Administration of growth hormone or IGF-I to pregnant rats on a reduced diet throughout pregnancy does not prevent fetal intrauterine growth retardation and elevated blood pressure in adult offspring

Increasing evidence from human epidemiological studies suggests that poor growth before birth is associated with postnatal growth retardation and the development of cardiovascular disease in adulthood. We have shown previously that nutritional deprivation in the pregnant rat leads to intrauterine growth retardation (IUGR), postnatal growth failure, changes in the endocrine parameters of the somatotrophic axis, and to increased blood pressure in later life. In the present study, we investigated whether administration of insulin-like growth factor-I (IGF-I) or bovine growth hormone (GH) during pregnancy could prevent IUGR and/or alter long-term outcome. Dams h-om day 1 of pregnancy throughout gestation received a diet of nd libitum available food or a restricted dietary intake of 30% of ad libitum fed dams. From day 10 of gestation, dams were treated for 10 days with three times daily subcutaneous injections of saline (100 mu l), IGF-I (2 mu g/g body weight) or GH (2 mu g/g body weight). Maternal weight gain was significantly increased (P

Increased ovulation rate in Merino ewes immunized against small synthetic peptide fragments of the inhibin alpha subunit

Four experiments were carried out in Merino ewes during a period of 4 years to determine the long-term effects of immunization against different synthetic peptides mimicking the amine terminal of the or subunit of porcine inhibin. Peptides were conjugated to human serum albumin and 100-200 mu g emulsified in Freund's complete adjuvant for the primary immunization. Usually two booster injections were given at monthly intervals with 50-100 mu g conjugated peptide using either incomplete Freund's adjuvant or Montanide : Marcel. In some experiments a further immunization was carried in the next year. Blood samples were taken 10 days after each immunization, during the luteal phase, for estimation of gonadotrophin concentrations and determination of inhibin antibody titres. One day after blood sampling cloprostenol was used to induce luteolysis and laparoscopy was performed in the subsequent oestrous cycle. Immunization of ewes with synthetic peptides 1-32, 1-26, 7-26 and 8-30 resulted in large increases in the ovulation rate (OR). An approximately two-fold increase in OR was observed following the first booster immunization with these peptides and a three- to five-fold increase after the second booster immunization. Immunization with these large peptides resulted in a sustained increase in OR for a period of at least 1 year after the second booster immunization. Of the shorter peptides, peptides 10-26 and 13-26 gave a reasonable ovulatory response, although it was more difficult to obtain a response with peptides 1-16, 8-22, 13-25, 8-19 and 10-19; peptides 7-13 and 1-6 gave no response (but were examined for one breeding season only). The smaller peptides led to lower inhibin antibody titres that were not necessarily associated with increased follicle-stimulating hormone (FSH) or OR. More intensive blood sampling in one experiment showed that following primary immunization against peptide 1-32 there was a transient increase in plasma FSH which did not lead to an increased OR. Moreover, a prolonged period of raised FSH after the first booster was significantly correlated with increased OR. In these animals antibody titres were only slightly increased after primary immunization, but after the first booster immunization higher titres were observed that were significantly correlated with trough FSH values and the subsequent OR. These results are interpreted as showing that (1) to obtain an increase in OR peptides 1-32, 1-26 and 7-26 are suitable as immunogens; (2) smaller peptides are less reliable, often require multiple injections, and the response may be delayed; and (3) an extended period of raised plasma FSH is needed to give a large ovulatory response.

Between-year fluctuations in schizophrenia birth rate and associations with the Southern Oscillation Index, cloud cover and sunshine

Our group have recently proposed that low prenatal vitamin D may be a risk-modifying factor for schizophrenia. Climate variability impacts on vitamin D levels in a population via fluctuations in the amount of available UV radiation. In order to explore this hypothesis, we examined fluctuations in the birthrates for people with schizophrenia born between 1920 and 1967 and three sets of variables strongly associated with UV radiation. These included: (a) the Southern Oscillation Index (SOI), a marker of El Nino which is the most prominent meteorological factor that influences Queensland weather: (b) measures of cloud cover and (c) measures of sunshine. Schizophrenia births were extracted from the Queensland Mental Health register and corrected for background population birth rates. Schizophrenia birth rates had several apparently non-random features in common with the SO1. The prominent SO1 fluctuation event that occurred between 1937 and 1943 is congruent with the most prominent fluctuation in schizophrenia birth rates. The relatively flat profile of SOI activity between 1927 and 1936 also corresponds to the flattest period in the schizophrenia time series. Both time series have prominent oscillations in the 3 ~, year range between 1946 and 1960. Significant associations between schizophrenia birth rates and measures of both sunshine and cloud cover were identified,and all three time series shared periodicity in the 3-4 year range. The analyses suggest that the risk of schizophrenia is higher for those born during times of increased cloud cover,reduced sunshine and positive SO1. These ecological analyses provide initial support for the vitamin D hypothesis, however alternative non-genetic candidate exposures also need to be considered. Other sites with year-to-year fluctuations in cloud cover and sunshine should examine patterns of association between these climate variables and schizophrenia birth rates. The Stanley Foundation supported this project.

