Laureate Professor Roger Smith is a man of many talents and interests. As the Co-Director of the University of Newcastle's Priority Research Centre for Reproductive Science, and the Director of the University's Mothers and Babies Research Centre and the Department of Endocrinology at John Hunter Hospital, he's also a man with many responsibilities. Not limiting himself to a singular field, the passionate academic freely studies "anything and everything" that sparks his intrigue.
"These range from explorations of potential new treatments for women in premature labour and women with postpartum haemorrhage, to the use of nanoparticles to treat thyroid and ovarian cancers."
Roger recalls having this affinity for the natural world from a young age. Working on the proviso that the "proof is in the picture," the esteemed educator tells of a photograph of his toddler-self feeding elephants, and its importance in kick starting his research career.
Seeking to satisfy this time-honoured thirst for knowledge about his own species, Roger studied medicine at the University of Sydney. Graduating in 1973, he spent the next two years at Royal North Shore Hospital followed by time in Western Australia and New Zealand, before undertaking a PhD at the University of London.
"My interest in people is not just in terms of their diseases, but also about how they interact with each other."
After completing his doctorate in 1981, Roger returned to Australia and joined the University of Newcastle.
Most recently, and perhaps most interestingly, Roger has been undertaking a research assignment on lemurs in Madagascar.
"The females are dominant over the males and their clitorises are bigger than penises, due to the different steroids produced during pregnancy."
"Oestrogen and progesterone normally regulate the onset of labour but they do all of these crazy things in lemurs so we don't yet know why they give birth when they do."
"People from the island's west coast have collected samples of poo from pregnant female lemurs and they've been transported here for analysis and comparison with samples obtained from Taronga Western Plains Zoo in Dubbo."
Spanning a generous handful of time zones, Roger's current work also sees him conducting work in Nepal. The clinical endocrinologist is on the hunt for ways to improve maternal mortality in the developing country, ambitiously and admirably looking to reduce its "exceedingly high" death rates during pregnancy.
Collaborating with a Nepalese postgraduate student, Roger is hoping to change this situation with a simple but powerful song.
"So we're going to run a competition in schools for a lyrical number that involves some key messages about respecting women."
"Once the final song is chosen, it will be taught to travelling minstrels who will then sing it at every house in the intervention area."
Back home, Roger is endeavouring to 'close the gap' where Aboriginal health is concerned. He has set up programs in both Tamworth and Walgett, renting and renovating buildings for art and ante-natal research purposes.
"Indigenous women have double the rate of premature birth and double the rate of growth retarded babies," the multitasking scholar affirms.
"We've employed Aboriginal artists and elders, as well as dieticians, midwives and lactation consultants to pass on their knowledge to expectant mothers."
Learning just as much from these women as he is by teaching them, Roger asserts the rural venture has so far been an "overwhelming success."
When asked where he would like to see the future of medicine and public health, Roger is quick to answer.
"So I could tell you to eat less, start exercising and stop smoking, but then you go back to your world surrounded by family and friends who probably drink more than they should, smoke and don't exercise often."
Believing how we behave and think is "largely determined" by the people around us, Roger is calling for doctors to influence the social networks of individuals.
"If someone has obesity or smokes, for example, I want to meet their partner and friends and relatives."
A self-described ‘specialised zoologist,’ Professor Roger Smith is keen on understanding the idiosyncrasies, interactions and inner workings of multiple animal
I am an internationally recognised leader in the pathophysiology of human pregnancy. I have been awarded medals and published in Nature, Nature Medicine and the New England Journal of Medicine and Scientific American; Science has reviewed my work. I have been a visiting Professor at Harvard, Yale and the NIH Perinatal Research Branch.
Preterm birth accounts for 70% of neonatal mortality and is a common cause for intellectual handicap among survivors. Approximately 50% of cases of cerebral palsy are associated w... [more]
Preterm birth accounts for 70% of neonatal mortality and is a common cause for intellectual handicap among survivors. Approximately 50% of cases of cerebral palsy are associated with preterm birth, in turn preterm birth increases the risk of cerebral palsy by 40 times! (Goldenberg, 2002). Preterm labor thus afflicts individuals at the very beginning of their lives, depriving them of opportunities and increasing health and educational costs for families and society in general. Unfortunately the rates of preterm birth have not changed for over 30 years due to an inability to predict the event and lack of effective therapies. This clinical problem has driven research into the mechanisms that regulate the timing of human birth and the disorders which cause preterm birth. For reasons of ethics most research in the past has focused on animal work, especially in the sheep. Unfortunately studies have revealed substantial differences between parturition in humans and that in other animals. Thus animal studies provide us with clues as to how systems operate to regulate delivery in mammals but frustrate us with uncertainty as to whether particular mechanisms operate in the human. Experimental in vivo studies provide the strongest evidence for cause and effect, yet the closer we come to the human state in our near relatives the apes, the larger the ethical constraints on experimental studies become.
© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society. Maternal obesity duri... [more]
© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society. Maternal obesity during pregnancy has a detrimental impact on offspring renal development and function. This is pertinent to Indigenous Australians as they are twice as likely as non-Indigenous Australians to develop chronic kidney disease (CKD). The aim of this study was to examine whether there was an association between maternal adiposity and fetal kidney growth in late gestation (>28¿weeks) and kidney function in infants, 28¿weeks gestation by bioelectrical impedance analysis. Fetal kidney structure was assessed by ultrasound. Renal function indicators (urinary albumin:creatinine and protein:creatinine) were measured in infants from a spot urine collection from nappies. Multiple linear regression and multi-level mixed effects linear regression models with clustering were used to account for repeated measures of urine. 147 mother-child pairs were examined. Estimated fetal weight (EFW), but not fetal kidney size, was positively associated with maternal adiposity and pre-pregnancy BMI. When adjusted for smoking, combined kidney volume relative to EFW was negatively associated with maternal percentage body fat. Infant kidney function was not influenced by maternal adiposity and pre-pregnancy BMI (n¿=¿84 observations). Current findings show that Indigenous babies born to obese mothers have reduced kidney size relative to EFW. We suggest that these babies are experiencing a degree of glomerular hyperfiltration in utero, and therefore are at risk of developing CKD in later life, especially if their propensity for obesity is maintained. Although no impact on renal function was observed at <2.5¿years¿of age, long-term follow-up of offspring is required to evaluate potential later life impacts.
BACKGROUND: Newborns are at greatest risk of dying at and shortly after the time of birth. Newborn mortality remains an urgent concern and is an important indicator of child healt... [more]
BACKGROUND: Newborns are at greatest risk of dying at and shortly after the time of birth. Newborn mortality remains an urgent concern and is an important indicator of child health, development and well-being. Studies examining the effectiveness of antenatal care on maternal and newborn health outcomes have provided conflicting results. The aim of this review and meta-analysis was to determine the pooled effect of antenatal care on neonatal mortality in sub-Saharan Africa. METHODS: We searched PubMed, Medline, EMBASE, CINAHL and Google Scholar from September to November 2016 and then updated our search on April 13, 2019. Two independent reviewers extracted data from eligible studies. The quality of each included study was assessed using the Risk of Bias Assessment tool for Non-Randomized Studies (RoBANS). The results were reported based on risk ratio (RR) with 95% confidence intervals (CI) using a random-effects model. RESULTS: Eight hundred and ninety eight studies were initially identified. During screening, 23 studies were found to be relevant for data extraction. Of these, only twelve studies fulfilled the inclusion criteria and were included in the analysis. In five of the twelve studies included in the analysis, antenatal care service utilization had a significant association with neonatal mortality. The pooled risk ratio by the random-effects model was 0.61 (95% CI: 0.43, 0.86) for neonates born to women who received at least one antenatal care visit by a skilled provider as compared to neonates born to women who did not receive antenatal care. CONCLUSION: This review indicates that utilization of at least one antenatal care visit by a skilled provider during pregnancy reduces the risk of neonatal mortality by 39% in sub-Saharan African countries. Thus, in order to accelerate progress towards the reduction of newborn deaths, all pregnant women should receive antenatal care during pregnancy.
© 2019 Australian College of Midwives Background: In Ethiopia, maternal health service utilization is still unacceptably low. The societal and cultural factors that constrain wome... [more]
© 2019 Australian College of Midwives Background: In Ethiopia, maternal health service utilization is still unacceptably low. The societal and cultural factors that constrain women from attending these services have not yet been sufficiently explored. Using qualitative methods, we aimed to explore the factors that delay maternal health service utilization in eastern Ethiopia. Method: A total of 13 audio-recorded focus group discussions were conducted comprising 88 participants. We conducted separate group discussions with reproductive aged women, mothers-in-law, traditional birth attendants, husbands, and Health Extension Workers to capture their knowledge, practices, feelings, thoughts and attitudes towards maternal health service utilization. The recorded sessions were transcribed into the local language and then translated into English for analysis. Result: The study identified a number of factors that may delay maternal health service utilization. Factors were grouped using the Three Delays model as a framework. Low level of awareness regarding need, poor involvement of husband, perceived absence of health problems, social power, community misperceptions and cultural restrictions, negative attitudes towards male midwives, acceptance of traditional birth attendants and poor social networking were Delay One factors. Lack of physical accessibility and high transportation costs were categorised as Delay Two factors for skilled birth care attendance. Perceived or experienced poor quality of care were categorised as Delay Three factors for both skilled birth and postnatal care utilization. Conclusion: Despite the ongoing government measures to improve maternal health service utilization in Ethiopia, numerous factors continue to contribute to delays in service use, which in turn contribute to high maternal mortality.
© Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2018. Childhood obesity rates are higher among Indigenous compared with ... [more]
© Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2018. Childhood obesity rates are higher among Indigenous compared with non-Indigenous Australian children. It has been hypothesized that early-life influences beginning with the intrauterine environment predict the development of obesity in the offspring. The aim of this paper was to assess, in 227 mother-child dyads from the Gomeroi gaaynggal cohort, associations between prematurity, Gestation Related-Optimal Weight (GROW) centiles, maternal adiposity (percentage body fat, visceral fat area), maternal non-fasting plasma glucose levels (measured at mean gestational age of 23.1 weeks) and offspring BMI and adiposity (abdominal circumference, subscapular skinfold thickness) in early childhood (mean age 23.4 months). Maternal non-fasting plasma glucose concentrations were positively associated with infant birth weight (P=0.005) and GROW customized birth weight centiles (P=0.008). There was a significant association between maternal percentage body fat (P=0.02) and visceral fat area (P=0.00) with infant body weight in early childhood. Body mass index (BMI) in early childhood was significantly higher in offspring born preterm compared with those born at term (P=0.03). GROW customized birth weight centiles was significantly associated with body weight (P=0.01), BMI (P=0.007) and abdominal circumference (P=0.039) at early childhood. Our findings suggest that being born preterm, large for gestational age or exposed to an obesogenic intrauterine environment and higher maternal non-fasting plasma glucose concentrations are associated with increased obesity risk in early childhood. Future strategies should aim to reduce the prevalence of overweight/obesity in women of child-bearing age and emphasize the importance of optimal glycemia during pregnancy, particularly in Indigenous women.
© 2018, The Author(s). Background:: It is hypothesised that epigenetic mechanisms including DNA methylation may underlie the relationship between early-life nutrition and child co... [more]
© 2018, The Author(s). Background:: It is hypothesised that epigenetic mechanisms including DNA methylation may underlie the relationship between early-life nutrition and child cognitive outcomes. This study aimed to identify dietary patterns associated with the intake of one-carbon metabolism nutrients in children aged 2¿3 years. Methods:: A validated 120-item semi-quantitative food frequency questionnaires at 2¿3 years of age were used to estimate the intake of one-carbon metabolism nutrients (methionine, folate, choline and vitamins B2, B6, B12) and to quantify mean number of serves consumed of the food groups specified by the Australian Guide to Healthy Eating (AGHE). Descriptive statistics were used to analyse the contribution of each food group and food items to the total intake of one-carbon metabolism nutrients. Linear regression was used to test for linear trends in food group servings by nutrient intake quintiles. Results:: No child (n = 60) from the Women And Their Children¿s Health (WATCH) study consumed the recommended number of serves for all AGHE food groups. Dairy and alternatives (18¿44%), discretionary foods (6¿33%) and meat and alternatives (6¿31%) were the main sources of most one-carbon metabolism nutrients. Most child intakes of one-carbon metabolism nutrients exceeded the nutrient reference values (NRVs), except for the intake of choline, for which the mean intake was 9% below the adequate intake (AI). Conclusion:: Dairy and alternatives, discretionary foods and meat and alternatives food groups contributed significantly to the children¿s intake of one-carbon metabolism nutrients. The children generally had low intakes of meat and alternative foods, which may explain their inadequate intake of choline.
© 2018 Elsevier Ltd Background: Postnatal care is critical to detect and manage postpartum complications in the early stages as well as to prevent potentially life-threatening hea... [more]
© 2018 Elsevier Ltd Background: Postnatal care is critical to detect and manage postpartum complications in the early stages as well as to prevent potentially life-threatening health conditions that lead to maternal death. However, postnatal care utilization is persistently low in Ethiopia. The aim of this study is to assess the magnitude and correlates of postnatal care utilization among reproductiveaged women in Kersa district, in eastern Ethiopia. Methods: A community based cross-sectional study was conducted in ten randomly selected sub-districts in Kersa district. Respondents were recruited using systematic random sampling techniques. Data were collected by an interviewer-administered questionnaire using iPads. A total of 1206 respondents¿ data were considered in the analysis. Frequency and percentage distributions of the variables were performed. Bivariate and multivariate logistic regression analyses were undertaken to identify the predisposing, enabling and need factors associated with postnatal care utilization. An Odds Ratio with 95% confidence interval was used to ascertain the direction and strength of the association. Results: Less than one in thirteen women attended postnatal care after their last delivery in the study community. The multivariate analysis demonstrated that postnatal care utilization is associated with receiving education on maternal health, best friend's use of maternal care, head of the household, and experience of postpartum complications. Receiving education on maternal health (AOR, 2.32; 95% CI: 1.38, 3.89) and best friend's use of maternal care (AOR, 2.41; 95% CI: 1.39, 4.19) were significant predisposing factors that independently predicted postnatal care utilization. Furthermore, head of the household was a significantly associated enabling factor for postnatal care utilization (AOR, 0.24; 95% CI: 0.07, 0.81). The experience of postpartum complications (AOR, 0.10; 95% CI: 0.05, 0.20) was the only need factor that was associated with postnatal care utilization. Conclusion: Postnatal care utilization is extremely low in the study district. Strengthening health education and promotion activities on maternal health, peer education programs within the women's social networks, strengthening women empowerment programs, and women's mobilization to seek postnatal care before the occurrence of complications are essential actions that can improve postnatal care utilization.
© 2018 Background: Low birthweight is more common in infants of indigenous (Aboriginal and/or Torres Strait Islander) than of White Australian mothers. Controversy exists on wheth... [more]
© 2018 Background: Low birthweight is more common in infants of indigenous (Aboriginal and/or Torres Strait Islander) than of White Australian mothers. Controversy exists on whether fetal growth is normally different in different populations. Objective: We sought to determine the relationships of birthweight, birthweight percentiles, and smoking with perinatal outcomes in indigenous vs nonindigenous infants to determine whether the White infant growth charts could be applied to indigenous infants. Study Design: Data were analyzed for indigenous status, maternal age and smoking, and perinatal outcomes in 45,754 singleton liveborn infants of at least 20 weeks gestation or 400 g birthweight delivered in New South Wales, Australia, between June 2010 and July 2015. Results: Indigenous infants (n=6372; 14%) had a mean birthweight 67 g lower than nonindigenous infants (P<.0001; with adjustment for infant sex and maternal body mass index). Indigenous mean birthweight percentile was 4.2 units lower (P<.0001). Adjustment for maternal age, smoking, body mass index, and infant sex reduced the difference in birthweight/percentiles to nonsignificance (12 g; P=.07). Conclusion: Disparities exist between indigenous and non-indigenous Australian infants for birthweight, birthweight percentile, and adverse outcome rates. Adjustment for smoking and maternal age removed any significant difference in birthweights and birthweight percentiles for indigenous infants. Our data indicate that birthweight percentiles should not be adjusted for indigenous ethnicity because this normalizes disadvantage; because White and indigenous Australians have diverged for approximately 50,000 years, it is likely that the same conclusions apply to other ethnic groups. The disparities in birthweight percentiles that are associated with smoking will likely perpetuate indigenous disadvantage into the future because low birthweight is linked to the development of chronic noncommunicable disease and poorer educational attainment; similar problems may affect other indigenous populations.
© 2018 The Authors Nephrology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Nephrology Aim: Indigenous Australians have an increased ri... [more]
© 2018 The Authors Nephrology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Nephrology Aim: Indigenous Australians have an increased risk of developing chronic kidney disease (CKD). Indigenous women have a higher rate of CKD than men. In a cohort of Indigenous and non-Indigenous preterm neonates, we assessed total renal volume (TRV) (a proxy indicator for nephron number). We hypothesized that there would be no difference in renal volume between these two groups at term corrected (37 weeks gestation). Methods: Normally grown preterm neonates less than 32 weeks of gestation were recruited and at term corrected dates, the neonates underwent renal ultrasonography (TRV measurements), urine microalbumin-creatinine ratio and serum analysis for Cystatin C measurement for estimated glomerular filtration rate (eGFR) calculation. Results: One hundred and five neonates (38 Indigenous; 67 non-Indigenous) were recruited. Indigenous neonates were significantly more premature and of lower birth weight. At term corrected age, Indigenous neonates had a significantly smaller TRV (18.5 (4.2) vs 21.4 (5.1) cm3; P = 0.027) despite no significant difference in body weight. Despite having a smaller TRV, there was no significant difference in eGFR between Indigenous and Non-indigenous neonates (47.8 [43.2¿50.4] vs 46.2 [42.6¿53.3] ml/min per 1.73 m2; P = 0.986). These infants achieve similar eGFR through hyperfiltration, which likely increases their future risk of CKD. There was no difference in microalbumin-creatinine ratio. Female Indigenous neonates, however, had significantly smaller TRV compared with Indigenous male neonates (15.9 (3.6) vs 20.6 (3.6) cm3; P = 0.006), despite no difference in eGFR, birth weight, gestational age, and weight at term corrected. Conclusion: The difference in TRV is likely to be an important risk factor for the difference in morbidity and mortality from renal disease reported between male and female Indigenous adults.
© Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2019. Adverse pregnancy outcomes including prematurity and low birth wei... [more]
© Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2019. Adverse pregnancy outcomes including prematurity and low birth weight (LBW) have been associated with life-long chronic disease risk for the infant. Stress during pregnancy increases the risk of adverse pregnancy outcomes. Many studies have reported the incidence of adverse pregnancy outcomes in Indigenous populations and a smaller number of studies have measured rates of stress and depression in these populations. This study sought to examine the potential association between stress during pregnancy and the rate of adverse pregnancy outcomes in Australian Indigenous women residing in rural and remote communities in New South Wales. This study found a higher rate of post-traumatic stress disorder, depression and anxiety symptoms during pregnancy than the general population. There was also a higher incidence of prematurity and LBW deliveries. Unfortunately, missing post-traumatic stress disorder and depressive symptomatology data impeded the examination of associations of interest. This was largely due to the highly sensitive nature of the issues under investigation, and the need to ensure adequate levels of trust between Indigenous women and research staff before disclosure and recording of sensitive research data. We were unable to demonstrate a significant association between the level of stress and the incidence of adverse pregnancy outcomes at this stage. We recommend this longitudinal study continue until complete data sets are available. Future research in this area should ensure prioritization of building trust in participants and overestimating sample size to ensure no undue pressure is placed upon an already stressed participant.
© 2017 Informa UK Limited, trading as Taylor & Francis Group. Purpose: The objective of this study was to investigate the association between prematurity, vascular endotheli... [more]
© 2017 Informa UK Limited, trading as Taylor & Francis Group. Purpose: The objective of this study was to investigate the association between prematurity, vascular endothelial growth factor A (VEGF-A), VEGFR-1 (soluble fms-like tyrosine kinase-1 (sFLT-1)) and retinopathy of prematurity (ROP). Methods: A cohort of 53 neonates (gestation <28 weeks) was recruited into this study and peripheral venous samples for VEGF and sFLT-1 measurement were obtained between gestational ages 320¿326 weeks. Results: The mean birth weight for the preterm neonates was 850 (178) g and the median gestational age was 26.4 [24.7¿27.4] weeks. The median VEGF-A level was 1348 [608¿2216] pg/mL and the median sFLT-1 level was 178 [103¿244] pg/mL. Thirty-three neonates (33/53) developed various stages of ROP during their stay in the neonatal unit but only five neonates developed severe (stage 3) ROP needing treatment. The neonates with ROP were smaller (birth weight 801 (111) vs. 990 (175) g; p <.0001), more preterm (gestation 25.4 [24.2¿26.0] vs. 27.1 [26.8¿27.9] weeks; p <.0001) and received supplemental oxygen for a longer duration (1140 [218¿1813] vs. 04 [40¿434] hours; p=.012). There was no statistically significant difference in the VEGF-A level or sFLT-1 levels between those who developed ROP and those who did not. There was a positive correlation between VEGF and both birth weight and gestation, respectively. There was no correlation between sFLT1 and birth weight or gestation. VEGF-A/sFLT-1 ratio in babies treated for ROP was significantly lower compared to those not treated (2.8 [1.0¿5.7] vs. 9.9 [5.6¿13.7]; p =.04). A logistic regression model identified gestational age to be a statistically significant predictor of ROP (odds ratio 0.03 (0.001¿0.550); p =.019). Conclusions: There is no direct correlation between systemic VEGF-A or sFLT-1 plasma levels and severity of ROP in extremely preterm neonates. The link between VEGF and ROP remains to be fully understood.
© 2018 Background: Preventable maternal mortality is related to delays in recognizing the problem, transport to a facility, and receiving appropriate care on arrival. Reducing mat... [more]
© 2018 Background: Preventable maternal mortality is related to delays in recognizing the problem, transport to a facility, and receiving appropriate care on arrival. Reducing maternal mortality in low-literacy settings is particularly challenging. In the rural villages of Nepal, the maternal mortality rate is among the highest in the world; the reasons include illiteracy and lack of knowledge of the needs of pregnant women. Culturally, singing and dancing are part of Nepalese daily life and present an opportunity to transmit knowledge of antenatal care and care at birth with a view to reducing the first 2 delays. Objective: We hypothesized that health messages regarding the importance of antenatal care and skilled birth assistance would be effectively transmitted by songs in the limited literacy environment of rural Nepal. Study Design: We randomly grouped 4 rural village development committees comprising 36 villages into 2 (intervention and control) clusters. In the intervention group, local groups were invited to write song lyrics incorporating key health messages regarding antenatal care to accompany popular melodies. The groups presented their songs and dances in a festival organized and judged by the community. The winning songs were performed by the local people in a song and dance progression through the villages, houses, and fields. A wall chart with the key health messages was also provided to each household. Knowledge of household decision makers (senior men and women) was assessed before and after the intervention and at 12 months using a structured questionnaire in all households that also assessed behavior change. Results: Structured interviews were conducted at baseline, immediately postintervention in the control and intervention areas (intervention n = 735 interviews, control n = 775), and at 12 months in the intervention area only (n = 867). Knowledge scores were recorded as the number of correct items out of 36 questions at baseline and postintervention, and of 21 questions at follow-up. Postintervention, test score doubled in the intervention group from a mean of 11.60/36¿22.33/36 (P <.001), with no practically significant change in the control population (17.48/36¿18.26/36). Improvement was greatest among the most illiterate members of the community (6.8/36¿19.8/36, P <.001). At 12 months follow-up, a majority of the participants (63.9%) indicated that they provided information learned from the songs to their neighbors and friends, and 41.3% reported still singing the songs from the intervention. Conclusion: The use of songs bypassed the limitations of literacy in communicating health messages that are key to improving maternal care in this low-literacy rural setting within a developing country. The improvements were maintained without further intervention for 12 months. With appropriate sociocultural adaptation to local contexts, this low-cost method of community education may be applicable to improving maternal health knowledge and behavior change in other low-resource and limited literacy settings that may lead to reductions in maternal mortality.
© 2018 The intrarenal renin-angiotensin system (iRAS) is implicated in the pathogenesis of hypertension, chronic kidney disease and diabetic nephropathy. Urinary angiotensinogen (... [more]
© 2018 The intrarenal renin-angiotensin system (iRAS) is implicated in the pathogenesis of hypertension, chronic kidney disease and diabetic nephropathy. Urinary angiotensinogen (uAGT) levels reflect the activity of the iRAS and are altered in women with preeclampsia. Since Indigenous Australians suffer high rates and early onset of renal disease, we hypothesised that Indigenous Australian pregnant women, like non-Indigenous women with pregnancy complications, would have altered uAGT levels. The excretion of RAS proteins was measured in non-Indigenous and Indigenous Australian women with uncomplicated or complicated pregnancies (preeclampsia, diabetes/gestational diabetes, proteinuria/albuminuria, hypertension, small/large for gestational age, preterm birth), and in non-pregnant non-Indigenous women. Non-Indigenous pregnant women with uncomplicated pregnancies, had higher uAGT/creatinine levels than non-Indigenous non-pregnant women (P < 0.01), and levels increased as pregnancy progressed (P < 0.001). In non-Indigenous pregnant women with pregnancy complications, uAGT/creatinine was suppressed in the third trimester (P < 0.01). In Indigenous pregnant women with uncomplicated pregnancies, there was no change in uAGT/creatinine with gestational age and uAGT/creatinine was lower in the 2nd and 3rd trimesters than in non-Indigenous pregnant women with uncomplicated pregnancies (P < 0.03, P < 0.007, respectively). The uAGT/creatinine ratios of Indigenous women with uncomplicated or complicated pregnancies were the same. A decrease in uAGT/creatinine with advancing gestational age was associated with increased urinary albumin/creatinine, as is seen in preeclampsia, but it was not specific for this disorder. The reduced uAGT/creatinine in Indigenous pregnant women may reflect subclinical renal dysfunction which limits the ability of the kidney to maintain sodium balance and could indicate an increased risk of pregnancy complications and/or future renal disease.
© 2017 Society for Endocrinology Printed in Great Britain. Recent advances in the arena of theranostics have necessitated a re-examining of previously established fields. The exis... [more]
© 2017 Society for Endocrinology Printed in Great Britain. Recent advances in the arena of theranostics have necessitated a re-examining of previously established fields. The existing paradigm of therapeutic thyroid-stimulating hormone receptor (TSHR) targeting in the post-surgical management of differentiated thyroid cancer using levothyroxine and recombinant human thyroid-stimulating hormone (TSH) is well understood. However, in an era of personalized medicine, and with an increasing awareness of the risk profile of longstanding pharmacological hyperthyroidism, it is imperative clinicians understand the molecular basis and magnitude of benefit for individual patients. Furthermore, TSHR has been recently re-conceived as a selective target for residual metastatic thyroid cancer, with pilot data demonstrating effective targeting of nanoparticles to thyroid cancers using this receptor as a target. This review examines the evidence for TSHR signaling as an oncogenic pathway and assesses the evidence for ongoing TSHR expression in thyroid cancer metastases. Priorities for further research are highlighted.
© Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2017. Dilation and abnormal tortuosity of retinal vessels are the hallma... [more]
© Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2017. Dilation and abnormal tortuosity of retinal vessels are the hallmarks of severe retinopathy of prematurity (ROP) in premature infants. The stages of ROP are defined by vessel appearance at the interface between the vascular and avascular retinal areas. Deregulated signaling pathways involving hypoxia-inducible factors such as vascular endothelial growth factor (VEGF) are involved in the pathogenesis of ROP. VEGF-antagonists are increasingly being used as 'off-label medication' to treat this condition, with some success. We present Baby SM (female), who was born prematurely at 24 weeks gestation in a tertiary neonatal intensive care unit, and with a birth weight of 640 g. On screening at 35 weeks postmenstrual age (PMA), she was noted to have ROP, which became severe by 37 weeks PMA. She received one dose of intravitreal VEGF antagonist (Bevacizumab), resulting in a decrease in vessel tortuosity and dilation. However, repeat imaging at 4 weeks showed a re-emergence of vessel tortuosity. We believe the observed changes demonstrate an inherent retinal microvascular plasticity in premature neonates. With improved survival of extremely premature neonates and the availability of retinal imaging technology, we are now able to observe this plasticity.
© 2017 Lim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reprodu... [more]
© 2017 Lim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Objective The objective of the study was to analyse placental hormone profiles in twin pregnancies to determine if they could be used to predict preterm birth. Study design Progesterone, estradiol, estriol and corticotropin-releasing hormone were measured using competitive immunoassay and radioimmunoassay in serum and saliva samples of 98 women with twin pregnancies,at 3 or more gestational timepoints. Hormone profiles throughout gestation were compared between very preterm (<34 weeks; n = 8), preterm (<37 weeks; n = 40) and term (37+ weeks; n = 50) deliveries. Results No significant differences were found between preterm and term deliveries in either absolute hormone concentrations or ratios. Estimated hormone concentrations and ratios at 26 weeks did not appear to predict preterm delivery. Salivary and serum hormone concentrations were generally poorly correlated. Conclusion Our results suggest that serial progesterone, estradiol, estriol and corticotropin-releasing hormone measurements in saliva and serum are not robust biomarkers for preterm birth in twin pregnancies.
© 2016, The Author(s). Postnatal depression (PND) is common and negatively affects the mother¿infant relationship; oxytocin (OT) has been found to have positive effects on parenti... [more]
© 2016, The Author(s). Postnatal depression (PND) is common and negatively affects the mother¿infant relationship; oxytocin (OT) has been found to have positive effects on parenting, although psychiatric disorders may reduce these effects. Thus, we explored the role of OT in mothers diagnosed with PND. A within-subject, randomized controlled double-blind design was used to test the effects of nasal administration of OT or placebo on sensitive caregiving. The outcome measures were perceptual and caregiving responses to prerecorded cry sounds, as well as observed maternal sensitivity. We found that in the OT condition mothers with PND were more likely to rate an infant cry as more urgent and they were more likely to indicate they would chose a harsh caregiving strategy in response. There was no effect of OT on maternal sensitive interaction with their own baby. Further research is required prior to consideration of OT administration in depressed mothers of infants.
© 2016, Biomedical Engineering Society. Research insights into uterine function and the mechanisms of labour have been hindered by the lack of suitable animal and cellular models.... [more]
© 2016, Biomedical Engineering Society. Research insights into uterine function and the mechanisms of labour have been hindered by the lack of suitable animal and cellular models. The use of traditional culturing methods limits the exploration of complex uterine functions, such as cell interactions, connectivity and contractile behaviour, as it fails to mimic the three-dimensional (3D) nature of uterine cell interactions in vivo. Animal models are an option, however, use of these models is constrained by ethical considerations as well as translational limitations to humans. Evidence indicates that these limitations can be overcome by using 3D culture systems, or 3D Bioprinters, to model the in vivo cytological architecture of the tissue in an in vitro environment. 3D cultured or 3D printed cells can be used to form an artificial tissue. This artificial tissue can not only be used as an appropriate model in which to study cellular function and organisation, but could also be used for regenerative medicine purposes including organ or tissue transplantation, organ donation and obstetric care. The current review describes recent developments in cell culture that can facilitate the development of myometrial 3D structures and tissue engineering applications.
© 2017 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists Background: Pregnancy can be a stressful time for many women. There is ample evidence of nu... [more]
© 2017 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists Background: Pregnancy can be a stressful time for many women. There is ample evidence of numerous physical and mental health inequities for Indigenous Australians. For those Indigenous women who are pregnant, it is established that there is a higher incidence of poor physical perinatal outcomes when compared with non-Indigenous Australians. However, little evidence exists that examines stressful events and post-traumatic stress disorder (PTSD) symptoms in pregnant women who are members of this community. Aims: To quantify the rates of stressful events and PTSD symptoms in pregnant Indigenous women. Methods: One hundred and fifty rural and remote Indigenous women were invited to complete a survey during each trimester of their pregnancy. The survey measures were the stressful life events and the Impact of Events Scale. Results: Extremely high rates of PTSD symptoms were reported by participants. Approximately 40% of this group exhibited PTSD symptoms during their pregnancy with mean score 33.38 (SD¿=¿14.37) significantly higher than a study of European victims of crisis, including terrorism attacks (20.6, SD¿=¿18.5). Conclusions: The extreme levels of PTSD symptoms found in the women participating in this study are likely to result in negative implications for both mother and infant. An urgent response must be mounted at government, health, community development and research levels to address these findings. Immediate attention needs to focus on the development of interventions to address the¿high¿levels of PTSD symptoms that pregnant Australian Indigenous women¿experience.
© 2017 - IOS Press and the authors. All rights reserved. BACKGROUND: Serum creatinine (SCr) measurement to determine glomerular filtration rate (GFR) in neonates has many pitfalls... [more]
© 2017 - IOS Press and the authors. All rights reserved. BACKGROUND: Serum creatinine (SCr) measurement to determine glomerular filtration rate (GFR) in neonates has many pitfalls. Cystatin C (CysC) appears to be a more reliable biomarker. METHODS:We investigated the effect of birth weight on SCr and CysC measurements in a cohort of 74 infants, consisting of both term and ex-premature infants at term postmenstrual age. SCr and Cys C measurements were carried out at the same time. RESULTS: Eighty six infants were recruited into this study out of which complete data were available in 80 infants. The cohort consists of both term and premature infants at term PMA (31 terms and 49 preterms). The median SCr level was 17 [12-26] umol/L and mean CysC level was 1.64 [0.27] mg/L. SCr had a significant correlation with weight (r = 0.3; P = 0.011), whereas serum CysC had no correlation with the infant's weight (r = 0.01; P = 0.95). There were no statistically significant difference in SCr and CysC between male and female infants. CONCLUSION: Unlike CysC, SCr had a significant correlation with birth weight. SCr based GFR measurement may cause a delay in diagnosis of acute kidney injury in smaller neonates.
© Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2016. Indigenous Australians have high rates of chronic diseases, the ca... [more]
© Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2016. Indigenous Australians have high rates of chronic diseases, the causes of which are complex and include social and environmental determinants. Early experiences in utero may also predispose to later-life disease development. The Gomeroi gaaynggal study was established to explore intrauterine origins of renal disease, diabetes and growth in order to inform the development of health programmes for Indigenous Australian women and children. Pregnant women are recruited from antenatal clinics in Tamworth, Newcastle and Walgett, New South Wales, Australia, by Indigenous research assistants. Measures are collected at three time points in pregnancy and from women and their children at up to eight time points in the child's first 5 years. Measures of fetal renal development and function include ultrasound and biochemical biomarkers. Dietary intake, infant feeding and anthropometric measurements are collected. Standardized procedures and validated tools are used where available. Since 2010 the study has recruited over 230 women, and retained 66 postpartum. Recruitment is ongoing, and Gomeroi gaaynggal is currently the largest Indigenous pregnancy-through-early-childhood cohort internationally. Baseline median gestational age was 39.1 weeks (31.5-43.2, n=110), median birth weight was 3180 g (910-5430 g, n=110). Over one third (39.3%) of infants were admitted to special care or neonatal nursery. Nearly half of mothers (47.5%) reported tobacco smoking during pregnancy. Results of the study will contribute to knowledge about origins of chronic disease in Indigenous Australians and nutrition and growth of women and their offspring during pregnancy and postpartum. Study strengths include employment and capacity-building of Indigenous staff and the complementary ArtsHealth programme.
