The Role of RFRP Neurons in the Allostatic Control of Reproductive Function.

Reproductive function is critical for species survival; however, it is energetically costly and physically demanding. Reproductive suppression is therefore a physiologically appropriate adaptation to certain ecological, environmental, and/or temporal conditions. This 'allostatic' suppression of fertility enables individuals to accommodate unfavorable reproductive circumstances and safeguard survival. The mechanisms underpinning this reproductive suppression are complex, yet culminate with the reduced secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus, which in turn suppresses gonadotropin release from the pituitary, thereby impairing gonadal function. The focus of this review will be on the role of RFamide-related peptide (RFRP) neurons in different examples of allostatic reproductive suppression. RFRP neurons release the RFRP-3 peptide, which negatively regulates GnRH neurons and thus appears to act as a 'brake' on the neuroendocrine reproductive axis. In a multitude of predictable (e.g., pre-puberty, reproductive senescence, and seasonal or lactational reproductive quiescence) and unpredictable (e.g., metabolic, immune and/or psychosocial stress) situations in which GnRH secretion is suppressed, the RFRP neurons have been suggested to act as modulators. This review examines evidence for and against these roles.

Leptin, but not Estradiol, Signaling in PACAP Neurons Modulates Puberty Onset.

The adipose-derived hormone leptin critically modulates reproductive function, such that its absence results in hypothalamic hypogonadism. Pituitary adenylate cyclase-activating polypeptide (PACAP)-expressing neurons are potential mediators of leptin's action on the neuroendocrine reproductive axis because they are leptin-sensitive and involved in both feeding behavior and reproductive function. In the complete absence of PACAP, male and female mice exhibit metabolic and reproductive abnormalities, yet there is some sexual dimorphism in the reproductive impairments. We tested whether PACAP neurons play a critical and/or sufficient role in mediating leptin's effects on reproductive function by generating PACAP-specific leptin receptor (LepR) knockout and rescue mice, respectively. We also generated PACAP-specific estrogen receptor alpha knockout mice to determine whether estradiol-dependent regulation of PACAP was critically involved in the control of reproductive function and whether it contributed to the sexually dimorphic effects of PACAP. We showed that LepR signaling in PACAP neurons is critically involved in the timing of female, but not male, puberty onset, but not fertility. Rescuing LepR-PACAP signaling in otherwise LepR-deficient mice was unable to rescue the reproductive deficits observed in LepR null mice but led to a marginal improvement in body weight and adiposity in females. Finally, PACAP-specific estrogen receptor alpha knockout did not lead to any changes in body weight or puberty onset compared with control mice. These data highlight that PACAP is a critical mediator of some of leptin's, but not estradiol's, influence on puberty onset in females, but is not critically involved in relaying leptin's effects in males or in adult females.

Dentistry responding in domestic violence and abuse (DRiDVA) feasibility study: a qualitative evaluation of the implementation experiences of dental professionals.

BACKGROUND: Domestic Violence and Abuse (DVA) is a persistent public health problem in the UK. Healthcare settings offer an opportunity to ask patients about DVA, either opportunistically or in response to the presence of injuries. However, it has been suggested that dental practices and dental teams have not been actively involved supporting adult patients when presenting with injuries that might have resulted from DVA. This qualitative study was conducted to satisfy the evaluative component of the Dentistry Responding in Domestic Violence and Abuse (DRiDVA) feasibility study. METHODS: In total, 30 participants took part in the study; nine associate dentists and practice principals/owners took part in one-to-one interviews and 21 auxiliary staff took part across two focus group discussion sessions. Data were analysed using the seven step Framework Analysis process. RESULT: Three key themes were identified from the data, focusing on barriers to enquiring about domestic violence and abuse, Facilitators of identification and referral of DVA in dental settings, and recommendations for further adaptation of intervention to dental settings. CONCLUSION: DVA training coupled with robust referral pathways to a named specialist DVA advocate increases knowledge and awareness of the signs of DVA and confidence in making onward referrals. Further research is needed to understand how to increase dental professional willingness to ask patients about DVA.

