-institution-based training to the selection of trainees by a centralized binational process. The success of this system is based on rigorous standardized evaluation of candidates' academic achievements, anatomical knowledge, references, and interview performance. Similarly, the accreditation of hospitals to train successful candidates has been standardized. The authors review the evolution of trainee selection and the accreditation of training posts in Australia and New Zealand. METHODS: The records of the Neurosurgical Society of Australasia Surgical Education and Training Board were reviewed for documents pertaining to the selection of neurosurgical trainees and the accreditation of training posts. Application records and referee scores from 2014 to the present were reviewed to encompass process changes, in particular the change from written referee reports to standardized interviews of referees. Surgical logbook case numbers for 23 trainees completing training in 2016, 2017, and 2018 were collated and presented in an aggregated, de-identified form as a measure of adherence to accreditation standards. Written evaluations of the training experience were also sought from two trainees reflecting on the selection process, the quality of training posts, and training limitations. RESULTS: While a time-consuming process, the method of obtaining referee reports by interview has resulted in a wider spread of scores, more able to separate high- and low-scoring applicants than other components of the selection process. Review of the training post accreditation records for the last 2 years showed that adherence to standards has resulted in loss of accreditation for one unit and shortened periods of review for units with more minor deficiencies. Two applications for accreditation have been denied. Examination of caseload data showed that trainees more than fulfill minimum requirements in accredited training posts, confirming the robust nature of this aspect of unit accreditation. CONCLUSIONS: A key factor determining the success of neurosurgical training in Australia and New Zealand has been a willingness to evolve selection and other processes to overcome challenges as they become apparent. According to available analyses, the revised referee process and strict accreditation standards appear effective. The benefits and challenges of the current training system are discussed in the context of a paucity of international literature.

Major depressive disorder (MDD) poses one of the highest disease burdens worldwide. Yet, current treatments targeting serotonergic and noradrenaline reuptake systems are insufficient to provide long-term relief from depressive symptoms in most patients, indicating the need for new treatment targets. Having the ability to influence behavior similar to depressive symptoms, as well as communicate with neuronal and neuroendocrine systems, the innate immune system is a strong candidate for MDD treatments. Given the complex nature of immune signaling, the main question becomes: What is the role of the innate immune system in MDD? The current review presents evidence that toll-like receptor 4 (TLR4), via driving both peripheral and central immune responses, can interact with serotonergic neurotransmission and cause neuroendocrine disturbances, thus integrating with widely observed hallmarks of MDD. Additionally, through describing the multi-directional communication between immune, neural and endocrine systems in stress, TLR4-related mechanisms can mediate stress-induced adaptations, which are necessary for the development of MDD. Therefore, apart from exogenous pathogenic mechanisms, TLR4 is involved in immune changes as a result of endogenous stress signals, playing an integral part in the pathophysiology, and could be a potential target for pharmacological treatments to improve current interventions for MDD.

Oxytocin is often portrayed as a hormone specific to social behavior, reflective of positive welfare states, and linked to mental states. Research on oxytocin in domesticated animal species has been few to date but is rapidly increasing (in dog, pig, cattle, sheep), with direct implications for animal welfare. This review evaluates the evidence for the specificity of oxytocin as an indicator of: 1. Social, 2. Positive, and 3. Psychological well-being. Oxytocin has most often been studied in socially relevant paradigms, with a lack of non-social control paradigms. Oxytocin research appears biased toward investigating positive valence, with a lack of control in valence or arousal. Oxytocin actions are modulated by the environmental and social contexts, which are important factors to consider. Limited evidence supports that oxytocin's actions are linked to psychological states; nevertheless whether this is a direct effect of oxytocin per se remains to be demonstrated. Overall, it is premature to judge oxytocin's potential as an animal welfare indicator given the few and discrepant findings and a lack of standardization in methodology. We cover potential causes for discrepancies and suggest solutions through appropriate methodological design, oxytocin sampling or delivery, analysis and reporting. Of particular interest, the oxytocinergic system as a whole remains poorly understood. Appreciation for the differences that social contact and group living pose in domesticated species and the way they interact with humans should be key considerations in using oxytocin as a psychosocial indicator of well-being.