© 2015 Elsevier Ltd. Background: The maternal hypothalamic-pituitary-adrenal-axis (HPAA) undergoes dramatic activation during pregnancy. Increased cortisol and corticotrophin-rele... [more]
© 2015 Elsevier Ltd. Background: The maternal hypothalamic-pituitary-adrenal-axis (HPAA) undergoes dramatic activation during pregnancy. Increased cortisol and corticotrophin-releasing-hormone (CRH) associate with low birthweight and preterm labor. In non-pregnant obesity, the HPAA is activated but circulating cortisol levels are normal or lower than in lean women. We hypothesized that maternal cortisol levels would be lower in obese pregnancy, and would associate with increased fetal size and length of gestation. Method: Fasting serum cortisol was measured at 16, 28 and 36 weeks gestation and at 3-6 months postpartum in 276 severely obese and 135 lean women. In a subset of obese (n = 20) and lean (n = 20) we measured CRH, hormones that regulate bioavailable cortisol (corticosteroid-binding-globulin, estradiol, estriol, and progesterone). Urinary glucocorticoid metabolites were measured in pregnant (obese n = 6, lean n = 5) and non-pregnant (obese n = 7, lean n = 7) subjects. Results: Maternal cortisol and HPAA hormones were lower in obese pregnancy. Total urinary glucocorticoid metabolites increased significantly in lean pregnancy, but not in obese. Lower maternal cortisol in obese tended to be associated with increased birthweight (r = -0.13, p = 0.066). In obese, CRH at 28 weeks correlated inversely with gestational length (r = -0.49, p = 0.04), and independently predicted gestational length after adjustment for confounding factors (mean decrease in CRH of -0.25 pmol/L (95% CI -0.45 to -0.043 pmol/L) per/day increase in gestation). Conclusion: In obese pregnancy, lower maternal cortisol without an increase in urinary glucocorticoid clearance may indicate a lesser activation of the HPAA than in lean pregnancy. This may offer a novel mechanism underlying increased birthweight and longer gestation in obese pregnancy.
© 2015 Dietitians Association of Australia Aim: To compare dietary intakes of young children to the Australian Guide to Healthy Eating (AGHE) and Nutrient Reference Values (NRVs).... [more]
© 2015 Dietitians Association of Australia Aim: To compare dietary intakes of young children to the Australian Guide to Healthy Eating (AGHE) and Nutrient Reference Values (NRVs). Methods: Dietary intakes of 54 children (50% girls) aged two to three years (mean 2.7 years) from the Women and Their Children's Health (WATCH) study were reported by mothers using a validated 120-item food frequency questionnaire. Daily consumption of AGHE food group servings, macronutrients, and micronutrients were compared to the AGHE and NRVs using t-test with significance set at P < 0.05. Results: No child achieved all AGHE targets, with the majority consuming less breads/cereals (1.9 vs 4.0 servings/day), vegetables (1.3 vs 2.5), and meat/alternatives (0.7 vs 1.0), all P < 0.0001. Adequate servings were observed for dairy (2.2 vs 1.5) and fruit (1.3 vs 1.0). Macronutrients were within recommended ranges, although 96% exceeded saturated fatty acid recommendations. Children who met selected NRVs consumed more fruit (1.4 vs 1.0; P < 0.0086), dairy (2.2 vs 1.5; P < 0.0001) and discretionary foods (2.6 vs =1.0; P < 0.0001) but less breads/cereals (2.0 vs 4.0; P < 0.0001) and vegetables (1.3 vs 2.5; P < 0.0001) servings, compared to the AGHE recommended servings. Conclusions: Child dietary intakes did not align with AGHE, while adequate nutrient profiles were achieved by various dietary patterns. Future studies involving data from larger, representative samples of children are warranted.
© 2015 Xin Pan et al. Corticotropin releasing hormone (CRH) production by the human placenta increases exponentially as pregnancy advances, and the rate of increase predicts gesta... [more]
© 2015 Xin Pan et al. Corticotropin releasing hormone (CRH) production by the human placenta increases exponentially as pregnancy advances, and the rate of increase predicts gestational length. CRH gene expression is regulated by cAMP in trophoblasts through a cyclic AMP-response element (CRE), which changes its transcription factor binding properties upon methylation. Here we determined whether methylation of the CRH proximal promoter controls basal and cAMP-stimulated CRH expression in BeWo cells, a well-characterized trophoblastic cell line. We treated the cells with 8-Br-cAMP and the DNA methyltransferase inhibitor 5-aza-2' deoxycytidine (5-AZA-dC) and determined the effects on CRH mRNA level and promoter methylation. Clonal bisulfite sequencing showed partial and allele independent methylation of CpGs in the CRH promoter. CRH mRNA expression and the methylation of a subset of CpGs (including CpG2 in the CRE) increased spontaneously during culture. 8-Br-cAMP stimulated CRH expression without affecting the increase in methylation. 5-AZA-dC decreased methylation and augmented 8-Br-cAMP-stimulated CRH expression, but it blocked the spontaneous increase of CRH mRNA level. We conclude that the CRH promoter is a dynamically and intermediately methylated genomic region in BeWo cells. Promoter methylation did not inhibit CRH gene expression under the conditions employed; rather it determined the contribution of alternative cAMP-independent pathways and cAMP-independent mechanisms to CRH expression control.
© 2015 Pringle, Rae, Weatherall, Hall, Burns, Smith, Lumbers and Blackwell. Sudden infant death syndrome (SIDS), neonatal deaths, and deaths from infection are higher among Indige... [more]
© 2015 Pringle, Rae, Weatherall, Hall, Burns, Smith, Lumbers and Blackwell. Sudden infant death syndrome (SIDS), neonatal deaths, and deaths from infection are higher among Indigenous Australians. This study aimed to determine the effects of inflammatory responses and exposure to cigarette smoke, two important factors associated with sudden death in infancy, on preterm birth, and birth weight in a cohort of Indigenous mothers. Indigenous Australian women (n = 131) were recruited as part of a longitudinal study while attending antenatal care clinics during pregnancy; blood samples were collected up to three times in pregnancy. Serum cotinine, indicating exposure to cigarette smoke, was detected in 50.4% of mothers. Compared with non-Indigenous women, the cohort had 10 times the prevalence of antibodies to Helicobacter pylori (33 vs. 3%). Levels of immunoglobulin G, antibodies to H. pylori, and C-reactive protein (CRP) were all inversely correlated with gestational age (P < 0.05). CRP levels were positively associated with maternal body mass index (BMI; ¿ = 0.449, P = 0.001). The effects of cigarette smoke (cotinine) and inflammation (CRP) were assessed in relation to risk factors for SIDS: gestational age at delivery and birth weight. Serum cotinine levels were negatively associated with birth weight (¿ = -0.37, P < 0.001), this correlation held true for both male (¿ = -0.39, P = 0.002) and female (¿ = -0.30, P = 0.017) infants. Cotinine was negatively associated with gestational age at delivery (¿ = -0.199, P = 0.023). When assessed by fetal sex, this was significant only for males (¿ = -0.327, P = 0.011). CRP was negatively associated with gestational age at delivery for female infants (¿ = -0.46, P < 0.001). In contrast, maternal BMI was significantly correlated with birth weight. These data highlight the importance of putting programs in place to reduce cigarette smoke exposure in pregnancy and to treat women with chronic infections such as H. pylori to improve pregnancy outcomes and decrease risk factors for sudden death in infancy.
© 2015 by the authors; licensee MDPI, Basel, Switzerland. The prenatal environment can influence development of offspring blood pressure (BP), which tracks into adulthood. This pr... [more]
© 2015 by the authors; licensee MDPI, Basel, Switzerland. The prenatal environment can influence development of offspring blood pressure (BP), which tracks into adulthood. This prospective longitudinal study investigated whether maternal pregnancy dietary intake is associated with the development of child BP up to age four years. Data are from 129 mother-child dyads enrolled in the Women and Their Children¿s Health study. Maternal diet was assessed using a validated 74-item food frequency questionnaire at 18 to 24 weeks and 36 to 40 weeks, with a reference period of the previous three months. Child systolic and diastolic BP were measured at 3, 6, 9, 12, 24, 36 and 48 months, using an automated BP monitor. Using mixed-model regression analyses adjusted for childhood growth indices, pregnancy intakes of percentage of energy (E%) polyunsaturated fat (ß coefficient 0.73; 95% CI 0.003, 1.45; p = 0.045), E% omega-6 fatty acids (ß coefficient 0.89; 95% CI 0.09, 1.69; p = 0.03) and protein-to-carbohydrate (P:C) ratio (ß coefficient -14.14; 95% CI -27.68, -0.60; p = 0.04) were associated with child systolic BP trajectory up to 4 years. Child systolic BP was greatest at low proportions of dietary protein (40% of energy) intakes. There may be an ideal maternal macronutrient ratio associated with optimal infant BP. Maternal diet, which is potentially modifiable, may play an important role in influencing offspring risk of future hypertension.
© 2015 by the authors; licensee MDPI, Basel, Switzerland. Overweight and obesity is prevalent among women of reproductive age (42% BMI > 25 kg/m2) and parity is associated with... [more]
© 2015 by the authors; licensee MDPI, Basel, Switzerland. Overweight and obesity is prevalent among women of reproductive age (42% BMI > 25 kg/m2) and parity is associated with risk of weight gain. Weight gain greater than that recommended by the Institute of Medicine (IOM)is also associated with lower rates of breastfeeding initiation and duration in women. The aim of this pilot randomised controlled trial is to examine the feasibility of recruiting and maintaining a cohort of pregnant women with the view of reducing postpartum weight retention and improving breastfeeding outcomes. Women (BMI of 25¿35 kg/m2 (n = 36)) were recruited from the John Hunter Hospital antenatal clinic in New South Wales, Australia. Participants were stratified by BMI and randomised to one of three groups with follow-up to six months postpartum. Women received a dietary intervention with or without breastfeeding support from a lactation consultant, or were assigned to a wait-list control group where the dietary intervention was issued at three months postpartum. Feasibility and acceptability was assessed by participation rates and questionnaire. Analysis of variance and covariance was conducted to determine any differences between groups. Sixty-nine per cent of the participants were still enrolled at six months postpartum. This pilot demonstrated some difficulties in recruiting women from antenatal clinics and retaining them in the trial. Although underpowered; the results on weight; biomarkers and breastfeeding outcomes indicated improved metabolic health.
© 2015 Burns, Hall, Smith and Blackwell. Inflammatory responses have been implicated in several forms of infant deaths (sudden expected deaths and stillbirths) and the initiation ... [more]
© 2015 Burns, Hall, Smith and Blackwell. Inflammatory responses have been implicated in several forms of infant deaths (sudden expected deaths and stillbirths) and the initiation of pre-term births. In this study, we examined matched samples of term maternal blood, cord blood, and amniotic fluid obtained from 24 elective cesarean deliveries for both pro- and anti-inflammatory cytokines thought to be important in maintaining a balanced response leading to successful pregnancy outcome. These included interleukin (IL)-1ß, IL-6, IL-8, tumor necrosis factor-a (TNF-a), interferon-¿ (IFN-¿), IL-10, and IL-1 receptor antagonist (IL-1ra). Amniotic fluid levels for each of the cytokines examined were significantly higher than those for cord blood or maternal plasma. While pro-inflammatory cytokines were higher in amniotic fluid associated with male fetuses compared with females, the major significant difference was higher levels of IL-1ra in amniotic fluid associated with female fetuses. Our study supports similar findings for cytokines during mid-trimester, which noted that amniotic fluid levels were higher than those in maternal blood. Our study suggests that maternal decidua secretes additional IL-ra in the presence of a female conceptus which improves the likelihood of a good outcome compared to pregnancies with male fetuses.
© 2015 Tolosa et al. Background Pregnancy increases susceptibility to influenza. The placenta releases an immunosuppressive endogenous retroviral protein syncytin-1.We hypothesise... [more]
© 2015 Tolosa et al. Background Pregnancy increases susceptibility to influenza. The placenta releases an immunosuppressive endogenous retroviral protein syncytin-1.We hypothesised that exposure of peripheral monocytes (PBMCs) to syncytin-1 would impair responses to H1N1pdm09 influenza. Methods and Findings Recombinant syncytin-1 was produced. PBMCs from non-pregnant women (n=10) were exposed to H1N1pdm09 in the presence and absence of syncytin-1 and compared to responses of PBMCs from pregnant women (n=12). PBMCs were characterised using flow cytometry, release of interferon (IFN)-a, IFN-¿, IFN-¿, IL-10, IL-2, IL-6 and IL-1ß were measured by cytometric bead array or ELISA. Exposure of PBMCs to H1N1pdm09 resulted in the release of IFN-a, (14,787 pg/mL, 95% CI 7311-22,264 pg/mL) IFN-¿ (1486 pg/mL, 95% CI 756-2216 pg/mL) and IFN-¿ (852 pg/mL, 95% CI 193-1511 pg/mL) after 48 hours. This was significantly impaired in pregnant women (IFN-a; p<0.0001 and IFN-¿; p<0.001). Furthermore, in the presence of syncytin-1, PBMCs demonstrated marked reductions in IFN-a and IFN-¿, while enhanced release of IL-10 as well as IL-6 and IL-1ß. Conclusions Our data indicates that a placental derived protein, syncytin-1 may be responsible for the heightened vulnerability of pregnant women to influenza.
© 2014 Wiley Periodicals, Inc. Background Successful parenting requires maternal behaviors that promote infant survival such as protection from predators. In animal studies, oxyto... [more]
© 2014 Wiley Periodicals, Inc. Background Successful parenting requires maternal behaviors that promote infant survival such as protection from predators. In animal studies, oxytocin (OT) has been linked to maternal aggression to protect offspring. No human study has explored this topic. Mothers with a diagnosis of postnatal depression (PND) are at higher risk of neglecting their infants. We hypothesized that intranasal OT administration would increase the protective behaviors of mothers with PND, toward their infants. Methods Sixteen mothers with a diagnosis of PND participated in a double-blind, randomized-controlled, within-subject pilot study. Participants received intranasal OT during one visit and placebo spray on the alternate visit. Maternal protective behavior toward their infant was measured, in the presence of a socially intrusive stranger. Results The enthusiastic stranger paradigm stimulated participants' protective responses in the presence of an intrusive stranger. Furthermore, this protective response of mothers with a diagnosis of PND was increased in the OT condition. Conclusions The study introduces a new paradigm, the enthusiastic stranger paradigm, which may be used to examine a neglected type of parental behavior, that is, protection of offspring. The protective response of mothers with PND increased, in line with the 'tend and defend' effects of OT in animal models. In future work it should be tested whether this protection effect can also be found in nonclinical samples, or whether it is specific for clinically depressed mothers.
© 2015 by the authors. We present a hypothesis for a mechanism involving self-organization of small functional units that leads to organ-level synchronization of uterine contracti... [more]
© 2015 by the authors. We present a hypothesis for a mechanism involving self-organization of small functional units that leads to organ-level synchronization of uterine contractions in human labor. This view is in contrast to the long-held presumption that the synchronized behavior of the uterus is subject to well-defined internal organization (as is found in the heart) that exists prior to the onset of labor. The contractile units of the uterus are myocytes, which contract in response to both mechanical stretch and electrical stimulation. Throughout pregnancy progesterone maintains quiescence by suppression of "contraction-associated proteins" (CAPs). At the end of pregnancy a functional withdrawal of progesterone and an increasingly estrogenic environment leads to an increase in the production of CAPs. One CAP of particular importance is connexin 43, which creates gap junctions between the myocytes that cause them to become electrically coupled. The electrical connectivity between myocytes, combined with an increase in intrauterine pressure at the end of pregnancy shifts the uterus towards an increasingly unstable critical point, characterized by irregular, uncoordinated contractions. We propose that synchronous, coordinated contractions emerge from this critical point through a process of self-organization, and that the search for a uterine pacemaker has been unfruitful for the sole reason that it is non-existent.
Human ether-a-go-go-related gene (hERG) potassium channels determine cardiac action potential and contraction duration. Human uterine contractions are underpinned by an action pot... [more]
Human ether-a-go-go-related gene (hERG) potassium channels determine cardiac action potential and contraction duration. Human uterine contractions are underpinned by an action potential that also possesses an initial spike followed by prolonged depolarization. Here we show that hERG channel proteins (a-conducting and ßinhibitory subunits) and hERG currents exist in isolated patch-clamped human myometrial cells. We show that hERG channel activity suppresses contraction amplitude and duration before labour, thereby facilitating quiescence. During established labour, expression of ß-inhibitory protein is markedly enhanced, resulting in reduced hERG activity that is associated with an increased duration of uterine action potentials and contractions. Thus, changes in hERG channel activity contribute to electrophysiological mechanisms that produce contractions during labour. We also demonstrate that this system fails in women with elevated BMI, who have enhanced hERG activity as a result of low ß-inhibitory protein expression, which likely contributes to the weak contractions and poor labour outcomes observed in many obese women necessitating caesarean delivery. © 2014 Macmillan Publishers Limited.