Wall material properties of yeast cells. Part II. Analysis

In the preceding paper (Part I) force-deformation data were measured with the compression experiment in conjunction with the initial radial stretch ratio and the initial wall-thickness to cell-radius ratio for baker's yeast (Saccharomyces cerevisiae). In this paper, these data have been analysed with the mechanical model of Smith et al. (Smith, Moxham & Middelberg (1998) Chemical Engineering Science, 53, 3913-3922) with the wall constitutive behaviour defined a priori as incompressible and linear-elastic. This analysis determined the mean Young's modulus ((E) over bar), mean maximum von Mises stress-at-failure (<(sigma)over bar>(VM,f)) and mean maximum von Mises strain-at failure (<(epsilon)over bar>(VM,f)) to be (E) over bar = 150 +/- 15 MPa, <(sigma)over bar>(VM,f) = 70 +/- 4 MPa and <(epsilon)over bar>(VM,f) = 0.75 +/- 0.08, respectively. The mean Young's modulus was not dependent (P greater than or equal to 0.05) on external osmotic pressure (0-0.8 MPa) nor compression rate (1.03-7.68 mu m/s) suggesting the incompressible linear-elastic relationship is representative of the actual cell-wall constitutive behaviour. Hydraulic conductivities were also determined and were comparable to other similar cell types (0-2.5 mu m/MPa s). The hydraulic conductivity distribution was not dependent on external osmotic pressure (0-0.8 MPa) nor compression rate (1.03-7.68 mu m/s) suggesting inclusion of cell-wall permeability in the mechanical model is justified. <(epsilon)over bar>(VM,f) was independent of cell diameter and to a first-approximation unaffected (P greater than or equal to 0.01) by external osmotic pressure and compression rate, thus providing a reasonable failure criterion. This criterion states that the cell-wall material will break when the strain exceeds <(epsilon)over bar>(VM,f) = 0.75 +/- 0.08. Variability in overall cell strength during compression was shown to be primarily due to biological variability in the maximum von Mises strain-at-failure. These data represent the first estimates of cell-wall material properties for yeast and the first fundamental analysis of cell-compression data. They are essential for describing cell-disruption at the fundamental level of fluid-cell interactions in general bioprocesses. They also provide valuable new measurements for yeast-cell physiologists. (C) 2000 Elsevier Science Ltd. All rights reserved.

Death and readmission in the year after hospital admission with cardiovascular disease: the Hunter Area Heart and Stroke Register

Objectives: To compare outcomes one year after hospital admission for patients initially discharged with a diagnosis of acute myocardial infarction (AMI), other ischaemic heart disease (other IHD), congestive heart failure (CHF) or stroke. Design: Cohort study. Setting: Hunter Area Heart and Stroke Register, which registers all patients admitted with heart disease or stroke to any of the 22 hospitals in the Hunter Area Health Service in New South Wales. Patients: 4981 patients with AMI, other IHD, CHF or stroke admitted to hospital as an emergency between 1 July 1995 and 30 June 1997 and followed for at least one year. Main outcome measures: Death from any cause or emergency hospital readmission for cardiovascular disease. Results: In-hospital mortality varied from 1% of those with other IHD to 22% of those with stroke. Almost a third of all patients discharged alive (and 38% of those aged 70 or more) had died or been readmitted within one year. This varied from 22% of those with stroke to 49% of those with CHF. The causes of death and readmission were from a spectrum of cardiovascular disease, regardless of the cause of the original hospital admission. Conclusions: Data from this population register show the poor outcome, especially with increasing age, among patients admitted to hospital with cardiovascular disease. This should alert us to determine whether optimal secondary prevention strategies are being adopted among such patients.