Deletion of Androgen Receptors From Kisspeptin Neurons Prevents PCOS Features in a Letrozole Mouse Model.

Polycystic ovarian syndrome (PCOS) is the leading cause of anovulatory infertility and is a heterogenous condition associated with a range of reproductive and metabolic impairments. While its etiology remains unclear, hyperandrogenism and impaired steroid negative feedback have been identified as key factors underpinning the development of PCOS-like features both clinically and in animal models. We tested the hypothesis that androgen signaling in kisspeptin-expressing neurons, which are key drivers of the neuroendocrine reproductive axis, is critically involved in PCOS pathogenesis. To this end, we used a previously validated letrozole (LET)-induced hyperandrogenic mouse model of PCOS in conjunction with Cre-lox technology to generate female mice exhibiting kisspeptin-specific deletion of androgen receptor (KARKO mice) to test whether LET-treated KARKO females are protected from the development of reproductive and metabolic PCOS-like features. LET-treated mice exhibited hyperandrogenism, and KARKO mice exhibited a significant reduction in the coexpression of kisspeptin and androgen receptor mRNA compared to controls. In support of our hypothesis, LET-treated KARKO mice exhibited improved estrous cyclicity, ovarian morphology, and insulin sensitivity in comparison to LET-treated control females. However, KARKO mice were not fully protected from the effects of LET-induced hyperandrogenism and still exhibited reduced corpora lutea numbers and increased body weight gain. These data indicate that increased androgen signaling in kisspeptin-expressing neurons plays a critical role in PCOS pathogenesis but highlight that other mechanisms are also involved.

Dentistry responding to domestic violence and abuse: a dental, practice-based intervention and a feasibility study for a cluster randomised trial.

Objectives Assess the feasibility of using the Identification and Referral to Improve Safety (IRIS) intervention in a general dental practice setting and evaluating it using a cluster randomised trial design. IRIS is currently used in general medical practices to aid recognition and support referral into specialist support of adults presenting with injuries and other presenting factors that might have resulted from domestic violence and abuse. Also, to explore the feasibility of a cluster randomised trial design to evaluate the adapted IRIS.Design Feasibility study for a cluster randomised trial of a practice-based intervention.Setting Greater Manchester general dental practices.Results It was feasible to adapt the IRIS intervention used in general medical practices to general dental practices in terms of training the clinical team and establishing a direct referral pathway to a designated advocate educator. General dental practices were keen to adopt the intervention, discuss with patients when presented with the opportunity and utilise the referral pathway. However, we could not use practice IT software prompts and data collection as for general practitioners because there is no unified dental IT system and because coding in dentistry for diagnoses, procedures and outcomes is not developed in the UK.Conclusion While it was feasible to adapt elements of the IRIS intervention to general dental practice and there was general acceptability, we did not have enough empirical data to plan a definitive cluster randomised trial design to evaluate the IRIS-dentistry intervention within general dental practices.

Central Irisin Signaling Is Required for Normal Timing of Puberty in Female Mice.

Timing of puberty requires exquisite coordination of genes, hormones, and brain circuitry. An increasing level of body adiposity, signaled to the brain via the fat-derived hormone leptin, is recognized as a major factor controlling puberty onset. However, it is clear that leptin is not the only metabolic cue regulating puberty, and that developmental regulation of this process also involves tissues other than adipose, with muscle development potentially playing a role in the timing of puberty. The proteolytic processing of fibronectin type 3 domain-containing protein 5 (FNDC5) releases a hormone, irisin. Irisin is primarily produced by muscle and is released into circulation, where levels increase dramatically as puberty approaches. We investigated the effects of a global deletion of the Fndc5 gene on pubertal timing. The absence of irisin induced a delay in puberty onset in female knockout mice compared with controls, without affecting body weight or gonadotropin-releasing hormone (GnRH) neuronal density. We next treated pre-pubertal wild-type male and female mice with an irisin receptor antagonist, cilengitide, for 7 days and observed a delay in first estrus occurrence compared to vehicle-treated control mice. Male puberty timing was unaffected. Next, we deleted the irisin receptor (integrin subunit alpha V) in all forebrain neurons and found a delay in the occurrence of first estrus in knockout females compared to controls. Taken together, these data suggest irisin plays a role in the timing of puberty onset in female mice via a centrally mediated mechanism.