Cortisol and oxytocin have been shown to interact in both the regulation of stress responses and in memory function. In the present study we administered cortisol to 35 healthy female subjects in a within-subject double-blind placebo-controlled design, while measuring oxytocin levels, adrenocorticotropic hormone (ACTH) levels, and free recall of pleasant and of unpleasant words. We found that cortisol administration suppressed ACTH levels and (1) induced a decrease in oxytocin associated with ACTH suppression and (2) an increase in oxytocin that was independent from ACTH suppression. This cortisol-induced increase in plasma oxytocin was associated with a selective decrease in immediate free recall of unpleasant words from primacy positions. The present results add to evidence that cortisol-induced increases in oxytocin could mediate some of the effects of stress and cortisol on memory, and possibly play a role in the regulation of the hypothalamo-pituitary-adrenal stress response. This mechanism could significantly impact affective and social behaviors, in particular during times of stress.

The role of endogenous oxytocin as neuromodulator of birth, lactation and social behaviors is well-recognized. Moreover, the use of oxytocin as a facilitator of social and other behaviors is becoming more and more accepted. Many positive effects have been attributed to intranasal oxytocin administration in animals and humans; with current research highlighting encouraging advances in its potential for use in mental health disorders. The new frontier will be investigating the effective use of oxytocin in pediatric populations. Limited animal data is available on this. Large-scale human studies focusing on autism are currently under way, but many other possibilities seem to lie in the future. However, we need to know more about the risks and effects of repeated use on the developing brain and body. This paper will provide an overview of the current understanding of the role of endogenous oxytocin and its related neuropeptide systems in influencing behaviors, in particular attachment, and will review (a) the literature on the use of intranasal oxytocin in young animals, children (age range birth-12 years) and adolescents (age range 13-19 years), (b) the expected benefits and risks based on the current research, and (c) the risks of oxytocin in children with severe psychopathology and early life trauma. The paper will conclude with a clinical perspective on these findings.

BACKGROUND: It is now recognized that many anticancer treatments positively modulate the antitumor immune response. Clinical and experimental studies have shown that inhibitors of the classical renin-angiotensin system (RAS) reduce tumor progression and are associated with better outcomes in patients with colorectal cancer. RAS components are expressed by most immune cells and adult hematopoietic cells, thus are potential targets for modulating tumor-infiltrating immune cells and can provide a mechanism of tumor control by the renin-angiotensin system inhibitors (RASi). AIM: To investigate the effects of the RASi captopril on tumor T lymphocyte distribution in a mouse model of colorectal liver metastases. METHODS: Liver metastases were established in a mouse model using an autologous colorectal cancer cell line. RASi (captopril 750 mg/kg) or carrier (saline) was administered to the mice daily via intraperitoneal injection, from day 1 post-tumor induction to endpoint (day 15 or 21 post-tumor induction). At the endpoint, tumor growth was determined, and lymphocyte infiltration and composition in the tumor and liver tissues were analyzed by flow cytometry and immunohistochemistry (IHC). RESULTS: Captopril significantly decreased tumor viability and impaired metastatic growth. Analysis of infiltrating T cells into liver parenchyma and tumor tissues by IHC and flow cytometry showed that captopril significantly increased the infiltration of CD3+ T cells into both tissues at day 15 following tumor induction. Phenotypical analysis of CD45+ CD3+ T cells indicated that the major contributing phenotype to this influx is a CD4 and CD8 double-negative T cell (DNT) subtype, while CD4+ T cells decreased and CD8+ T cells remained unchanged. Captopril treatment also increased the expression of checkpoint receptor PD-1 on CD8+and DNT subsets . CONCLUSION: Captopril treatment modulates the immune response by increasing the infiltration and altering the phenotypical composition of T lymphocytes and may be a contributing mechanism for tumor control.