Progesterone regulates female reproductive function predominantly through two nuclear progesterone receptors (PRs), PR-A and PR-B. During human parturition myometrial PR expressio... [more]
Progesterone regulates female reproductive function predominantly through two nuclear progesterone receptors (PRs), PR-A and PR-B. During human parturition myometrial PR expression is altered to favour PR-A, which activates pro-labour genes. We have previously identified histone H3 lysine 4 trimethylation (H3K4me3) as an activator of myometrial PR-A expression at labour. To further elucidate the mechanisms regulating PR isoform expression in the human uterus at labour, we have (i) determined the methylation profile of the cytosine-guanine dinucleotides (CpG) island in the promoter region of the PR gene and (ii) identified the histone-modifying enzymes that target the H3K4me3 mark at the PR promoters in term and preterm human myometrial tissues obtained before and after labour onset. Bisulphite sequencing showed that despite overall low levels of PR CpG island methylation, there was a significant decrease in methylated CpGs with labour in both preterm (P < 0.05) and term (P < 0.01) groups downstream of the PR-B transcription start site. This methylation change was not associated with altered PR-B expression, but may contribute to the increase in PR-A expression with labour. Chromatin immunoprecipitation revealed that the histone methyltransferase, SET and MYND domain-containing protein 3 (SMYD3), bound to the PR gene at significantly higher levels at the PR-A promoter compared with the PR-B promoter (P < 0.010), with no labour-associated changes observed. The H3K4 demethylase, Jumonji AT-rich interactive domain 1A (JARID1A), also bound to the PR-A, but not to the PR-B promoter prior to term labour, and decreased significantly at the onset of labour (P = 0.014), providing a mechanism for the previously reported increase in H3K4me3 level and PR-A expression with labour. Our studies suggest that epigenetic changes mediated by JARID1A, SMYD3 and DNA methylation may be responsible, at least in part, for the functional progesterone withdrawal that precipitates human labour. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.
Lymphocytic hypophysitis is an organ-specific autoimmune disease characterised by destruction of pituitary hormone-secreting cells due to attack by self-reactive T lymphocytes. Th... [more]
Lymphocytic hypophysitis is an organ-specific autoimmune disease characterised by destruction of pituitary hormone-secreting cells due to attack by self-reactive T lymphocytes. The spectrum of pituitary autoantibodies characterised by indirect immunofluorescence (IF) in these patients has not been substantially defined. The purpose of this study was to determine the spectrum of pituitary autoantibodies in 16 lymphocytic hypophysitis patients. Pituitary sections were prepared from guinea pigs and sera from 16 lymphocytic hypophysitis patients (13 biopsy proven and 3 suspected cases) and 13 healthy controls were evaluated for immunoreactivity to the pituitary tissue by immunofluorescence. A single patient was found to have high titre pituitary autoantibodies against guinea pig pituitary tissue. Immunoreactivity was directed against cells of the intermediate lobe. We present the case report of the patient who is a 24 year old woman that presented with headaches, polyuria and polydipsia. A uniformly enlarged pituitary mass was visible on MRI and a diagnosis of suspected lymphocytic hypophysitis was made. Based on our IF study, we postulate this patient has an autoimmune process directed towards the major cell type in the intermediate lobe, the melanotroph. Pre-adsorption with peptides representing adrenocorticotropic hormone, a-melanocyte stimulating hormone or ß-endorphin did not affect the IF signal suggesting our patient's pituitary autoantibodies may target some other product of Proopiomelanocortin (POMC) processing, such as corticotrophin-like intermediate peptide or ¿-lipoprotein. Alternatively, the autoantibodies may target a peptide completely unrelated to POMC processing. © 2013 Springer Science+Business Media New York.
© 2012 John Wiley & Sons Ltd. Post-partum weight retention (WR) occurs in 60-80% of women with some retaining =10kg with contributing factors reported as pre-pregnancy body ... [more]
© 2012 John Wiley & Sons Ltd. Post-partum weight retention (WR) occurs in 60-80% of women with some retaining =10kg with contributing factors reported as pre-pregnancy body mass index (BMI), gestational weight gain (GWG) and breastfeeding. A longitudinal study of pregnancy, with 12-month post-partum follow-up was conducted to determine factors associated with WR. Pregnant women (n=152) were recruited from the John Hunter Hospital antenatal clinic in New South Wales, Australia. Pre-pregnancy weight was self-reported; weight was measured four times during pregnancy (for GWG) and in the first 12 months post-partum. Infant feeding data were obtained via questionnaires. Breastfeeding was categorised as exclusive, predominant, complementary or not breastfeeding. Linear mixed models tested the predictors of WR, with and without adjustment for potential confounders. Compared with pre-pregnancy weight, 68% of women retained weight at 12 months, median (interquartile range) [4.5kg (2.1-8.9)]. After adjustment, GWG was positively associated with WR (P<0.01), but pre-pregnancy weight did not predict WR. For each additional week of any breastfeeding, 0.04kg less weight was retained. Compared with women who retained weight, those women who did retain had higher rates of exclusive breastfeeding at three months (P<0.05), but the number of weeks of exclusive breastfeeding failed to predict WR for all women. WR following childbirth is common and associated with GWG, while the number of weeks of 'any' breastfeeding contributed to post-partum weight loss. Whether these factors are modifiable strategies to optimise the weight status of women at this life stage requires further research.
Background: Postnatal depression is common and negatively affects the mother-baby relationship; oxytocin has been found to have positive effects on parenting behavior. We hypothes... [more]
Background: Postnatal depression is common and negatively affects the mother-baby relationship; oxytocin has been found to have positive effects on parenting behavior. We hypothesize that intranasal administration of oxytocin to mothers with depression will influence their parenting related expressed emotion, creating a better basis for sensitive parenting. Methods: Twenty-five postnatally depressed mothers with infants less than one year participated in a randomized, double-blind, placebo controlled within-subject clinical study in 2011. Mothers attended an out-patient perinatal psychiatry setting in NSW, Australia. They received 24. IU of oxytocin alternating with placebo approximately one week apart in random order, prior to completing outcome measures. The outcome measures were the Five Minute Speech Sample, the Self-Assessment Manikin and the Controlled Oral Word Association Test. Results: In the oxytocin condition mothers were sadder (p= .01), and they more often initially described their babies as difficult (p= .038), but they reported that the quality of their relationship with their infant was more positive (p= .036). Limitations: Despite an adequate sample size to answer our central hypothesis, a larger sample may have elucidated a moderating effect of childhood trauma. Conclusion: Oxytocin did not make depressed mothers happier but their perception of the relationship with their baby improved. Treatment with intranasal oxytocin might show some unwanted side-effects in depressed individuals. © 2012 Elsevier Inc.
Objective: To determine delivery outcome in women undergoing induction of labor for postdate pregnancy in relation to fetal gender. Study Design: A total of 365 nulliparous and 12... [more]
Objective: To determine delivery outcome in women undergoing induction of labor for postdate pregnancy in relation to fetal gender. Study Design: A total of 365 nulliparous and 127 multiparous women carrying singleton postdate pregnancies with unfavorable cervix were enrolled. Clinical characteristics and delivery outcome were analyzed in relation to fetal gender. Results: Women carrying male fetuses showed higher rate of caesarean section than those carrying females, in both nulliparous and multiparous women. Moreover, women carrying male fetuses presented more frequently with (i) interval between induction of labor and delivery >24 hours (P < .0002); (ii) augmentation of labor after cervical ripening (P < .0391); (iii) meconium-stained liquor (P< .0126); and (iv) higher neonatal weight (P < .0011) than those carrying females. Conclusion: Male fetuses are more likely to be associated with higher rates of cesarean section. In maternal fetal medicine, gender differences may add prognostic information on the delivery outcome in women induced for postdate pregnancy. © The Author(s) 2013.
Background: In 2006, it was reported that Focal and Segmental Glomerulosclerosis (FSGS), Minimal Change Disease (MCD) and Membranous Glomerulonephritis (MGN) were the commonest pr... [more]
Background: In 2006, it was reported that Focal and Segmental Glomerulosclerosis (FSGS), Minimal Change Disease (MCD) and Membranous Glomerulonephritis (MGN) were the commonest primary glomerular diseases identified from percutaneous kidney biopsies done in Jamaica for that year (n = 76). The sample size was thought to be small and might have affected the reported findings. So a three-year review of percutaneous kidney biopsies in Jamaica was carried out. Methods: Histology reports and clinical data were reviewed for percutaneous kidney biopsies performed from January 2005 to December 2007. Demographic data (age, gender), laboratory investigations such as serum urea, serum creatinine, proteinuria, haematuria, 24-hour urinary protein, and creatinine clearance, and clinical diagnosis were collected from the histology requisition form. Results: There was a total of 224 native kidney biopsies performed. There were 91 males (40.6%) and 133 females (59.4%). Age distribution showed a total number of 25 paediatric cases (11.2%) and 199 adult cases (88.8%). Proteinuria was present at 171 cases (76.3%) and haematuria in 86 cases (38.4%). Of the total biopsies done, 78 cases (39.2%) had primary glomerular diseases, 110 cases (55.3%) had secondary glomerular diseases and 11 (5.5%) biopsies were reported as either normal or inadequate for histological diagnosis. The most common reasons indicated for percutaneous kidney biopsy were proteinuria, haematuria and staging of lupus nephritis. Most common histological findings for primary glomerular disease after percutaneous kidney biopsy were FSGS (n = 34), MGN (n = 15) and MCD (n = 12). In secondary glomerular diseases (n = 110), there were more females (70.8%) than males. Systemic lupus erythematosus was present in 63.3%. Histology of lupus nephritis according to the International Society of Nephrologists classification shows Membranous Lupus Nephritis [MLN] (40.2%), Diffuse Lupus Nephritis [DLN] (19.5%) and Minimal Mesangial Lupus Nephritis [MMLN] (14.3%) as the common histological types. Conclusions: The most common histological finding for primary glomerular disease following percutaneous kidney biopsy was FSGS, MCD and MGN. Membranous Lupus Nephritis was the commonest histological type for lupus nephritis in this series.
Objectives. To identify factors significantly associated with post-traumatic stress disorder (PTSD), anxiety, and depression at 3 months post-injury; to develop a generic model to... [more]
Objectives. To identify factors significantly associated with post-traumatic stress disorder (PTSD), anxiety, and depression at 3 months post-injury; to develop a generic model to predict the occurrence of PTSD, anxiety, and depression at 3 months post-injury; and to validate this model in a test data set of patients. Design. Prospective cohort study. Methods. Participants were 823 patients attending an emergency department (ED) following accidental injury. Baseline questionnaires were completed, with 1 and 3 months postal follow-ups. Predictor variables demonstrating significant associations with two of the three outcome measures (3-month HAD anxiety and depression scores and PTSD symptoms) were included in multivariate regression models for each outcome. Non-significant predictor variables were removed until all remaining independent variables made the most significant contribution to each of the three models. Models were validated using a test dataset. Results. Previous history of mental health problems, neuroticism score and having PTSD symptoms at 1 month predicted adverse outcomes at 3 months. When used on the test datasets, the areas under the receiver operating curve (ROC) curve for the models predicting outcomes at 3 months were: PTSD = 0:91 (sensitivity = 88:5%); anxiety = 0.87 (sensitivity = 93:7%); and depression = 0:87 (sensitivity = 96:7%). Conclusions. The final model performed moderately well across the three outcomes and may be useful clinically as a generic rule-out tool to identify those who will not require follow up, watchful waiting or intervention. © 2009 The British Psychological Society.
We investigated the outcome of a cohort of black Jamaican patients with systemic lupus erythematosus (SLE) with nephritis. In 66 patients, 0 (0%), 15 (23%), 4 (6%), 32 (48%), 6 (9... [more]
We investigated the outcome of a cohort of black Jamaican patients with systemic lupus erythematosus (SLE) with nephritis. In 66 patients, 0 (0%), 15 (23%), 4 (6%), 32 (48%), 6 (9%), and 3 (5%) had classes 1, II, III, IV, V, and VI, respectively. Six (9%) had interstitial nephritis. The patients were placed in 2 groups for comparison. Group 1 (n = 36) consisted of classes III and IV and group 2 (n = 27), classes II and V, and interstitial nephritis. The patients in group 1 had significantly lower hemoglobin, higher mean serum creatinine, higher prevalence of hypertension, and chronicity scores. The duration of follow-up was similar between the 2 groups. The percent events free for ESRD or death at 1 year was 80.1% for group 1 and 77.4% for group 2; 2 years, 69.0% for group 1 and 77.4% group 2; 5 years, 69.0% for group 1 and 57.4% for group 2. The percent events free for death at 1 year was 93.4% in group 1 and 90.9% in group 2; at 2 years, 86.7% for group 1 and 90, 9% for group 2; and at 5 years was 86.7% for group 1 and 67.3% (29.5 to 88.0) for group 2. Sixteen patients (25.4%) developed ESRD or died. Prognosis was not different between the groups for ESRD or death (P = 0.22) or death alone (P = 0.63). © Copyright 2007 Southern Society for Clinical Investigation.
Objectives: The purpose of the study was to determine the period prevalence of acute renal failure (ARF) after coronary bypass surgery (CABG) at the University Hospital of the Wes... [more]
Objectives: The purpose of the study was to determine the period prevalence of acute renal failure (ARF) after coronary bypass surgery (CABG) at the University Hospital of the West Iindies and to identify risk factors. Method: A retrospective analysis of patients who underwent CABG during the period 1994-2004 was done. Data collected included; age, gender weight, the presence of hypertension (HTN), diabetes mellitus (DM), hypercholesterolaemia, previous myocardial infarction (MI), bloodpressure on admission, urea and creatinine one year prior to surgery, on admission for surgery and post-surgery, duration of intra-operative hypotension, duration of cardiopulmonary bypass, perfusion pressure and the perioperative medications. Results: The case notes of 62 patients (68.9%) were obtainedfor analysis. There were 47 (75.8%) males and 15 females (24.2%) - a 3:1 ratio. The prevalence of HTN and DM in the study sample was 78% and 72% respectively, hypercholesterolaemia was 31% and a previous MI was 29%. There were no differences based on gender. Post CABG complications were: persistent postoperative hypotension (6.8%), congestive cardiac failure (CCF) (6.89,66), arrhythmia (6.8%), sepsis (6.8%), lower respiratory tract infection (LRTI) and pleural effusion (5.1%), heart block (3.4%), pulmonary embolism (1.7%), cellulitis and haematoma formation were 1.7%. Three patients had increases in postoperative creatinine values> 89 µmol/L over the postoperative value resulting in a prevalence of ARF of 5%. One of the three patients died and none received dialysis. There were no statistical difference inpre-operative clinical and biochemical characteristics based on the presence or absence of ARF. The presence of diabetes and increased length of stay were significant predictors of increasing postoperative creatinine values adjusting for pre-operative creatinine values. In addition, the presence of diabetes mellitus and male gender were significant predictors of increasing postoperative urea values. Conclusion: DM is a significant risk factor for the development of ARF post CABG.
The actions of GH are mediated through a cell surface cytokine receptor. We previously demonstrated that naturally occurring truncated membrane bound GH receptors (GHRs) can block... [more]
The actions of GH are mediated through a cell surface cytokine receptor. We previously demonstrated that naturally occurring truncated membrane bound GH receptors (GHRs) can block GH receptor signaling. We have now investigated whether recombinant extracellular GHR can be conjugated to a myristoylated-peptide (mp) tail and inserted into cell membranes to modulate GHR signaling. Recombinant human extracellular domain (1-241) GHR was expressed in Escherichia coli, purified, and refolded from cell lysate. The free C-terminal cysteine was then reduced and conjugated to an activated preformed mp tail. The properties of the purified tailed GHR (GHR-mp) were then compared with those of the untailed purified GHR 1-241. Fluorescence-activated cell sorter analysis and cell surface binding assays demonstrated that GHR-mp inserted into the cell surface membranes of CHO cells, whereas untailed GHR 1-241 showed no insertion. In a cell-based bioassay GHR-mp partially inhibited wild-type GHR signaling, whereas GHR 1-241 had no effect. Truncated extracellular domain GHR can, when specifically modified with a membrane-localizing mp unit, insert into cell surface membranes and modulate GHR signaling. Copyright © 2007 by The Endocrine Society.
Uterine quiescence is essential for successful pregnancy. Cholesterol and triglycerides are markedly increased in pregnancy. Cholesterol is enriched in microdomains of the plasma ... [more]
Uterine quiescence is essential for successful pregnancy. Cholesterol and triglycerides are markedly increased in pregnancy. Cholesterol is enriched in microdomains of the plasma membrane known as rafts and caveolae. Both lipid rafts and caveolae have been implicated in cellular signaling cascades. The purpose of this work was to investigate whether manipulation of cholesterol content alters uterine contractility. Late pregnancy (19-21 days) rats were humanely euthanized and strips of longitudinal myometrium were then dissected. Force and Ca 2+ measurements were simultaneously recorded and cholesterol increased by the addition of 5 mg/ml cholesterol or 0.25 mg/ml low-density lipoproteins (LDLs) or reduced by 2% methyl-ß-cyclodextrin (MCD) or 2 U/ml cholesterol oxidase addition to the perfusate. Both LDLs and cholesterol profoundly inhibited spontaneous uterine force production and associated Ca 2+ transients; frequency, amplitude, and duration of contraction were all significantly reduced compared with preceding control contractions. Force and Ca 2+ were also reduced by cholesterol when 1 nM oxytocin was used to stimulate the myometrium. Uterine activity was significantly increased by cholesterol extraction with MCD or cholesterol oxidase treatment. Electron microscopy confirmed the lipid raft disrupting effect of MCD, as formerly electron microscopy-visible caveolae in the myometrial cell membrane all but disappeared after MCD treatment. These data show that uterine smooth muscle cell cholesterol content is critically important for functional activity. A novel finding of our study is that cholesterol is inhibitory for force generation. It may be one of the mechanisms operating to maintain uterine quiescence throughout gestation and may also contribute to difficulties in labor suffered by obese women. Copyright © 2005 the American Physiological Society.