Physiological regulation of leptin as an integrative signal of reproductive readiness.

Reproductive function is tightly regulated by both environmental and physiological factors. The adipose-derived hormone leptin has been identified as one such critical factor that relays information about peripheral energy availability to the centrally-governed HPG axis to ensure there is sufficient energy availability to support the high energy demands of mammalian reproduction. In the absence of adequate central leptin signaling, reproductive function is suppressed. While leptin levels are predominantly regulated by adiposity, circulating leptin levels are also under the modulatory influence of other factors, such as stress system activation, circadian rhythmicity, and immune activation and the inflammatory response. Furthermore, changes in leptin sensitivity can affect the degree to which leptin exerts its influence on the neuroendocrine reproductive axis. This review will discuss the different mechanisms by which leptin serves to integrate and relay information about metabolic, psychological, environmental and immune conditions to the central neuronal network that governs reproductive function.

Barriers to help-seeking from healthcare professionals amongst women who experience domestic violence - a qualitative study in Sri Lanka.

BACKGROUND: Domestic violence (DV) is a major global public health problem which is associated with significant adverse consequences. Although Sri Lankan women who experience DV receive treatment from healthcare professionals (HCPs) for DV related physical and psychological problems, disclosure of DV within health services is quite low. This study explored barriers to disclosure of DV to HCPs among Sri Lankan women who experience DV. METHOD: This qualitative study took place in the Central Province of Sri Lanka. Twenty women who had experienced DV were recruited from Gender Based Violence Centers (Mithuru Piyasa Centers) and a toxicology unit of the two selected hospitals. Participants were purposefully selected using maximum variation sampling technique. In-depth interviews were conducted until data saturation was reached. Interviews were recorded, and analyzed using thematic analysis. RESULTS: Survivor related barriers to help seeking included women's lack of knowledge and perceptions about the role of HCPs, lack of confidence in HCPs, fear of repercussions, personal attitudes towards DV, and their love and loyalty towards the perpetrator. Women preferred it if HCPs initiated discussions about DV, and they valued it when HCPs could be confidential and protect their privacy, and give enough time for DV related issues during consultations. A perpetrator related barrier was the controlling behavior of the perpetrator. Social stigma and social and cultural norms about the role of women emerged as the socio-cultural constraints to disclosure. CONCLUSIONS: Barriers to help seeking for DV from HCPs exist at individual, healthcare level, and societal level. Community programs are needed to increase women's access to healthcare services and interventions should be implemented to develop effective, preventive, and supportive strategies at the healthcare system level.

Deletion of PTP1B From Brain Neurons Partly Protects Mice From Diet-Induced Obesity and Minimally Improves Fertility.

Reproductive dysfunction in women has been linked to high caloric diet (HCD)-feeding and obesity. Central resistance to leptin and insulin have been shown to accompany diet-induced infertility in rodent studies, and we have previously shown that deleting suppressor of cytokine signaling 3, which is a negative regulator of leptin signaling, from all forebrain neurons partially protects mice from HCD-induced infertility. In this study, we were interested in exploring the role of protein tyrosine phosphatase 1B (PTP1B), which is a negative regulator of both leptin and insulin signaling, in the pathophysiology of HCD-induced obesity and infertility. To this end, we generated male and female neuron-specific PTP1B knockout mice and compared their body weight gain, food intake, glucose tolerance, and fertility relative to control littermates under both normal calorie diet and HCD feeding conditions. Both male and female mice with neuronal PTP1B deletion exhibited slower body weight gain in response to HCD feeding, yet only male knockout mice exhibited improved glucose tolerance compared with controls. Neuronal PTP1B deletion improved the time to first litter in HCD-fed mice but did not protect female mice from eventual HCD-induced infertility. While the mice fed a normal caloric diet remained fertile throughout the 150-day period of assessment, HCD-fed females became infertile after producing only a single litter, regardless of their genotype. These data show that neuronal PTP1B deletion is able to partially protect mice from HCD-induced obesity but is not a critical mediator of HCD-induced infertility.

