Still a 'boys' club': a qualitative analysis of how gender affects a career in anaesthesia in Australia and Aotearoa New Zealand.

Gender inequity remains an issue in anaesthesia despite increasing numbers of women training and achieving fellowship in the speciality. Women are under-represented in all areas of anaesthetic research, academia and leadership. The Gender Equity Subcommittee of the Australian and New Zealand College of Anaesthetists recently conducted a survey asking "Does gender still matter in the pursuit of a career in anaesthesia in 2022?". The survey was distributed to a randomly selected sample of 1225 anaesthetic consultants and completed by 470 respondents (38% response rate) with 793 free-text comments provided. Three overarching themes were identified: gender effects on the career and family interface; women do not fit the mould; and gender equity changes the status quo. Women respondents described a need to make a choice between career and family, which was not described by men, as well as stigmatisation of part-time work, a lack of access to challenging work and negative impacts of parental leave. Women respondents also described a sense of marginalisation within anaesthesia due to a 'boys' club' mentality, a lack of professional respect and insufficient structural supports for women in leadership. This was compounded for women from ethnically and culturally diverse backgrounds. A need for specific strategies to support anaesthetic careers for women was described as well as normalisation of flexibility in workplaces, combined with a broadening of our definition of success to allow people of all genders to experience fulfilment both at home and at work. This study is the first published qualitative data on factors affecting gender equity for anaesthetists in Australia and Aotearoa New Zealand. It highlights the need for further exploration, as well providing a foundation for changes in attitude and structural changes towards advancing gender equity.

Young@Heart: empowering the next generation of cardiovascular researchers.

In recognition of the increasing health burden of cardiovascular disease, the Dutch CardioVascular Alliance (DCVA) was founded with the ambition to lower the cardiovascular disease burden by 25% in 2030. To achieve this, the DCVA is a platform for all stakeholders in the cardiovascular field to align policies, agendas and research. An important goal of the DCVA is to guide and encourage young researchers at an early stage of their careers in order to help them overcome challenges and reach their full potential. Young@Heart is part of the DCVA that supports the young cardiovascular research community. This article illustrates the challenges and opportunities encountered by young cardiovascular researchers in the Netherlands and highlights Young@Heart's vision to benefit from these opportunities and optimise collaborations to contribute to lowering the cardiovascular disease burden together as soon as possible.

Inhibition of JNK activation through NF-kappaB target genes.

The proinflammatory cytokine tumour necrosis factor-alpha (TNF-alpha) regulates immune responses, inflammation and programmed cell death (apoptosis). The ultimate fate of a cell exposed to TNF-alpha is determined by signal integration between its different effectors, including IkappaB kinase (IKK), c-Jun N-terminal protein kinase (JNK) and caspases. Activation of caspases is required for apoptotic cell death, whereas IKK activation inhibits apoptosis through the transcription factor NF-kappaB, whose target genes include caspase inhibitors. JNK activates the transcription factor c-Jun/AP-1, as well as other targets. However, the role of JNK activation in apoptosis induced by TNF-alpha is less clear. It is unknown whether any crosstalk occurs between IKK and JNK, and, if so, how it affects TNF-alpha-induced apoptosis. We investigated this using murine embryonic fibroblasts that are deficient in either the IKKbeta catalytic subunit of the IKK complex or the RelA/p65 subunit of NF-kappaB. Here we show that in addition to inhibiting caspases, the IKK/NF-kappaB pathway negatively modulates TNF-alpha-mediated JNK activation, partly through NF-kappaB-induced X-chromosome-linked inhibitor of apoptosis (XIAP). This negative crosstalk, which is specific to TNF-alpha signalling and does not affect JNK activation by interleukin-1 (IL-1), contributes to inhibition of apoptosis.

Activation of NF-kappa B is required for hypertrophic growth of primary rat neonatal ventricular cardiomyocytes.

The transcription factor NF-kappaB regulates expression of genes that are involved in inflammation, immune response, viral infection, cell survival, and division. However, the role of NF-kappaB in hypertrophic growth of terminally differentiated cardiomyocytes is unknown. Here we report that NF-kappaB activation is required for hypertrophic growth of cardiomyocytes. In cultured rat primary neonatal ventricular cardiomyocytes, the nuclear translocation of NF-kappaB and its transcriptional activity were stimulated by several hypertrophic agonists, including phenylephrine, endothelin-1, and angiotensin II. The activation of NF-kappaB was inhibited by expression of a "supersuppressor" IkappaBalpha mutant that is resistant to stimulation-induced degradation and a dominant negative IkappaB kinase (IKKbeta) mutant that can no longer be activated by phosphorylation. Furthermore, treatment with phenylephrine induced IkappaBalpha degradation in an IKK-dependent manner, suggesting that NF-kappaB is a downstream target of the hypertrophic agonists. Importantly, expression of the supersuppressor IkappaBalpha mutant or the dominant negative IKKbeta mutant blocked the hypertrophic agonist-induced expression of the embryonic gene atrial natriuretic factor and enlargement of cardiomyocytes. Conversely, overexpression of NF-kappaB itself induced atrial natriuretic factor expression and cardiomyocyte enlargement. These findings suggest that NF-kappaB plays a critical role in the hypertrophic growth of cardiomyocytes and may serve as a potential target for the intervention of heart disease.