Previous functional neuroimaging studies of posttraumatic stress disorder (PTSD) have mainly focused on symptom-provocation paradigms in combat-related PTSD. We sought to elucidat... [more]
Previous functional neuroimaging studies of posttraumatic stress disorder (PTSD) have mainly focused on symptom-provocation paradigms in combat-related PTSD. We sought to elucidate the effect of non-combat-related PTSD on the physiology of social cognition. Thirteen patients with PTSD underwent functional magnetic resonance imaging (fMRI) while they engaged in tasks that (i) involve speculation on another's intention, (ii) invoke empathy and (iii) involve making judgments of the forgivability of others' actions; each versus 'baseline' social reasoning judgments. A post-therapy fMRI scan followed a course of modified cognitive behavioural therapy. Post-therapy, we found increased activation in brain regions predicted on the basis of foregoing work in healthy subjects. These included significant left middle temporal gyrus activation in post-therapy response to empathy judgments and posterior cingulate gyrus activation in post-therapy response to forgivability judgments. The specific regions of the human brain activated by empathy and forgivability judgments changed with symptom resolution in PTSD. Time and therapy are likely contributory factors that lead to a degree of 'normalisation' of the neural response to these social cognition tasks. © 2005 Elsevier Ireland Ltd. All rights reserved.
The prevalence of chronic renal failure (CRF)/end stage renal disease and the accessibility of long term renal replacement therapy in Jamaica were evaluated. The study was conduct... [more]
The prevalence of chronic renal failure (CRF)/end stage renal disease and the accessibility of long term renal replacement therapy in Jamaica were evaluated. The study was conducted at six Jamaican healthcare facilities between July 1998 and December 1999 and included 605 patients with CRF. Men with CRF (57% of patients, mean age of 56.7 years) were significantly older than women (mean age 53.2 years). Hypertension was the most commonly associated medical condition (60.8% of patients) followed by diabetes mellitus (31.4% of patients). The estimated crude point prevalence of CRF in persons 20 years and over at the end of 1999 was 327 per million population. More than one-third of patients with CRF (39%) were receiving renal replacement therapy, the most common modality being haemodialysis, and only 1.8% of patients had received kidney transplantation. The prevalence of chronic renal failure was not increased in areas known to have high soil cadmium levels. Chronic renal failure is a significant public health problem in Jamaica and is placing an increasing financial burden on the healthcare sector.
The regulation of contractile activity in smooth muscle cells involves rapid discrimination and processing of a multitude of simultaneous signals impinging on the membrane before ... [more]
The regulation of contractile activity in smooth muscle cells involves rapid discrimination and processing of a multitude of simultaneous signals impinging on the membrane before an integrated functional response can be generated. The sarcolemma of smooth muscle cells is segregated into caveolar regions-largely identical with cholesterol-rich membrane rafts - and actin-attachment sites, localized in non-raft, glycerophospholipid regions. Here we demonstrate that selective extraction of cholesterol abolishes membrane segregation and disassembles caveolae. Simultaneous measurements of force and [Ca2+]i in rat ureters demonstrated that extraction of cholesterol resulted in inhibition of both force and intracellular Ca 2+ signals. Considering the major structural reorganization of cholesterol-depleted sarcolemma, it is intriguing to note that decreased levels of membrane cholesterol are accompanied by a highly specific inhibition of phasic, but not tonic contractions. This implies that signalling cascades that ultimately lead to either phasic or tonic response may be spatially segregated in the plane of the sarcolemma. Replenishment of cholesterol restores normal contractile behavior. In addition, the tissue function is re-established by inhibiting the large-conductance K+-channel. Sucrose gradient ultracentrifugation in combination with Western blotting analysis demonstrates that its a-subunit is associated with detergent-resistant membranes, suggesting that the channel might be localized within the membrane rafts in vivo. These findings are important in understanding the complex signalling pathways in smooth muscle and conditions such as premature labor and hypertension.
It is clear that pH has many effects on vascular smooth muscle and the overall action of pH on force will depend on the type of vascular smooth muscle in question and the combined... [more]
It is clear that pH has many effects on vascular smooth muscle and the overall action of pH on force will depend on the type of vascular smooth muscle in question and the combined effects on all the potential modulatory mechanisms. The major effects of pH on force appear to be mediated via modulation of [Ca]i rather than changes in the sensitivity of the contractile machinery to Ca2+. There are still numerous gaps in our understanding of the actions of pH and as more data become available, we will be able to better understand the major mechanisms involved. © 2004 Kluwer Academic Publishers.
Preterm labour remains a major obstetric problem with only poor methods for prediction of preterm birth and treatments of preterm labour with limited efficacy. Regulation of human... [more]
Preterm labour remains a major obstetric problem with only poor methods for prediction of preterm birth and treatments of preterm labour with limited efficacy. Regulation of human parturition is demonstrably different from that in most animals restricting opportunities for relevant research. Recent work suggests a placental clock mechanism regulating the length of pregnancy through the production of the placental peptide Corticotrophin Releasing Hormone. At the end of pregnancy most animals initiate labour with a fall in circulating progesterone concentrations but this does not happen in humans. In humans a functional progesterone withdrawal is initiated by a change in myometrial expression of progesterone receptors, specifically increase expression of the PRA isoforms, which is a dominant repressor of the activating receptor PRB. This new knowledge may help design better strategies for prediction and treatment of preterm labour.
OBJECTIVE: The purpose of this study was to examine the relationship of maternal serum activin A, inhibin A, and follistatin with fetal growth and placental function. STUDY DESIGN... [more]
OBJECTIVE: The purpose of this study was to examine the relationship of maternal serum activin A, inhibin A, and follistatin with fetal growth and placental function. STUDY DESIGN: Inhibin A, activin A, and follistatin were measured in maternal serum that was stored from normally grown (control subjects, n = 50) and small-for-gestational-age pregnancies (n = 49), prospectively classified as normal small-for-gestational-age pregnancy or fetal growth-restricted pregnancy with the use of umbilical artery Doppler ultrasound. RESULTS: Activin A and inhibin A were significantly increased in fetal growth-restricted pregnancies compared with control subjects (activin A: regression coefficient, 0.54, P < .001; inhibin A: regression coefficient, 0.47, P = .003). The activin:follistatin ratio was significantly higher in fetal growth-restricted pregnancies compared with control subjects (P < .001). There were no significant differences between analyte levels of normal small-for-gestational-age pregnancies and control subjects. CONCLUSION: Maternal serum activin A, inhibin A, and activin:follistatin ratio are raised in fetal growth-restricted pregnancies but not in normal small-for-gestational age pregnancies. This provides further evidence of the difference between subgroups within small-for-gestational-age pregnancies and emphasizes the need to stratify for this in research.
We hypothesized that urocortin might be produced in the pituitary of the late-gestation ovine fetus in a manner that could contribute to the regulation of ACTH output. We used in ... [more]
We hypothesized that urocortin might be produced in the pituitary of the late-gestation ovine fetus in a manner that could contribute to the regulation of ACTH output. We used in situ hybridization and immunohistochemistry to identify urocortin mRNA and protein in late-gestation fetal pituitary tissue. Levels of urocortin mRNA rose during late gestation and were associated temporally with rising concentrations of pituitary proopiomelanocortin (POMC) mRNA. Urocortin was localized both to cells expressing ACTH and to non-ACTH cells by use of dual immunofluorescence histochemistry. Transfection of pituitary cultures with urocortin antisense probe reduced ACTH output, whereas added urocortin stimulated ACTH output from cultured pituitary cells. Cortisol infusion for 96 h in chronically catheterized late-gestation fetal sheep significantly stimulated levels of pituitary urocortin mRNA. We conclude that urocortin is expressed in the ovine fetal pituitary and localizes with, and can stimulate output of, ACTH. Regulation of urocortin by cortisol suggests a mechanism to override negative feedback and sustain feed-forward of fetal hypothalamic-pituitary-adrenal function, leading to birth.
High levels of saturated, branched-chain fatty acids are deleterious to cells and animals, resulting in lipid accumulation and cytotoxicity. Although fatty acid binding proteins (... [more]
High levels of saturated, branched-chain fatty acids are deleterious to cells and animals, resulting in lipid accumulation and cytotoxicity. Although fatty acid binding proteins (FABPs) are thought to be protective, this hypothesis has not previously been examined. Phytanic acid (branched chain, 16-carbon backbone) induced lipid accumulation in L cell fibroblasts similar to that observed with palmitic acid (unbranched, C16): triacylglycerol » free fatty acid > cholesterol > cholesteryl ester » phospholipid. Although expression of sterol carrier protein (SCP)-2, SCP-x, or liver FABP (L-FABP) in transfected L cells reduced [3H]phytanic acid uptake (57-87%) and lipid accumulation (21-27%), nevertheless [3H]phytanic acid oxidation was inhibited (74-100%) and phytanic acid toxicity was enhanced in the order L-FABP » SCP-x > SCP-2. These effects differed markedly from those of [3H]palmitic acid, whose uptake, oxidation, and induction of lipid accumulation were not reduced by L-FABP, SCP-2, or SCP-x expression. Furthermore, these proteins did not enhance the cytotoxicity of palmitic acid. In summary, intracellular FABPs reduce lipid accumulation induced by high levels of branched-chain but not straight-chain saturated fatty acids. These beneficial effects were offset by inhibition of branched-chain fatty acid oxidation that correlated with the enhanced toxicity of high levels of branched-chain fatty acid.
To better understand excitability, and hence contraction, the ionic currents underlying the action potential were identified and characterised in enzymatically isolated smooth mus... [more]
To better understand excitability, and hence contraction, the ionic currents underlying the action potential were identified and characterised in enzymatically isolated smooth muscle cells of the rat ureter. Using the whole-cell patch-clamp, under voltage-clamp conditions with K + in the pipette, three types of responses occurred to depolarisation: (1) sustained outward current and spontaneous transient outward currents (STOCs); (2) inward current; and (3) fast outward current. Investigation using different voltage protocols and pharmacological blockers and agonists revealed the presence of three outward and two inward currents. The outward currents were: (1) a sustained BK current, sensitive to low concentrations of tetraethylammonium (TEA) and featuring bursts of STOCs superimposed on it; (2) a fast, transient, A-type K current sensitive to 4-aminopyridine; and (3) a TEA and Ca 2+ -insensitive, late K + rectifier current. The inward currents were: (1) a fast L-type Ca 2+ channel current sensitive to nifedipine, Cd 2+ and potentiated by Ba 2+ ; and (2) a Ca 2+ -sensitive Cl - channel, which was inhibited by niflumic acid and Ba 2+ , and produced a large tail current upon repolarisation at the end of the voltage step. The I-V relationships and peak amplitudes of all the currents are described. The finding of a K + rectifier and Ca 2+ -activated Cl - channel distinguish the rat ureteric cells from those of the guinea-pig. Thus, as well as the previously established difference in sarcoplasmic reticulum Ca 2+ -release mechanisms, there is also a species difference in ion channel expression in this tissue. We relate these currents to their possible contribution to the characteristically extremely long lasting action potential in the rat ureter.
The effects of changing extracellular (pH o ) and intracellular pH (pH i ) on force and the mechanisms involved in the guinea pig portal vein were investigated to better understan... [more]
The effects of changing extracellular (pH o ) and intracellular pH (pH i ) on force and the mechanisms involved in the guinea pig portal vein were investigated to better understand the control of tone in this vessel. When pH o was altered, the effects on force and calcium were the same irrespective of whether force had been produced spontaneously by high-K depolarization or by norepinephrine; alkalinization increased tone, and acidification reduced it. Because pH o changes also lead to changes in ph i , we determined whether the effects on force could be explained by these induced pH i changes. It was found, however, that only with spontaneous activity did intracellular alkalinization increase force. In depolarized preparations, force was decreased, and, with norepinephrine, force was initially decreased and then increased. Thus the effects of pH o cannot be explained solely by changes in pH i . The role of the sarcoplasmic reticulum (SR) and surface membrane Ca 2+ -ATPase on the mechanism were investigated and shown not to be involved. Therefore, it is concluded that both pH o and pH i can have powerful modulatory effects on portal vein tone, that these effects are not identical, and that they are likely to be due to effects of pH on ion channels rather than the SR or plasma membrane Ca 2+ -ATPase.
In this study, local sewage sludge was acclimated to establish H2-producing enrichment cultures, which were used to convert sucrose to H2 with continuously stirred anaerobic biore... [more]
In this study, local sewage sludge was acclimated to establish H2-producing enrichment cultures, which were used to convert sucrose to H2 with continuously stirred anaerobic bioreactors. The steady-state behaviors of cell growth, substrate utilization, and product formation were closely monitored. Kinetic models were developed to describe and predict the experimental results from the H2-producing cultures. Operation at dilution rates (D) of 0.075-0.167 h-1 was preferable for H2 production, resulting in a H2 concentration of nearly 0.02 mol/l. The optimal hydrogen production rate was 0.105 mol/h occurring at D=0.125 h-1. The major volatile fatty acid produced was butyric acid (HBu), while acetic acid and propionic acid were also produced in lesser quantities. The major solvent product was ethanol, whose concentration was only 15% of that of HBu, indicating that the metabolic flow favors H2 production. The proposed model was able to interpret the trends of the experimental data. The maximum specific growth rate (µmax), Monod constant (Ks), and yield coefficient for cell growth (Yx/s) were estimated as 0.172 h-1, 68 mg COD/l, and 0.1 g/g, respectively. The model study also suggests that product formation in the continuous hydrogen-producing cultures was essentially a linear function of biomass concentration.
Although expression of liver fatty acid binding protein (L-FABP) modulates cell growth, it is not known if L-FABP also alters cell morphology and differentiation. Therefore, pluri... [more]
Although expression of liver fatty acid binding protein (L-FABP) modulates cell growth, it is not known if L-FABP also alters cell morphology and differentiation. Therefore, pluripotent embryonic stem cells were transfected with cDNA encoding L-FABP and a series of clones expressing increasing levels of L-FABP were isolated. Untransfected ES cells, as well as ES cells transfected only with empty vector, spontaneously differentiated from rounded adipocyte-like to fibroblast-like morphology, concomitant with marked reduction in expression of stage-specific embryonic antigen (SSEA-1). These changes in morphology and expression of SSEA-1 were greatest in ES cell clones expressing L-FABP above a threshold level. Immunofluorescence confocal microscopy revealed that L-FABP was primarily localized in a diffuse-cytosolic pattern along with a lesser degree of punctate L-FABP expression in the nucleus. Nuclear localization of L-FABP was preferentially increased in clones expressing higher levels of L-FABP. In summary, L-FABP expression altered ES cell morphology and expression of SSEA-1. Taken together with the fact that L-FABP was detected in the nucleus, these data suggested that L-FABP may play a more direct, heretofore unknown, role in regulating ES cell differentiation by acting in the nucleus as well as cytoplasm.
An analysis of the functional role of a diacidic motif (Asp 236 -Asp 237) ) in the third intracellular loop of the AT 1A angiotensin II (Ang II) receptor (AT 1 -R) revealed that s... [more]
An analysis of the functional role of a diacidic motif (Asp 236 -Asp 237) ) in the third intracellular loop of the AT 1A angiotensin II (Ang II) receptor (AT 1 -R) revealed that substitution of both amino acids with alanine (DD-AA) or asparagine (DD-NN) residues diminished Young II-induced receptor phosphorylation in COS-7 cells. However, Ang II-stimulated inositol phosphate production, mitogen-activated protein kinase, and AT 1 receptor desensitization and internalization were not significantly impaired. Overexpression of dominant negative G protein-coupled receptor kinase 2 (GRK2) K220M decreased agonist-induced receptor phosphorylation by ~40%, but did not further reduce the impaired phosphorylation of DD-AA and DD-NN receptors. Inhibition of protein kinase C by bisindolylmaleimide reduced the phosphorylation of both the wild-type and the DD mutant receptors by ~30%. The inhibitory effects of GRK2 K220M expression and protein kinase C inhibition by bisindolylmaleimide on agonist-induced phosphorylation were additive for the wild-type AT 1 -R, but not for the DD mutant receptor. Agonist-induced internalization of the wild-type and DD mutant receptors was similar and was unaltered by coexpression of GRK2 K220M . These findings demonstrate that an acidic motif at position 236/237 in the third intracellular loop of the AT 1 -R is required for optimal Young II-induced phosphorylation of its carboxyl-terminal tail by GRKs. Furthermore, the properties of the DD mutant receptor suggest that not only Young II-induced signaling, but also receptor desensitization and internalization, are independent of agonist-induced GRK-mediated phosphorylation of the AT 1 receptor.
In this review we discuss our current understanding of the cellular basis of uterine contractility, highlighting those areas requiring further study. It is clear that the basic pr... [more]
In this review we discuss our current understanding of the cellular basis of uterine contractility, highlighting those areas requiring further study. It is clear that the basic processes of excitation-contraction coupling lie within the myometrial cell, and that these may be modified by agonists. Pacemaker activity, however, remains a mystery. The contribution of extracellular calcium entry to contraction is shown to be vital, whilst the role of the sarcoplasmic reticulum remains controversial. Much current experimental focus is on pathways controlling and regulating contraction, and we discuss sensitisation mechanisms and question their role in intact uterine preparations.