Multiple Leptin Signalling Pathways in the Control of Metabolism and Fertility: A Means to Different Ends?

The adipocyte-derived 'satiety promoting' hormone, leptin, has been identified as a key central regulator of body weight and fertility, such that its absence leads to obesity and infertility. Plasma leptin levels reflect body adiposity, and therefore act as an 'adipostat', whereby low leptin levels reflect a state of low body adiposity (under-nutrition/starvation) and elevated leptin levels reflect a state of high body adiposity (over-nutrition/obesity). While genetic leptin deficiency is rare, obesity-related leptin resistance is becoming increasingly common. In the absence of adequate leptin sensitivity, leptin is unable to exert its 'anti-obesity' effects, thereby exacerbating obesity. Furthermore, extreme leptin resistance and consequent low or absent leptin signalling resembles a state of starvation and can thus lead to infertility. However, leptin resistance occurs on a spectrum, and it is possible to be resistant to leptin's metabolic effects while retaining leptin's permissive effects on fertility. This may be because leptin exerts its modulatory effects on energy homeostasis and reproductive function through discrete intracellular signalling pathways, and these pathways are differentially affected by the molecules that promote leptin resistance. This review discusses the potential mechanisms that enable leptin to exert differential control over metabolic and reproductive function in the contexts of healthy leptin signalling and of diet-induced leptin resistance.

Role of insulin in the neuroendocrine control of reproduction.

Infertility associated with insulin resistance is characterised by abnormal hormone secretion by the hypothalamus, pituitary gland and gonads. These endocrine tissues can maintain insulin sensitivity even when tissues such as the muscle and liver become insulin-resistant, resulting in excessive insulin stimulation as hyperinsulinaemia develops. Experiments conducted to determine the role of neuronal insulin signalling in fertility were unable to recapitulate early findings of hypogonadotrophic hypogonadism in mice lacking insulin receptors throughout the brain. Rather, it was eventually shown that astrocytes critically mediate the effects of insulin on puberty timing and adult reproductive function. However, specific roles for neurones and gonadotrophs have been revealed under conditions of hyperinsulinaemia and by ablation of insulin and leptin receptors. The collective picture is one of multiple insulin-responsive inputs to gonadotrophin releasing hormone neurones, with astrocytes being the most important player.

RFamide-Related Peptide Neurons Modulate Reproductive Function and Stress Responses.

RF-amide related peptide 3 (RFRP-3) is a neuropeptide thought to inhibit central regulation of fertility. We investigated whether alterations in RFRP neuronal activity led to changes in puberty onset, fertility, and stress responses, including stress and glucocorticoid-induced suppression of pulsatile luteinizing hormone secretion. We first validated a novel RFRP-Cre mouse line, which we then used in combination with Cre-dependent neuronal ablation and DREADD technology to selectively ablate, stimulate, and inhibit RFRP neurons to interrogate their physiological roles in the regulation of fertility and stress responses. Chronic RFRP neuronal activation delayed male puberty onset and female reproductive cycle progression, but RFRP-activated and ablated mice exhibited apparently normal fertility. When subjected to either restraint- or glucocorticoid-induced stress paradigms. However, we observed a critical sex-specific role for RFRP neurons in mediating acute and chronic stress-induced reproductive suppression. Female mice exhibiting RFRP neuron ablation or silencing did not exhibit the stress-induced suppression in pulsatile luteinizing hormone secretion observed in control mice. Furthermore, RFRP neuronal activation markedly stimulated glucocorticoid secretion, demonstrating a feedback loop whereby stressful stimuli activate RFRP neurons, which in turn further activate the stress axis. These data provide evidence for a neuronal link between the stress and reproductive axes.