Activation of NF-kappaB by hepatitis B virus X protein through an IkappaB kinase-independent mechanism.

pX, the hepatitis B virus-encoded transcription coactivator, is involved in viral infection in vivo. pX stimulates the activity of several transcription factors including nuclear factor-kappaB (NF-kappaB), but the mechanism of activation is poorly understood. The IkappaB kinase complex (IKK) mediates activation of NF-kappaB in response to various extracellular stimuli, including inflammatory cytokines like tumor necrosis factor and interleukin 1, human T cell lymphoma virus 1 Tax protein, and tumor promoters like phorbol esters. It is not known whether IKK also mediates activation of NF-kappaB by pX. Here we report that IKK was not essential for activation of NF-kappaB by pX. Expression of pX resulted in the degradation of IkappaBalpha in the absence of its phosphorylation at Ser(32) and Ser(36) residues. Although pX stimulated the activity of cotransfected IKK-beta when it was overexpressed, it failed to activate endogenous IKK. Furthermore, expression of pX stimulated NF-kappaB nuclear translocation and transcriptional activity in IKK-gamma-null fibroblast 5R cells. Our data indicate that pX stimulates NF-kappaB activity through a mechanism that is dependent on IkappaBalpha degradation but not on IKK activation.

A study of the endocrine manifestations of hepatic cirrhosis.

The clinical features and hormonal abnormalities were surveyed in 117 men with cirrhosis of the liver. Compared with healthy men of similar ages, the patients had significantly lower metabolic clearance rates, plasma production rates and total and free levels of testosterone, reduced testosterone responses to human chorionic gonadotrophin stimulation, higher oestradiol, luteinizing hormone and follicle stimulating hormone levels and higher binding capacities of sex steroid binding globulin. The peripheral conversion of testosterone to oestradiol was also found to be significantly increased. However, the metabolic clearance and plasma production rates of oestradiol were not significantly different from those of healthy men. Patients who were severely ill with liver failure and one with haemochromatosis had low levels of luteinizing hormone and follicle stimulating hormone and sub-normal responses to clomiphene and luteinizing hormone-releasing hormone. Higher plasma oestradiol levels were found in patients with gynaecomastia and spider naevi than in those without these signs. However, the clinical features of androgen deficiency--that is, testicular atrophy, impotence and loss of secondary sex hair--were only poorly related to the low testosterone levels, and production rates and longtitudinal studies indicated that the hormonal levels, endocrine features and severity of the liver disease could change independently. It is concluded that the clearance of oestradiol from plasma is not limited by liver disease in all patients, and that reduced degradation of oestrogens is not the initial event in the sequence leading to the hormonal abnormalities of cirrhosis. While gonadotrophin deficiency occurs with liver failure and in some patients with haemochromatosis, the more usual findings are of elevated gonadotrophin levels and a poor Leydig cell response to chorionic gonadotrophin. These suggest that the hypogonadism is primary in most patients with cirrhosis. The causes of the high oestradiol levels were not discovered. Increased peripheral conversion of precursors to oestradiol or increased testicular secretion of oestradiol are possibilities. The high binding capacities of sex steroid binding globulin were not significantly correlated with either the low testosterone or high oestradiol level and the cause of this abnormality remains uncertain. The low metabolic clearance rates of testosterone appeared to result from the increased plasma protein binding of testosterone. The discrepancies in the expected relationships between the hormone and clinical changes suggest that factors other than those studied are also involved in the genesis of the endocrine features of hepatic cirrhosis.

PIP: Blood levels of estradiol, testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH), sex steroid binding globulin (SSBG), and free steroids were surveyed in 117 men to define the pattern of hormonal abnormalities and to examine the relationships between the hormone levels and the development of the endocrine features of cirrhosis. When compared with healthy men of similar ages, the patients had significantly lower metabolic clearance rates (p .001), testosterone production rates (p .001), total and free levels of testosterone (p .001), reduced testosterone responses to human chorionic gonadotropin (HCG) stimulation, higher estradiol, LH, and FSH levels, and higher binding capacities of SSBG. The metabolic clearance and plasma production rates of estradiol were not markedly different from those of controls. Severely ill patients with liver failure of hemochromatosis had low levels of LH and FSH respones to clomiphene and LH-releasing hormone. Patients with gynecomastia and spider naevi had higher estradiol levels than in those without these signs. Longitudinal studies indicated that the hormonal levels, endocrine features, and severity of the liver disease could change independently. It is concluded that the clearance of estradiol from plasma is normal in most patients with liver disease and that reduced degradation of estrogens is not the initial event in the sequence leading to the hormonal abnormalities of cirrhosis. Usual findings of liver failure are elevated gonadotropin levels and a poor Leydig cell response to HCG which suggest that the hypogonadism is primary in most patients with cirrhosis. Discrepancies in the expected relationships between the hormone and clinical changes suggest that other factors than those studied are also involved in the genesis of hepatic cirrhosis.