Corticotrophin-releasing hormone (CRH) is a 41 amino acid neuropeptide that is expressed in the hypothalamus and the human placenta. Placental CRH production has been linked to th... [more]
Corticotrophin-releasing hormone (CRH) is a 41 amino acid neuropeptide that is expressed in the hypothalamus and the human placenta. Placental CRH production has been linked to the determination of gestational length in the human. Although encoded by a single copy gene, CRH expression in the placenta is regulated differently to the hypothalamus. Glucocorticoids stimulate CRH promoter activity in the placenta but inhibit it's activity in the hypothalamus, via mechanisms involving different regions of the CRH promoter. We discuss how various stimuli alter CRH promoter activity and why these responses are unique to the placenta.
Male mandrills (Mandrillus sphinx) have spectacular secondary sexual adornments. These include red and blue sexual skin on the face, rump, and genitalia; a sternal scent-marking g... [more]
Male mandrills (Mandrillus sphinx) have spectacular secondary sexual adornments. These include red and blue sexual skin on the face, rump, and genitalia; a sternal scent-marking gland; and a "fatted" rump. Mandrills are seasonal breeders, and in other seasonally-breeding primate species members of both sexes may show increased expression of secondary sexual characteristics during the mating season. We examined changes in male secondary sexual adornments and testosterone levels, in relation to seasonal changes in the female reproductive cycle and sexual skin morphology, in two semifree-ranging mandrill groups. Females showed circannual changes in sexual skin tumescence, and periods of tumescence peaked from May-July in a long-established group. However, formation of a second, smaller group, two years previous to commencement of the study, disrupted the seasonal pattern of sexual skin tumescence and births. As the groups occupied adjacent enclosures, it appears that social factors, as well as physical environment, affected the seasonal patterning of reproduction in females. Male mandrills, by contrast, did not exhibit marked circannual changes in secondary sexual traits. Although adult male testicular volume and circulating testosterone levels increased significantly during the mating season, sexual skin coloration and rump "fattedness" showed no consistent changes with season. There was some evidence to suggest that maturing males (ages 5-8 yr) showed increased development of red sexual skin during mating periods, but once males had fully developed secondary sexual adornments, they remained stable throughout the year. The possible reasons for this are discussed in relation to intermale competition and social organization in mandrills. © 2001 Wiley-Liss, Inc.
Agonist-induced phosphorylation of the human corticotropin-releasing factor type 1 receptor (hCRF1-R) was investigated using an influenza hemagglutinin (HA) epitope-tagged recepto... [more]
Agonist-induced phosphorylation of the human corticotropin-releasing factor type 1 receptor (hCRF1-R) was investigated using an influenza hemagglutinin (HA) epitope-tagged receptor transiently expressed in COS-7 cells. The HA-hCRF1-R migrated as a broad band (M(r) 60,000-70,000) in SDS-PAGE and showed increased mobility (M(r) ~ 48,000) after enzymatic deglycosylation with peptide-N-glycosidase F, consistent with the predicted size (47 kDa) of the nonglycosylated HA-hCRF1-R protein. A marked increase in HA-hCRF1-R phosphorylation was observed in HA-hCRF1-R-expressing COS-7 cells exposed to 1 µM ovine CRF for 5 min, whereas activation of protein kinase A (PRA) by 50 µM forskolin, or of Ca2+/calmodulin (CaM)-dependent kinases by 10 µM ionomycin, had little effect. These findings are consistent with preliminary data suggesting that CRF1-R phosphorylation mediated by G protein receptor kinase 3 (GRK3), but not by PKA or CaM-dependent kinases, has an important role in the homologous desensitization of brain CRF1-Rs. (C) 2000 Academic Press.
The angiotensin AT 2 receptor is an atypical seven transmembrane domain receptor that is coupled to activation of tyrosine phosphatase and inhibition of MAP kinase, and does not u... [more]
The angiotensin AT 2 receptor is an atypical seven transmembrane domain receptor that is coupled to activation of tyrosine phosphatase and inhibition of MAP kinase, and does not undergo agonist-induced internalization. An investigation of the occurrence and nature of AT 2 receptor phosphorylation revealed that phorbol ester-induced activation of protein kinase C (PKC) in HA-AT 2 receptor-expressing COS-7 cells caused rapid and specific phosphorylation of a single residue (Ser 354 ) located in the cytoplasmic tail of the receptor. Agonist activation of AT 2 receptors by angiotensin II (Ang II) also caused rapid PKC-dependent phosphorylation of Ser 354 that was prevented by the AT 2 antagonist, PD123177, and by inhibitors of PKC. In cells coexpressing AT 1 and AT 2 receptors, Ang II-induced phosphorylation of the AT 2 receptor was reduced by either PD123177 or the AT 1 receptor antagonist, DuP753, and was abolished by treatment with both antagonists or with PKC inhibitors. These findings indicate that the AT 2 receptor is rapidly phosphorylated via PKC during homologous activation by Ang II, and also undergoes heterologous PKC-dependent phosphorylation during activation of the AT 1 receptor. The latter process may regulate the counteracting effects of AT 2 receptors on growth responses to AT 1 receptor activation.
Little is known of the mechanisms leading to mitogen-activated protein kinase (MAPK) activation via G(q)-coupled receptors. We therefore examined the pathways by which angiotensin... [more]
Little is known of the mechanisms leading to mitogen-activated protein kinase (MAPK) activation via G(q)-coupled receptors. We therefore examined the pathways by which angiotensin II (Ang II) activates Raf-1 kinase, an upstream intermediate in the pathway to MAPK, via the G(q)-coupled AT 1 angiotensin receptor in bovine adrenal glomerulosa (BAG) cells. Ang II caused a rapid and transient activation of Raf-1 that reached a peak at 5-10 min. Ang II was a potent stimulus of Raf-1 activation with an ED 50 of 10 pM and a maximal response at 1 nM, although higher Ang II concentrations elicited a submaximal response. Ang II-stimulated Raf-1 activity was unaffected by down- regulation of protein kinase C and intracellular Ca 2+ chelation (using BAPTA) but was partially inhibited by pertussis toxin, and was abolished by manumycin A. Removal of extracellular Ca 2+ (by EGTA) or blockade of L type Ca 2+ channels (by nifedipine), as well as inhibition of MEK-1 kinase (by PD98059), enhanced Raf-1 activity, whereas wortmannin (100 nM) inhibited approximately one half of Ang II-stimulated Raf-1 activity. Hence, Raf-1 kinase activation by Ang II in BAG cells is dependent on Ras, is mediated in part via G(i) and phosphatidylinositol 3-kinase, and is negatively regulated via Ca 2+ influx and a downstream signaling element(s).
The nature and role of glycosylation in AT 1 angiotensin receptor (AT 1 -R) function were investigated by expressing glycosylation-deficient influenza hemagglutinin (HA) epitope-t... [more]
The nature and role of glycosylation in AT 1 angiotensin receptor (AT 1 -R) function were investigated by expressing glycosylation-deficient influenza hemagglutinin (HA) epitope-tagged rat AT(1a)-Rs (HA-AT(1a)-Rs) in COS-7 cells. All three asparagine residues (Asn 4 , Asn 176 , Asn 188 ) contained within consensus sites for N-linked glycosylation could be glycosylated in Cos-7 cells and appeared to be glycosylated on the endogenous AT 1 -R in bovine adrenal glomerulosa cells. Heterogeneity of glycosylation at each site accounted for the broad migration pattern of the AT 1 -R in SDS-PAGE. Mutation at each glycosylation site, either alone or in combination, had little effect on ligand binding parameters (although the N4K mutant had higher affinity) or signaling activity. However, an increasing number of mutated glycosylation sites was associated with decreasing cell surface receptor expression, which was minimal for the unglycosylated N4K/N176Q/N188Q receptor. Decreased surface expression of mutant HA-AT(1a)-Rs was correlated with decreased total cell receptor content as revealed by immunoblotting with an anti-HA antibody. These findings suggest that glycosylation enhances receptor stability, possibly by protecting nascent receptors from proteolytic degradation.
125 I-Ang I binding to atypical sites on Mycoplasma hyorhinis- contaminated IEC-18 cell membranes increased with increasing pH and [NaCl] (ED 50 at 500 mM; maximal 13-fold increas... [more]
125 I-Ang I binding to atypical sites on Mycoplasma hyorhinis- contaminated IEC-18 cell membranes increased with increasing pH and [NaCl] (ED 50 at 500 mM; maximal 13-fold increase at 2 M NaCl). Alkali metal chlorides and sodium halides increased binding with rank orders of Na + < K + < Rb + < Cs + = Li + and F - < Cl - < Br - < I. Covalent cross-linking of 125 I-Ang I labeled a discrete band of 97 kDa. These findings suggest that the site is not a G protein-coupled receptor, but may play a role in the sensing by Mycoplasma of the ionic composition and/or pH of its environment.
Near the end of human pregnancy the concentration of placental corticotropin-releasing hormone in maternal blood rises exponentially. The rate of elevation of corticotropin-releas... [more]
Near the end of human pregnancy the concentration of placental corticotropin-releasing hormone in maternal blood rises exponentially. The rate of elevation of corticotropin-releasing hormone and its duration through time have been linked to the time of onset of labor. Paradoxically, although glucocorticoids are known to inhibit corticotropin-releasing hormone production within the hypothalamic-pituitary-adrenal axis, cortisol actually increases corticotropin-releasing hormone levels in several areas outside the hypothalamus, including the placenta. Placental corticotropin-releasing hormone may be an important component of a system that controls the normal maturation of the fetus and signals the initiation of labor. Abnormal elevations in corticotropin-releasing hormone, which may be a hormonal response to stressors arising in either the mother, placenta, or fetus, may prove to participate in the premature onset of parturition.
Angiotensin II (Ang II) stimulates growth and mitogenesis in bovine adrenal glomerulosa cells, but little is known about the signaling pathways that mediate these responses. An an... [more]
Angiotensin II (Ang II) stimulates growth and mitogenesis in bovine adrenal glomerulosa cells, but little is known about the signaling pathways that mediate these responses. An analysis of the growth-promoting pathways in cultured bovine adrenal glomerulosa cells revealed that Ang II, acting via the AT1 receptor, caused rapid but transient activation of mitogen-activated protein kinase (MAPK), with an ED50 of 10-50 pM. Although neither Ca2+ influx nor Ca2+ release from intracellular stores was sufficient to activate MAPK, Ca2+ appeared to play a permissive role in this response. A major component of Ang II-induced MAPK activation was insensitive to pertussis toxin (PTX), although a minor PTX-sensitive component could not be excluded. Ang II also induced the rapid activation of ras and raf-1 kinase with time-courses that correlated with that of MAPK Activation of protein kinase C (PKC) by phorbol 12-myristate 13-acetate was sufficient to activate both MAPK and raf-1 kinase. However, whereas PKC depletion had no effect on Ang II-induced raf-1 kinase activation, it attenuated Ang II-induced MAPK activation. Ang II also stimulated a mobility shift of raf-1, reflecting hyperphosphorylation of the kinase. However, unlike its activation, raf-1 hyperphosphorylation was dependent on PKC and its time-course correlated not with activation, but rather with deactivation of the kinase. Taken together, these findings indicate that Ang II stimulates multiple pathways to MAPK activation via PKC and ras/raf-1 kinase in bovine adrenal glomerulosa cells.
The agonist-induced phosphorylation sites of the rat AT(1a) angiotensin receptor were analyzed using epitope-tagged mutant receptors expressed in Cos-7 cells. Angiotensin II-stimu... [more]
The agonist-induced phosphorylation sites of the rat AT(1a) angiotensin receptor were analyzed using epitope-tagged mutant receptors expressed in Cos-7 cells. Angiotensin II-stimulated receptor phosphorylation was unaffected by truncation of the cytoplasmic tail of the receptor at Ser342 (¿342) but was abolished by truncation at Ser325 (¿325). Truncation at Ser335 (¿335), or double-point mutations of Ser335 and Thr336 to alanine (ST-AA), reduced receptor phosphorylation by ~50%, indicating that in addition to Ser335 and/or Thr336, amino acids within the Ser326-Thr332 segment are also phosphorylated. Agonist-induced phosphorylation of the ST- AA and ¿335 receptors was partially inhibited by staurosporine, suggesting that the single protein kinase C consensus site in the Ser326-Thr332 segment (Ser331) is phosphorylated. The impairment of receptor phosphorylation was broadly correlated with the attenuation of agonist-induced internalization rates (¿325 < ¿335 < ST-AA < ¿342 ¿335 > ST-AA = ¿342 > wild-type). These results demonstrate that agonist-induced phosphorylation of the AT(1a) receptor is confined to an 11-amino-acid serine/threonine-rich segment of its carboxyl-terminal cytoplasmic tail and implicate this region in the mechanisms of receptor internalization and desensitization.
Guinea-pig ureteric smooth muscle is unusual in that intracellular acidification increases and alkalinization decreases force production. To help elucidate the mechanism underlyin... [more]
Guinea-pig ureteric smooth muscle is unusual in that intracellular acidification increases and alkalinization decreases force production. To help elucidate the mechanism underlying these effects on force we have investigated the effects of changing intracellular pH on both calcium and potassium currents in single cells isolated from the guinea-pig ureter to determine their possible role in force development. Depolarization to +40 mV resulted in a fast transient outward current which was inhibited by 4-aminopyridine but not tetraethylammonium. Intracellular alkalinization (20 mM trimethylamine) increased this current to 179 ± 24% of the control and resulted in the development of a slowly activating large outward current which was inhibited by tetraethylammonium and washout. Acidification (40 mM sodium butyrate) decreased the fast transient outward current to 58 ± 3% of the control and did not produce a slowly activating current. When potassium was replaced by caesium in the pipette solution, depolarization to 0 mV resulted in an inward calcium current which was abolished by nifedipine. Intracellular alkalinization increased this current to 126 ± 11% of the control whereas acidification had the opposite effect, decreasing it to 55 ± 10%. Furthermore, current-clamp experiments showed that intracellular alkalinization inhibited the amplitude of the action potential, therefore decreasing excitability of the cell. From our results, we suggest that the predominant effects of intracellular pH on force production in the guinea-pig ureter are mediated via the modulation of outward potassium currents (thereby reducing excitability of the tissue) rather than the effects on the inward calcium current.
A polyclonal antibody was raised in rabbits against a fusion protein immunogen consisting of bacterial maltose-binding protein coupled to a 92-amino acid C-terminal fragment of th... [more]
A polyclonal antibody was raised in rabbits against a fusion protein immunogen consisting of bacterial maltose-binding protein coupled to a 92-amino acid C-terminal fragment of the rat AT(1b) angiotensin II (Ang II) receptor. The antibody immunoprecipitated the photoaffinity-labeled bovine AT1 receptor (AT1-R), but not the rat AT2 receptor, and specifically stained bovine adrenal glomerulosa cells and AT(1a) receptor-expressing Cos-7 cells, as well as the rat adrenal zona glomerulosa and renal glomeruli. The antibody was employed to analyze Ang II-induced phosphorylation of the endogenous AT1-R immunoprecipitated from cultured bovine adrenal glomerulosa cells. Receptor phosphorylation was rapid, sustained for up to 60 min, and enhanced by pretreatment of the cells with okadaic acid. Its magnitude was correlated with the degree of ligand occupancy of the receptor. Activation of protein kinase A and protein kinase C (PKC) also caused phosphorylation of the receptor, but to a lesser extent than Ang II. Inhibition of PKC by staurosporine augmented Ang II-stimulated AT1-R phosphorylation, suggesting a negative regulatory role of PKC on the putative G protein-coupled receptor kinase(s) that mediates the majority of AT1-R phosphorylation. The antibody should permit further analysis of endogenous AT1-R phosphorylation in Ang II target cells.
Successful completion of mammalian pregnancy requires a reorganization of the maternal physiology to create an environment optimal for the growth and development of the fetus. To ... [more]
Successful completion of mammalian pregnancy requires a reorganization of the maternal physiology to create an environment optimal for the growth and development of the fetus. To a large extent this physiological transformation is effected by the specialized endocrine functions of the placenta. The ability of the simple structure of the placentamprimarily cytotrophoblast and syncytiotrophoblast to produce a complex array of peptide and steroid hormones each with a specific gestationally determined production patternmremains a fascinating enigma. © 1998 Elsevier B.V. All rights reserved.
Specific high-affinity (Kd = 3.4 nM) binding sites for 125 I-labelled angiotensin I ([ 125 I]Ang I) were identified on an epithelial cell line (IEC-18) derived from the rat small ... [more]
Specific high-affinity (Kd = 3.4 nM) binding sites for 125 I-labelled angiotensin I ([ 125 I]Ang I) were identified on an epithelial cell line (IEC-18) derived from the rat small intestine. The sites, which also have high affinity for Ang II, are insensitive to both AT 1 - and AT 2 -specific angiotensin receptor antagonists, The rank order of potency with which various angiotensin peptides inhibited[ 125 I]Ang I binding to the cells (Ang I = Ang II > Ang(1-7) > [Sar 1 ,Ile 8 ]-Ang II > Ang(3-8) > Ang III) also distinguishes these sites from AT 1 and AT 2 angiotensin receptors. © 1995.