Barriers to women's disclosure of domestic violence in health services in Palestine: qualitative interview-based study.

BACKGROUND: Domestic violence (DV) damages health and requires a global public health response and engagement of clinical services. Recent surveys show that 27% of married Palestinian women experienced some form of violence from their husbands over a 12 months' period, but only 5% had sought formal help, and rarely from health services. Across the globe, barriers to disclosure of DV have been recorded, including self-blame, fear of the consequences and lack of knowledge of services. This is the first qualitative study to address barriers to disclosure within health services for Palestinian women. METHODS: In-depth interviews were carried out with 20 women who had experienced DV. They were recruited from a non-governmental organisation offering social and legal support. Interviews were recorded, transcribed and translated into English and the data were analysed thematically. RESULTS: Women encountered barriers at individual, health care service and societal levels. Lack of knowledge of available services, concern about the health care primary focus on physical issues, lack of privacy in health consultations, lack of trust in confidentiality, fear of being labelled 'mentally ill' and losing access to their children were all highlighted. Women wished for health professionals to take the initiative in enquiring about DV. Wider issues concerned women's social and economic dependency on their husbands which led to fears about transgressing social and cultural norms by speaking out. Women feared being blamed and ostracised by family members and others, or experiencing an escalation of violence. CONCLUSIONS: Palestinian women's agency to be proactive in help-seeking for DV is clearly limited. Our findings can inform training of health professionals in Palestine to address these barriers, to increase awareness of the link between DV and many common presentations such as depression, to ask sensitively about DV in private, reassure women about confidentiality, and increase awareness among women of the role that health services can play in DV.

Women's experiences of a randomised controlled trial of a specialist psychological advocacy intervention following domestic violence: A nested qualitative study.

BACKGROUND: Women's experience of domestic violence and abuse (DVA) is associated with mental illness which may not be addressed by domestic violence advocacy. The study aimed to compare the experiences of women receiving a psychological intervention with women receiving usual advocacy in a randomized controlled trial (PATH: Psychological Advocacy Towards Healing), to illuminate the trial results by exploring women's experiences of benefits and difficulties. METHODS: A qualitative study nested within the PATH trial, based in two DVA agencies in the UK. A purposive sample of thirty-one intervention and usual care participants were interviewed up to three interviews over a year. Thematic analysis was carried out, incorporating concepts from the Trans-Theoretical Model of change. FINDINGS: The PATH trial reports a clinically relevant improvement in mental health outcomes for women receiving the intervention compared to usual advocacy. The qualitative study reveals which elements of the intervention were beneficial or problematic, which outcomes were most meaningful and relevant to participants and highlights reasons for variations in adherence. Women valued the educational, psychological and emotional elements of the intervention, they felt safe to explore repressed emotions for the first time and experienced a reduction in self-blame, improved sense of identity and greater self-esteem. They also incorporated new skills and self-help techniques to enable sustainable change. Women receiving usual advocacy reported un-met needs for psychological and emotional support. Adherence was affected by women's 'psychological 'readiness' to engage, the competing demands of practical issues such as housing insecurity, legal proceedings or the availability of child care, and breaks in the continuity of professional care. CONCLUSIONS: Continuity and regularity of sessions with a trained specialist worker was key to women's recovery. Individual assessment of 'readiness' would optimise the timing of delivery to maximise adherence and benefit.

Integration of Circadian and Metabolic Control of Reproductive Function.