Spontaneous contraction of uterine smooth muscle is enhanced by alkalinization and depressed by acidification. We have investigated the ionic currents responsible for this in sing... [more]
Spontaneous contraction of uterine smooth muscle is enhanced by alkalinization and depressed by acidification. We have investigated the ionic currents responsible for this in single myometrial cells. Intracellular acidification (20 mM butyrate) at constant external pH depressed the magnitude of the calcium current to 58±6% of control, but had little effect on outward currents. Similar but slower effects were also observed when the extracellular pH was lowered to 6.9 (56±9% of control). Correspondingly, when the intracellular or extracelluar pH was elevated (20 mM NH 4 Cl or pH 7.9 respectively) the calcium current magnitude increased (165±15 % in NH 4 Cl; 136±2 % at pH 7.9) and there was, again, no effect on the outward currents. These observations are consistent with the effects of pH on spontaneous contractile activity being due to an effect on the membrane calcium current. © 1995 Springer-Verlag.
The proliferation of sparse cultures of RIE-1 rat intestinal epithelial cells was potently inhibited by transforming growth factor type ß 1 (TGF-ß 1 ), with a half-maximal effect ... [more]
The proliferation of sparse cultures of RIE-1 rat intestinal epithelial cells was potently inhibited by transforming growth factor type ß 1 (TGF-ß 1 ), with a half-maximal effect at 10-30 pg/ml. As judged by [ 3 H]thymidine incorporation assays, this growth inhibitory action became apparent 4-6 h after addition of TGF-ß 1 to the cells. RIE-1 cells express high-affinity (K(D) ~ 5.6 pM) receptors for 125 I-TGF-ß 1 . Affinity cross linking experiments labelled two major species of putative TGF-ß 1 receptors with M(r) values of 235,000 and 65,000. Medium conditioned by confluent cultures of RIE-1 cells contained latent TGF-ß-like activity that was activated at low pH. These findings support a model of autocrine growth inhibition of intestinal crypt cells by TGF-ß.
Activation of protein kinase C (PKC) by angiotensin II or 12-O-tetradecanoylphorbol-13-acetate (TPA) was associated with a mitogenic response in RIE-1 rat intestinal epithelial ce... [more]
Activation of protein kinase C (PKC) by angiotensin II or 12-O-tetradecanoylphorbol-13-acetate (TPA) was associated with a mitogenic response in RIE-1 rat intestinal epithelial cells. However, whereas in control experiments using Swiss 3T3 cells TPA stimulated phosphorylation of the major PKC substrate, MARCKS, the agent did not induce the phosphorylation of any protein with the electrophoretic mobility pattern of MARCKS in RIE-1 cells. However, TPA was able to activate PKC in RIE-1 cells since the agent reduced ('transmodulated') 125 I-EGF binding to the cells. The failure of TPA to induce phosphorylation of MARCKS in RIE-1 cells was due to the lack of expression of MARCKS protein and mRNA by these cells. MARCKS is not therefore required for mitogenic signalling via PKC in RIE-1 cells.
Addition of 12-O-tetradecanoylphorbol-13-acetate to RIE-1 rat intestinal epithelial cells stimulated a rapid (mean 3-fold) increase in the subsequent binding of 125 I-labelled ang... [more]
Addition of 12-O-tetradecanoylphorbol-13-acetate to RIE-1 rat intestinal epithelial cells stimulated a rapid (mean 3-fold) increase in the subsequent binding of 125 I-labelled angiotensin II which was reversed or prevented when cellular protein kinase C was depleted. The increased binding was due, in part, to an up-regulation in the number of AT 1 angiotensin receptors on RIE-1 cells, without any significant change in their binding affinity. Since this rapid up-regulation was independent of receptor synthesis, it may result from an increased availability (to extracellular ligand) of preformed, but previously 'cryptic', AT 1 angiotensin receptors. © 1994.
1. 1. The proliferation of RIE-1 rat intestinal epithelial cells was potently but reversibly inhibited by transforming growth factor-ß 1 (TGF-ß 1 ). In early-passage cultures, com... [more]
1. 1. The proliferation of RIE-1 rat intestinal epithelial cells was potently but reversibly inhibited by transforming growth factor-ß 1 (TGF-ß 1 ). In early-passage cultures, complete growth arrest was observed when sparse cultures were treated with TGF-ß 1 (1 ng/ml). 2. 2. However, increasing the initial cell culture density resulted in decreased TGF-ß 1 -mediated inhibition of cell proliferation. 3. 3. Independent of this population density effect, RIE-1 cells also exhibit a marked phenotypic transition around passage-8 to -10, such that later-passage cells were less responsive to growth inhibition by TGF-ß 1 ]. © 1994.
Proliferation of the rat intestinal epithelial cell-line, RIE-1, has previously been shown to be stimulated by certain polypeptide growth factors acting via receptors that possess... [more]
Proliferation of the rat intestinal epithelial cell-line, RIE-1, has previously been shown to be stimulated by certain polypeptide growth factors acting via receptors that possess intrinsic tyrosine kinase activity. In this study, we show that the octapeptide hormone angiotensin II (AII), apparently acting through the AT 1 G-protein-coupled receptor, is also a mitogen for RIE-1 cells. Maximal stimulation of DNA synthesis and cellular proliferation occurred at an AII concentration of 10-100 nM, with half-maximal stimulation at 1 nM. The mitogenic response to AII was completely inhibited by the AT 1 angiotensin-receptor antagonist, DuP753, but not by the AT 2 -receptor antagonist, PD123319. The early signalling responses activated by AII in RIE-1 cells include increased production of inositol phosphates, a transient increase in the intracellular concentration of free calcium, an activation of protein kinase C, and a rapid change in the pattern of cellular protein-tyrosine phosphorylation. These results implicate an activation of the inositol lipid signalling pathway via the AT 1 receptor subtype in the AII-stimulated mitogenic response of this normal epithelial cell line.
Whereas direct activation of protein kinase C (PKC) by the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA) increased the subsequent binding of 125 I-labelled angiotensin... [more]
Whereas direct activation of protein kinase C (PKC) by the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA) increased the subsequent binding of 125 I-labelled angiotensin II ( 125 I-AII; 0.5 nM) to RIE-1 cells, ligand-mediated activation of the kinase via angiotensin II (AII), which activates the phosphoinositide (PI) pathway in these cells, had no effect. The apparent inability of AII to increase 125 I-AII binding is unlikely to result from simultaneous, but opposing actions of AII on angiotensin receptor number and affinity since the peptide also had no effect on the saturation binding of 125 I-AII (10 nM) to the cells. Since 125 I-AII binding was unaffected both by AII pretreatment in PKC-depleted cells, and by the calcium ionophore, ionomycin, in PKC-replete cells, an attenuating action of AII (opposing any PKC-mediated increase) on 125 I-AII binding mediated via the calcium limb of the PI pathway is also unlikely. Instead, the contrasting effects of AII and TPA on 125 I-AII binding to RIE-1 cells appear to relate to the degree of PKC activation elicited by each agent.
The relative binding affinities of non-peptide antagonists, and the sensitivity of 125 I-angiotensin II ( 125 I-AII) binding to the reducing agent, dithiothreitol, indicated the p... [more]
The relative binding affinities of non-peptide antagonists, and the sensitivity of 125 I-angiotensin II ( 125 I-AII) binding to the reducing agent, dithiothreitol, indicated the presence of AT 1 angiotensin receptors on RIE-1 rat intestinal epithelial cells. Consistent with this finding, AT 1 angiotensin receptor mRNA was detected in RIE-1 cells using Northern blotting, whereas no mas transcripts (which also encode an angiotensin receptor) were detectable using a RNAse protection assay. At 37°C, 125 I-AII rapidly bound to RIE-1 cells and internalised into an acid-inaccessible compartment, which resulted in the depletion of 125 I-AII from the binding medium. Following overnight incubation of RIE-1 cells with 125 I-AII at 4°C, the majority of bound ligand was also, unexpectedly, found to be inaccessible to subsequent acid elution. After warming these cultures to 37°C, acid-inaccessible 125 I-radioactivity rapidly disappeared from the cells, and 125 I-labelled degradation products accumulated in the medium. Scatchard analysis of the concentration-dependent binding of 125 I-AII solely to the acid-accessible sites on RIE-1 cells revealed little difference to the K(D) value obtained from total 125 I-AII binding (to both acid-accessible and -inaccessible sites), but only ~ 15% of the number of sites.
Like RIE-1 cells, two of the IEC series of rat intestinal epithelial cell lines were found to express functional angiotensin receptors. As in RIE-1 cells, treatment of IEC-6 or IE... [more]
Like RIE-1 cells, two of the IEC series of rat intestinal epithelial cell lines were found to express functional angiotensin receptors. As in RIE-1 cells, treatment of IEC-6 or IEC-18 cells with angiotensin II (AII) activated phosphatidylinositol-4,5-bisphosphate (PIP 2 ) hydrolysis although (in contrast to RIE-1 cells) the magnitude of AII-induced PIP 2 hydrolysis was small and not associated with a mitogenic response in either IEC cell line. In terms of their other functional responses to AII (activation of protein kinase C (PKC) and a small elevation of cyclic AMP), IEC-6 cells are otherwise similar to RIE-1 cells whereas IEC-18 cells exhibit some phenotypic differences to the other two cell types. Thus, whereas IEC-6 and RIE-1 cells each express the AT 1 subtype of angiotensin receptor, the higher affinity receptors on IEC-18 cells are 'atypical', being insensitive to both AT 1 - and AT 2 -specific angiotensin receptor antagonists. Furthermore, in contrast to its effects in IEC-6 and RIE-1 cells, AII neither activates PKC nor modulates cyclic AMP levels in IEC-18 cells. Whereas IEC-18 cells express the myristoylated alanine-rich C-kinase substrate (MARCKS), immunoreactive MARCKS was not detected in IEC-6 or RIE-1 cells. © 1994 Academic Press. All rights reserved.
The regulation of growth factor receptors by protein kinase C was investigated in rat intestinal epithelial (RIE-1) cells. Short-term treatment of the cells with the phorbol ester... [more]
The regulation of growth factor receptors by protein kinase C was investigated in rat intestinal epithelial (RIE-1) cells. Short-term treatment of the cells with the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate, was employed to activate the kinase and longer-term exposure to the agent was used to assess the effects of protein kinase C depletion. Phorbol ester concentrations as low as 30 nM were found to down-regulate immunoreactive protein kinase C over 6 h, which correlated with the rapid loss of functional kinase activity. Whereas protein kinase C reduced the binding of 125 I-labelled EGF, it increased the binding of 125 I-labelled angiotensin II to RIE-1 cells. However, the kinase simultaneously inhibited the activation by angiotensin receptors of phophatidylinositol 4,5 bisphosphate hydrolysis.
Swiss 3T3 cells express high-affinity receptors for angiotensin II (K(D) = 0.8 nM, 110,000 receptors/cell). Binding of the peptide to these receptors did not activate phosphatidyl... [more]
Swiss 3T3 cells express high-affinity receptors for angiotensin II (K(D) = 0.8 nM, 110,000 receptors/cell). Binding of the peptide to these receptors did not activate phosphatidylinositol 4,5 bisphosphate hydrolysis, and did not increase intracellular [Ca 2+ ] or activate protein kinase C. The relative binding affinities of highly-selective antagonists characterised these receptors as the AT 2 subtype. However, in contrast to the signalling events reported in some other cells that express AT 2 receptors, AII had no apparent effect on either cyclic GMP levels or phosphotyrosine phosphatase activity in Swiss 3T3 cells. Furthermore, angiotensin II (either alone or in combination with growth factors) was not mitogenic to Swiss 3T3 cells.
The adrenergic neurone blocking agents, guanethidine and bretylium, have been tested for inhibitory activity against the actions of some relaxant drugs (BRL 38227, noradrenaline, ... [more]
The adrenergic neurone blocking agents, guanethidine and bretylium, have been tested for inhibitory activity against the actions of some relaxant drugs (BRL 38227, noradrenaline, sodium nitroprusside, theophylline) in vascular, intestinal and uterine smooth muscle. In guinea-pig isolated taenia caeci pre-contracted with KCl (25 mm), BRL 38227 (0.1¿10 µm) and noradrenaline (10 nm-100 µm) each caused concentration-dependent relaxation. Guanethidine and bretylium (50 µm) each antagonized the relaxation to BRL 38227 but not that to noradrenaline. At high concentration (500 µm), the adrenergic neurone blocking agents antagonized the action of BRL 38227 and, to some extent, that of noradrenaline. In rat isolated aorta pre-contracted with noradrenaline (300 nm), BRL 38227 (0.0125¿3.2 µm) and sodium nitroprusside (0.3¿100 nm) each produced concentration-dependent smooth muscle relaxation. Guanethidine and bretylium (5¿500 µm) each antagonized the action of BRL 38227 without antagonizing that of sodium nitroprusside. Rats were pretreated with 17-ß oestradiol benzoate. Tension waves were then induced from segments of isolated, oestrogen-dominated uterus by transmural electrical stimulation or by oxytocin (0.2 nm). These tension waves were inhibited by BRL 38227 (0.025¿3.2 µm) or theophylline (0.05¿0.8 mm) in a concentration-dependent manner. Guanethidine (50 µm) antagonized the action of BRL 38227 in both the electrically- and oxytocin-driven tissues. In the electrically-driven tissues, guanethidine (50 µm) did not antagonize the inhibition to theophylline. In KCl (25 mm)-treated guinea-pig taenia caeci, guanethidine (50 µm) inhibited the efflux of 86Rb+ evoked by BRL 38227 (10 µm) but not that evoked by noradrenaline (10 µm). In contrast, apamin (100 nm) reduced the efflux of 86Rb+ which was promoted by noradrenaline, but did not affect efflux induced by BRL 38227. 6 It is concluded that the adrenergic neurone blocking agents, guanethidine and bretylium (each at 50 µm), selectively inhibit the relaxant action of BRL 38227 in vascular, intestinal and uterine smooth muscle. If this inhibition reflects direct blockade of the K+-channel (KKCO) which is opened by BRL 38227, then the adrenergic neurone blocking agents act as inhibitors selective for KKCO as opposed to the small, apamin-sensitive (SKCa) and large (BKCa) conductance, Ca2+-dependent K+-channels. 1992 British Pharmacological Society
Plasma cortisol, adrenocorticotrophic hormone (ACTH), ß-endorphin and corticotrophin releasing hormone or factor (CRF) all rise progressively as pregnancy advances, and fall postn... [more]
Plasma cortisol, adrenocorticotrophic hormone (ACTH), ß-endorphin and corticotrophin releasing hormone or factor (CRF) all rise progressively as pregnancy advances, and fall postnatally. The placenta produces large amounts of CRF in the third trimester and this is released into the maternal circulation. Present evidence suggests that it stimulates the maternal pituitary to produce ACTH while desensitizing the maternal pituitary to further stimulation with CRF. Maternal control of ACTH production is retained, allowing a persistent response to stress and a diurnal rhythm, perhaps through the secretion of vasopressin. The placenta also produces pro-opiomelanocortin peptides; however, the nature of the fragments produced from the precursor differs from that formed in the anterior pituitary of the mother and the role of these fragments in the control of maternal adrenal function is unclear. These changes in the hypothalamo-pituitary-adrenal axis during pregnancy are associated with loss of the normal suppression of cortisol by dexamethasone and elevated basal levels of cortisol with preservation of a diurnal rhythm, features also found in some patients with endogenous depression. Several studies have suggested a relationship between alterations in maternal concentrations of cortisol and ß-endorphin and the development of postnatal mood disturbances. © 1991 Baillière Tindall.
Transcranial Doppler ultrasonography was used to evaluate 2 patients who developed hyperperfusion syndromes after carotid endarterectomy. During the initial postoperative period, ... [more]
Transcranial Doppler ultrasonography was used to evaluate 2 patients who developed hyperperfusion syndromes after carotid endarterectomy. During the initial postoperative period, each patient had symptoms that were associated with elevated flow velocities in the ipsilateral cerebral vasculature. In addition, vascular resistance of these vessels was found to be abnormally low, as reflected by the Gosling pulsatility index. As the patients' symptoms improved, flow velocities decreased to normal levels and pulsatilities were noted to increase proportionately.
Management of patients harboring infectious intracranial aneurysms remains controversial because of the technical problems associated with the obliteration of these lesions as wel... [more]
Management of patients harboring infectious intracranial aneurysms remains controversial because of the technical problems associated with the obliteration of these lesions as well as their frequent regression during antibiotic therapy. A case of a ruptured bacterial aneurysm of the distal middle cerebral artery in which a segment of the artery was found to be inflamed and necrotic is presented. The ruptured portion of the sac was clipped, leaving a small tag of aneurysmal tissue. Five days later, this tag was found to have expanded into a second aneurysm. This second lesion resolved with antibiotic therapy. Because of the responsiveness of infected cerebral arteries to the appropriate antibiotics, a less than radical surgical tactic may be a successful alternative to excision of the diseases arterial segment followed by distal revascularization in treating these lesions.
Transcranial Doppler (TCD) evaluation of the intracranial vessels was performed in sixty-six patients, 51 of whom received conventional angiography either prior to or subsequent t... [more]
Transcranial Doppler (TCD) evaluation of the intracranial vessels was performed in sixty-six patients, 51 of whom received conventional angiography either prior to or subsequent to the ultrasonic arteriogram. Of the 14 patients evaluated for arteriovenous malformations (AVMs), TCD indicated the existence of the AVM in 10 cases. Of those 10 cases, 9 correlated with angiography. Twenty-one patients with aneurysms were evaluated with TCD and only 2 were detected. Twenty-three patients suspected of having ischemic disease were evaluated with TCD, which indicated the presence of stenosis in 21 patients. Twenty of those patients received conventional angiography, with 18 demonstrating significant stenosis.