Optimal fertility in humans and animals relies on the availability of sufficient metabolic fuels, information about which is communicated to the brain via levels of the hormones leptin and insulin. The circadian clock system is also critical; this input is especially evident in the precise timing of the female-specific surge of GnRH and LH secretion that triggers ovulation the next day. Chronodisruption and metabolic imbalance can both impair reproductive activity, and these two disruptions exacerbate each other, such that they often occur simultaneously. Kisspeptin neurons located in the anteroventral periventricular nucleus of the hypothalamus are able to integrate both circadian and metabolic afferent inputs and use this information to modulate the timing and magnitude of the preovulatory GnRH/LH surge. In an environment in which exposure to high caloric diets and chronodisruptors such as artificial night lighting, shift work, and transmeridian travel have become the norm, the implications of these factors for couples struggling to conceive deserve closer attention and more public education.

Leptin and insulin do not exert redundant control of metabolic or emotive function via dopamine neurons.

Leptin and insulin's hunger-suppressing and activity-promoting actions on hypothalamic neurons are well characterized, yet the mechanisms by which they modulate the midbrain dopamine system to influence energy balance remain less clear. A subset of midbrain dopamine neurons express receptors for leptin (Lepr) and insulin (Insr). Leptin-dopamine signaling reduces running reward and homecage activity. However, dopamine-specific deletion of Lepr does not affect body weight or food intake in mice. We hypothesized insulin-dopamine signaling might compensate for disrupted leptin-dopamine signaling. To investigate the degree to which insulin and leptin exert overlapping (i.e. redundant) versus discrete control over dopamine neurons, we generated transgenic male and female mice exhibiting dopamine-specific deletion of either Lepr (Lepr KO), Insr (Insr KO) or both Lepr and Insr (Dbl KO) and assessed their feeding behavior, voluntary activity, and energy expenditure compared to control mice. No differences in body weight, daily food intake, energy expenditure or hyperphagic feeding of palatable chow were observed between Lepr, Insr or Dbl KO mice and control mice. However, consistent with previous findings, Lepr KO (but not Insr or Dbl KO) male mice exhibited significantly increased running wheel activity compared to controls. These data demonstrate that insulin and leptin do not exert redundant control of dopamine neuron-mediated modulation of energy balance. Furthermore, our results indicate neither leptin nor insulin plays a critical role in the modulation of dopamine neurons regarding hedonic feeding behavior or anxiety-related behavior.

'Who does this patient belong to?' boundary work and the re/making of (NSTEMI) heart attack patients.

This ethnography within ten English and Welsh hospitals explores the significance of boundary work and the impacts of this work on the quality of care experienced by heart attack patients who have suspected non-ST segment elevation myocardial infarction (NSTEMI) /non-ST elevation acute coronary syndrome. Beginning with the initial identification and prioritisation of patients, boundary work informed negotiations over responsibility for patients, their transfer and admission to different wards, and their access to specific domains in order to receive diagnostic tests and treatment. In order to navigate boundaries successfully and for their clinical needs to be more easily recognised by staff, a patient needed to become a stable boundary object. Ongoing uncertainty in fixing their clinical classification, was a key reason why many NSTEMI patients faltered as boundary objects. Viewing NSTEMI patients as boundary objects helps to articulate the critical and ongoing process of classification and categorisation in the creation and maintenance of boundary objects. We show the essential, but hidden, role of boundary actors in making and re-making patients into boundary objects. Physical location was critical and the parallel processes of exclusion and restriction of boundary object status can lead to marginalisation of some patients and inequalities of care (A virtual abstract of this paper can be viewed at: https://www.youtube.com/channel/UC_979cmCmR9rLrKuD7z0ycA).

Dopamine Neuron-Restricted Leptin Receptor Signaling Reduces Some Aspects of Food Reward but Exacerbates the Obesity of Leptin Receptor-Deficient Male Mice.

The contribution of leptin-induced modulation of dopamine neurons to feeding behavior and energy homeostasis remains unclear. Midbrain dopamine neurons regulate the reward value of food, and direct leptin administration to the midbrain reduces food intake. However, selective deletion of leptin receptors (Leprs) from dopamine neurons has no effect on body weight, food intake, or hedonic responses, suggesting that leptin acts indirectly or demonstrating that sufficient compensation occurs to mask any direct leptin-dopamine effects. To further explore the role of direct Lepr-dopamine neuron signaling in the control of feeding behavior and energy homeostasis, we generated mice in which Leprs were expressed exclusively in dopamine transporter (DAT)-expressing neurons (LeprDAT). We then assessed weekly body weight, daily food intake, hyperphagic feeding, and leptin-induced suppression of feeding in the LeprDAT mice compared with their Lepr-deficient (LeprNULL) and wild-type control (LeprCON) littermates. We also used metabolic cages to characterize running wheel activity, home-cage activity, and total energy expenditure. As expected, LeprNULL mice exhibited increased body weight and food intake compared with LeprCON mice. LeprDAT male mice exhibited acute leptin-induced suppression of food intake and reduced hedonic feeding but also exhibited significantly increased postweaning body weight gain compared with the LeprNULL mice. This was associated with significantly reduced home-cage activity counts, although no differences in food intake were observed between the LeprDAT and LeprNULL mice. These data demonstrate that restoring Lepr signaling exclusively in dopamine neurons reduces some aspects of food reward and activity but does not ameliorate the obesity phenotype of Lepr-deficient mice.

Aligning the planets: The role of nurses in the care of patients with non-ST elevation myocardial infarction.

BACKGROUND: Studies have shown variation in care for patients with non-ST elevation myocardial infarction (NSTEMI), including in the roles of specialist and advanced practice nurses in diagnosis, treatment and coordination of care. AIM: The aim of this study was to describe the roles and responsibilities of specialist and advanced practice nurses in providing care for patients with NSTEMI. METHODS: Secondary analysis of observational field notes and interviews from an ethnographic study of variation in care for NSTEMI patients in 10 UK hospitals conducted 2011-2012. Data were thematically analysed to identify key concepts and themes related to the roles of specialist nurses. RESULTS: Seven of 10 hospitals had roles for specialist nurses in NSTEMI care. The major theme related to high demand and the complexity of patients and organizations ('Aligning the planets'). In this theme, nurses contributed to improving services or compensating for deficiencies ('Making the system work versus making up for the system'). Data collection for audit could take precedence over time with patients ('Paying worship to the paper'). Nurses expressed a sense of ownership of cardiovascular patients that drove their desire to provide quality of care ('They are our patients').

Neuroendocrine integration of nutritional signals on reproduction.

Reproductive function in mammals is energetically costly and therefore tightly regulated by nutritional status. To enable this integration of metabolic and reproductive function, information regarding peripheral nutritional status must be relayed centrally to the gonadotropin-releasing hormone (GNRH) neurons that drive reproductive function. The metabolically relevant hormones leptin, insulin and ghrelin have been identified as key mediators of this 'metabolic control of fertility'. However, the neural circuitry through which they act to exert their control over GNRH drive remains incompletely understood. With the advent of Cre-LoxP technology, it has become possible to perform targeted gene-deletion and gene-rescue experiments and thus test the functional requirement and sufficiency, respectively, of discrete hormone-neuron signaling pathways in the metabolic control of reproductive function. This review discusses the findings from these investigations, and attempts to put them in context with what is known from clinical situations and wild-type animal models. What emerges from this discussion is clear evidence that the integration of nutritional signals on reproduction is complex and highly redundant, and therefore, surprisingly difficult to perturb. Consequently, the deletion of individual hormone-neuron signaling pathways often fails to cause reproductive phenotypes, despite strong evidence that the targeted pathway plays a role under normal physiological conditions. Although transgenic studies rarely reveal a critical role for discrete signaling pathways, they nevertheless prove to be a good strategy for identifying whether a targeted pathway is absolutely required, critically involved, sufficient or dispensable in the metabolic control of fertility.