Transcranial Doppler (TCD) ultrasonography was used to perform multiple examinations of 24 patients who sustained cranial injuries, 23 of whom progressed to death. In the 20 of th... [more]
Transcranial Doppler (TCD) ultrasonography was used to perform multiple examinations of 24 patients who sustained cranial injuries, 23 of whom progressed to death. In the 20 of these 23 patients for whom an adequate TCD signal could be obtained, a characteristic reverberating wave form pattern was observed, with an associated net flow velocity of 20 cm/sec was associated with functional recovery. Correlations of neurological function, TCD tracings, and net flow velocities permitted identification of characteristic hemodynamic changes that preceded cerebral circulatory arrest. Early changes included decreased flow velocity as well as an increase in pulse pressure. Late changes consisted of a persistent increase of pulse pressure with the appearance of retrograde flow velocities during diastole. In the end stage, complete diastolic retrograde flow velocities were found. These gave rise to the characteristic reverberating pattern mentioned earlier. Identification of flow velocity reversal alone, however, proved to be inadequate for making the diagnosis of brain death. Evaluation of net flow velocity (calculated at bedside) was found to be a more sensitive determinant of brain death and closely paralleled the patients' neurological function.
Transcranial Doppler (TCD) was used to assess collateral flow and to quantitate perfusion velocity changes in a group of 18 patients requiring temporary or permanent surgical occl... [more]
Transcranial Doppler (TCD) was used to assess collateral flow and to quantitate perfusion velocity changes in a group of 18 patients requiring temporary or permanent surgical occlusion of the internal carotid artery for treatment of their cerebrovascular lesions. Velocity measurements were correlated with times of occlusion and neurological outcome in order to assess safe vessel occlusion times and the need for an intraoperative shunt. These data were used to calculate a perfusion velocity index (PV(i)), which indicated that values > 2 were well tolerated, and values of < 1 were associated with ischemic signs. In addition, preoperative TCD examinations were combined with compressive maneuvers of the carotid artery in the neck to evaluate the feasibility of carotid clamp ligation for the treatment of giant intracranial aneurysms deemed unsuitable for direct clipping. When maintenance of neurological function and intracranial vessel flow velocities were found to be normal, with aneurysmal flow velocities of zero, ligation of the carotid artery could safely be undertaken. Finally, TCD allowed continuous surveillance of cerebral hemodynamics, which gave immediate assurance of postoperative ICA patency, as well as the ability to identify high velocity states associated with hyperperfusion syndromes, which occurred in two patients.
Patients treated with barbiturate coma for elevated intracranial pressure after head injury may suffer brain death. Since such patients have an iatrogenically induced absence of n... [more]
Patients treated with barbiturate coma for elevated intracranial pressure after head injury may suffer brain death. Since such patients have an iatrogenically induced absence of neurological function, brain death cannot be diagnosed clinically. Furthermore, as demonstrated by two of our patients, monitoring of intracranial pressure, even in the face of brain death, may show a low intracranial pressure and an intracranial pulse, suggesting the presence of adequate cerebral perfusion pressure and, therefore, brain viability. Under these circumstances, however, significant intracranial blood flow may be absent. Therefore, we suggest that a patient in barbiturate coma should undergo serial blood flow studies, even when the intracranial pressure is low and an intracranial pulse is present, to determine whether brain death has occurred.
Microvascular Doppler recordings were taken from the nidus and draining system of a dural spinal cord arteriovenous malformation during operative treatment. Doppler signals readil... [more]
Microvascular Doppler recordings were taken from the nidus and draining system of a dural spinal cord arteriovenous malformation during operative treatment. Doppler signals readily showed the direction of blood flow in the draining vein and the hemodynamic effects of surgical maneuvers. Recording during alterations of mean arterial blood pressure and partial carbon dioxide pressure (pCO2) demonstrated lack of autoregulation and impaired CO2 reactivity in the AVM nidus. Microvascular Doppler techniques provide useful intraoperative assessment of the hemodynamics of arteriovenous malformations of the spinal cord.
1. Endogenous opioids have been implicated in the control of breathing in neonates, but their role in ventilatory control in adults remain unclear. 2. We studied the relationship ... [more]
1. Endogenous opioids have been implicated in the control of breathing in neonates, but their role in ventilatory control in adults remain unclear. 2. We studied the relationship between circulating immunoreactive ß-endorphin and the ventilatory and mouth occlusion pressure responses to hypercapnia in 12 healthy male subjects. In addition, we examined the effect of repetitive hypercapnia on plasma ß-endorphin and cortisol levels. 3. A weak but significant negative relationship between the ventilatory response to hypercapnia and basal plasma ß-endorphin levels was observed (r = -0.35, P < 0.01). A similar negative relationship was noted between mouth occlusion pressure response to hypercapnia and basal plasma ß-endorphin levels (r = -0.36, P < 0.01). 4. Repetitive hypercapnia prevented the fall in plasma cortisol that occurred under control conditions (P < 0.02) but had no effect on plasma ß-endorphin. 5. We conclude that plasma ß-endorphin may play a role in the central chemical of breathing in man.
By use of immunoblot analysis, we demonstrate the presence of a nerve growth factor with a relative molecular mass (Mr) of 53,000 in submaxillary glands of adult male and female m... [more]
By use of immunoblot analysis, we demonstrate the presence of a nerve growth factor with a relative molecular mass (Mr) of 53,000 in submaxillary glands of adult male and female mice in addition to the 13,000 form previously discovered in this tissue. Both the Mr 53,000 and 13,000 forms of nerve growth factor are present at equal concentrations in salivary glands of male mice while the Mr 53,000 form is present at a greater concentration than the Mr 13,000 form in the glands of female mice. Testosterone pretreatment, however, specifically augments the Mr 13,000 form of nerve growth factor in the salivary glands of female mice. The existence of nerve growth factor with molecular weight of 53,000, which is higher than the molecular size predicted for the two precursor forms of nerve growth factor, suggest the possibility that one of the nerve growth factor precursors or a product derived from it may undergo post-translational modification in submaxillary glands of mice. © 1988 Academic Press, Inc.
Abstract The ovary contains ß-endorphin but it is not clear whether it secretes this opioid peptide in amounts sufficient to increase ß-endorphin concentrations in the peripheral ... [more]
Abstract The ovary contains ß-endorphin but it is not clear whether it secretes this opioid peptide in amounts sufficient to increase ß-endorphin concentrations in the peripheral circulation, and hence effect ß-endorphin-sensitive mechanisms controlling hypo-thalamic secretion of gonadotropin-releasing hormone and pituitary secretion of gonadotrophins. To examine the possible ovarian contribution to the circulating pool of ß-endorphin and related peptides we measured the plasma concentrations of immunoreactive ß-endorphin and the cosynthesized glycopeptide, pro-¿-melanotropin, in different phases of a normal menstrual cycle. Ovarian steroids and pituitary gonadotrophins showed the expected cyclical changes. Plasma cortisol, immunoreactive ß-endorphin and immunoreactive pro-¿-melanotropin concentrations were not significantly different in different phases of the cycle. There was no discernible relationship between plasma concentrations of either immunoreactive ß-endorphin or pro-¿-melanotropin and any of oestradiol, progesterone, luteinising hormone and follicle-stimulating hormone overall or during any phase of the menstrual cycle. The results suggest that the ovary does not contribute significantly to the pool of ß-endorphin and related peptides in circulating blood. © 1987 Japanese Society of Obstetrics and Gynaecology
Experiments were undertaken in rats to investigate the effects of in vivo infusion of ß-endorphin (BEP) on subsequent Con A-induced proliferation and interleukin 2 (IL-2) producti... [more]
Experiments were undertaken in rats to investigate the effects of in vivo infusion of ß-endorphin (BEP) on subsequent Con A-induced proliferation and interleukin 2 (IL-2) production by spleen cells in vitro. BEP administration induced a dose-dependent enhancement of the proliferative response to Con A. Infusion of the opiate antagonist naloxone (NAL) inhibited the Con A response and infusion of NAL prior to BEP resulted in even further inhibition. None of these treatments resulted in detectable alterations in IL-2 production after 48 h in culture. To demonstrate a direct interaction between BEP and lymphocytes, spleen cells were incubated in vitro with varying concentrations of BEP and/or NAL. Enhanced Con A-induced proliferation was observed following incubation with BEP in the range 10-12 to 10-9M (levels comparable to the effective in vivo doses) and this effect was abrogated by NAL pretreatment (10-6M). These data indicate a role for BEP in enhancing lymphocyte reactivity which is to some extent dependent on opiate receptors on the cell surface. This report extends the evidence obtained from in vitro experiments implicating endogenous opioids in modulation of host immunity by demonstrating that these effects can be obtained in vivo. © 1987.
Cerebrospinal fluid (CSF) samples were taken from rats implanted with chronic cisternal cannulae and assayed for methionine-enkephalin, ß-endorphin and corticotropin (ACTH). Immon... [more]
Cerebrospinal fluid (CSF) samples were taken from rats implanted with chronic cisternal cannulae and assayed for methionine-enkephalin, ß-endorphin and corticotropin (ACTH). Immonubilization stress had little apparent effect on immunoreactive levels of the peptides in the CSF. Gel chromatographic analysis of the ß-endorphin- and ACTH-immunoreactive profiles in rat CSF revealed several peaks. ß-Endorphin-immunoreactive peaks were present at the expected positions of pro-opiocortin, ß-lipotropin and ß-endorphin. ACTH-immunoreactive peaks eluted at positions coresponding to pro-opiocortin, the 20-23K ACTH biosynthetic intermediate, 14K ACTH, and 4.5K ACTH. These results suggest that rat CSF contains peptides of the pro-opiocortin family similar to those previously described in rat pituitary. © 1983.
The met-enkephalin analogue, D-Ala 2 -MePhe 4 -met-enkephalin-(C)-ol (DAMME), was given i.v. to 6 normal subjects. Elevations in plasma prolactin and growth hormone (GH) occurred ... [more]
The met-enkephalin analogue, D-Ala 2 -MePhe 4 -met-enkephalin-(C)-ol (DAMME), was given i.v. to 6 normal subjects. Elevations in plasma prolactin and growth hormone (GH) occurred in association with significant falls in plasma epinephrine and norepinephrine. Dopamine rose 90 min after saline, but this was not seen after DAMME. Circulating melatonin and met-enkephalin levels failed to change. The data suggest that opiates may inhibit the release of plasma catecholamines, but do not alter endogenous levels of circulating met-enkephalin or elevate melatonin.
The pattern of change of PAPP-A was established in three separate groups of patients. Day-to-day change from the 38th week was measured in six healthy patients whose pregnancies e... [more]
The pattern of change of PAPP-A was established in three separate groups of patients. Day-to-day change from the 38th week was measured in six healthy patients whose pregnancies ended in spontaneous labour. The slow fluctuations of PAPP-A suggest that values found in labour are a consequence of events prior to the onset of labour. Increases of PAPP-A during the last few days of pregnancy and into labour were compared in patients going into labour spontaneously and patients who were induced. The induced patients showed a sharper increase in PAPP-A during this interval than the spontaneous onset group. A comparison at an earlier stage of pregnancy of PAPP-A increase was made between normal pregnancies going into labour on or before 280 days and those who went into labour later. Between 31 ± 1 and 35 ± 1 weeks, those who delivered in the earlier group showed a sharper rise in PAPP-A. It seems likely that the behaviour of PAPP-A in late pregnancy is the consequence of uterine activity and it seems unlikely that an increasing level of PAPP-A in itself has anything to do with the initiation of spontaneous labour. © 1981, W. B. Saunders Company Ltd.. All rights reserved.
Thirteen patients with either Addison's disease, or Cushing's disease treated by bilateral adrenalectomy, were infused with the long-acting met-enkephalin analogue DAMME... [more]
Thirteen patients with either Addison's disease, or Cushing's disease treated by bilateral adrenalectomy, were infused with the long-acting met-enkephalin analogue DAMME. In patients with Addison's disease significant and pronounced falls in ACTH and N- and C-terminal ß-LPH were seen; chromatography suggested that ß-endorphin fell concomitantly. Three out of four patients with Cushing's disease who had not received pituitary irradiation, also showed a decrease in plasma ACTH and N- and C-terminal ß-LPH; however, no change was seen in any of the irradiated patients. The changes were naloxone reversible. The levels of plasma met-enkephalin were normal and did not change after DAMME in any group of patients. These results are interpreted as suggesting that there are inhibitory opiate receptors controlling the release of ACTH, ß-LPH, and ß-endorphin. Copyright © 1981, Wiley Blackwell. All rights reserved
Nine patients with hypogonadotrophic hypogonadism (five due to isolated gonadotrophin deficiency and four due to craniopharyngioma) were treated with daily subcutaneous injections... [more]
Nine patients with hypogonadotrophic hypogonadism (five due to isolated gonadotrophin deficiency and four due to craniopharyngioma) were treated with daily subcutaneous injections of a long acting LHRH analogue, Hoe 766. Therapy was continued for between 27 and 38 weeks and doses varied between 1¿25 and 5 µg per day. At monthly intervals patients were assessed by their LH and FSH response to 100 µg of LHRH and by second hourly sampling for LH, FSH and testosterone for the 24 hours after their Hoe 766 dose. Regardless of the diagnosis or the dose of Hoe 766 the LH response to Hoe 766 and to LHRH deteriorated with increasing duration of therapy. Plasma FSH values became low after only 1 week of therapy and failed to improve. Peak plasma testosterone during therapy correlated with peak plasma LH regardless of the duration of treatment (r = 0±43, P < 0±05, n = 22). Peak plasma LH on LHRH stimulation tests correlated with peak plasma LH on Hoe 766 24 hour studies independently of the length of treatment or the dose of Hoe 766 (r=0±62, P < 0±01, n = 18). In this group of patients peak plasma LH on LHRH stimulation tests did not correlate with basal plasma LH. Throughout the study in all patients testosterone was subnormal at 08.00 h. If testosterone rose after Hoe 766 it did so within the first 12 hours following the injection and had returned to baseline levels by 08.00 h the following day. It is concluded that prolonged daily administration of Hoe 766 within the dose range studied leads to loss of pituitary LH and FSH responses to both Hoe 766 and LHRH. Our results suggest that the loss of LH responsiveness is not due to testosterone feedback inhibition or selective resistance to Hoe 766, but may be explained by depletion of gonadotrophin stores in the pituitary gland. Copyright © 1979, Wiley Blackwell. All rights reserved
Angiotensin II (Ang II) receptors of the AT 1 subtype are coupled to heterotrimeric G nucleotide-binding proteins, G(q/11), to activate phospholipase C-ß isoforms with production ... [more]
Angiotensin II (Ang II) receptors of the AT 1 subtype are coupled to heterotrimeric G nucleotide-binding proteins, G(q/11), to activate phospholipase C-ß isoforms with production of inositol 1,4,5-trisphosphate (InsP 3 ) and diacylglycerol. The resultant release of intracellular Ca 2+ and increased Ca 2+ influx are major determinants of several acute cellular responses initiated by Ang II, including secretion of aldosterone from the adrenal cortex and smooth muscle contraction. However, cellular events related to more prolonged effects of Ang II, such as hypertrophic and hyperplastic responses, are triggered by intracellular signaling cascades that are less dependent on Ca 2+ signals. The Ang II-induced activation of Raf-1 kinase, p42 MAP-kinase and c-fos expression in response to Ang II in adrenal glomerulosa cells does not require Ca 2+ influx. Moreover, the dose- response relationships for Raf-1 activation, MAP-kinase activation and mitogenesis show significantly higher sensitivity to Ang II than the InsP 3 , Ca 2+ -release and aldosterone secretory responses. The sensitivities of both Raf-1 kinase and MAP-kinase stimulation by Ang II to the inhibitors of phosphoinositide kinases, wortmannin and LY 294002, suggest that inositol phospholipids may play a role in these activation events unrelated to their role in Ca 2+ signaling. To investigate the changes of various inositides after stimulation at the single cell level, fluorescent probes were developed in which pleckstrin homology domains with distinct binding specificities to inositol phospholipids were fused to the green fluorescent protein and expressed in NIH 3T3 cells. The use of these probes revealed heterogeneity of the inositol lipid pools and their complex relationship to Ca 2+ signals. The use of these tools will help to further clarify the complex role of these lipids in initiating Ca 2+ -dependent and -independent signaling responses.
The map is a representation of a researchers co-authorship with collaborators across the globe. The map displays the number of publications against a country, where there is at least one co-author based in that country. Data is sourced from the University of Newcastle research publication management system (NURO) and may not fully represent the authors complete body of work.
Laureate ProfessorMothers and Babies Research Centre School of Medicine and Public HealthFaculty of Health and Medicine
Newcastle endocrinologist, Laureate Professor Roger Smith, has urged a re-think on the use of hormone replacement therapy (HRT) after studying the risk of hip fracture in both elderly women and men.
Having endured the grief of losing two children, former Wallabies player Dean Mumm and wife Sarah are linking with the Borne Foundation and Hunter Medical Research Institute (HMRI) to raise funds and awareness for research into premature birth.
University of Newcastle researchers have secured more than $6 million in the latest round of National Health and Medical Research Council (NHMRC) funding
The Federal Government has provided a crucial $1.5 million grant to the University of Newcastle’s Gomeroi gaaynggal health centre at Tamworth and Walgett
Professor Roger Smith has been awarded more than $469,000 in NHMRC Development Grant funding commencing in 2016 for his research project Achieving Targeted
Activated Coconut Carbon
UON researchers have discovered a ‘switch’ that fails to engage in some pregnancies, which could lead to labour complications
The recent death of the lead singer of Yothu Yindi, is a high-profile example of an event all too common in Aboriginal Australia.
Professor Roger Smith and team have found a parallel between the labouring uterus and the behaviour of...
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