Increasing the efficiency of solute leaching: impacts of flow interruption with drainage of the "preferential flow paths"

Most soils contain preferential flow paths that can impact on solute mobility. Solutes can move rapidly down the preferential flow paths with high pore-water velocities, but can be held in the less permeable region of the soil matrix with low pore-water velocities, thereby reducing the efficiency of leaching. In this study, we conducted leaching experiments with interruption of the flow and drainage of the main flow paths to assess the efficiency of this type of leaching. We compared our experimental results to a simple analytical model, which predicts the influence of the variations in concentration gradients within a single spherical aggregate (SSA) surrounded by preferential flow paths on leaching. We used large (length: 300 mm, diameter: 216 mm) undisturbed field soil cores from two contrasting soil types. To carry out intermittent leaching experiments, the field soil cores were first saturated with tracer solution (CaBr2), and background solution (CaCl2) was applied to mimic a leaching event. The cores were then drained at 25- to 30-cm suction to empty the main flow paths to mimic a dry period during which solutes could redistribute within the undrained region. We also conducted continuous leaching experiments to assess the impact of the dry periods on the efficiency of leaching. The flow interruptions with drainage enhanced leaching by 10-20% for our soils, which was consistent with the model's prediction, given an optimised equivalent aggregate radius for each soil. This parameter quantifies the time scales that characterise diffusion within the undrained region of the soil, and allows us to calculate the duration of the leaching events and interruption periods that would lead to more efficient leaching. Application of these methodologies will aid development of strategies for improving management of chemicals in soils, needed in managing salts in soils, in improving fertiliser efficiency, and in reclaiming contaminated soils. (C) 2000 Elsevier Science B.V. All rights reserved.

Role of phosphorylation in the conformation of tau peptides implicated in Alzheimer's disease

A series of peptides corresponding to isolated regions of Tau (tau) protein have been synthesized and their conformations determined by H-1 NMR spectroscopy. Immunodominant peptides corresponding to tau(224-240) and a bisphosphorylated derivative in which a single Thr and a single Ser are phosphorylated at positions 231 and 235 respectively, and which are recognized by an Alzheimer's disease-specific monoclonal antibody, were the main focus of the study. The nonphosphorylated peptide adopts essentially a random coil conformation in aqueous solution, but becomes slightly more ordered into P-type structure as the hydrophobicity of the solvent is increased by adding up to 50% trifluoroethanol (TFE). Similar trends are observed for the bisphosphorylated peptide, with a somewhat stronger tendency to form an extended structure, There is tentative NMR evidence for a small population of species containing a turn at residues 229-231 in the phosphorylated peptide, and this is strongly supported by CD spectroscopy. A proposal that the selection of a bioactive conformation from a disordered solution ensemble may be an important step (in either tubulin binding or in the formation of PHF) is supported by kinetic data on Pro isomerization. A recent study showed that Thr231 phosphorylation affected the rate of prolyl isomerization and abolished tubulin binding. This binding was restored by the action of the prolyl isomerase Pin1. In the current study, we find evidence for the existence of both trans and cis forms of tau peptides in solution but no difference in the equilibrium distribution of cis-trans isomers upon phosphorylation. Increasing hydrophobicity decreases the prevalence of cis forms and increases the major trans conformation of each of the prolines present in these molecules. We also synthesized mutant peptides containing Tyr substitutions preceding the Pro residues and found that phosphorylation of Tyr appears to have an effect on the equilibrium ratio of cis-trans isomerization and decreases the cis content.

The effect of solidification rate on the structure of magnesium-aluminium eutectic grains

A magnesium-aluminium alloy of eutectic composition was solidified under two different cooling conditions, producing a low and a high growth rate of the eutectic solid-liquid interface. The high growth rate specimen contained smaller eutectic grains and cells, with a smaller interphase spacing compared with the low growth rate specimen. The high growth rate specimen also contained some primary Mg17Al12 dendrites, suggesting that the coupled zone is skewed towards the Mg phase with increased undercooling, A lamellar eutectic morphology was observed in the low growth rate specimen, while the morphology was fibrous in the high growth rate specimen.

The mechanical properties of Saccharomyces cerevisiae

Cell-wall mechanical properties play an integral part in the growth and form of Saccharomyces cerevisiae, In contrast to the tremendous knowledge on the genetics of S. cerevisiae, almost nothing is known about its mechanical properties. We have developed a micromanipulation technique to measure the force required to burst single cells and have recently established a mathematical model to extract the mechanical properties of the cell wall from such data, Here we determine the average surface modulus of the S, cerevisiae cell wall to be 11.1 +/- 0.6 N/m and 12.9 +/- 0.7 N/m in exponential and stationary phases, respectively, giving corresponding Young's moduli of 112 +/- 6 MPa and 107 +/- 6 MPa, This result demonstrates that yeast cell populations strengthen as they enter stationary phase by increasing wall thickness and hence the surface modulus, without altering the average elastic properties of the cell-wall material. We also determined the average breaking strain of the cell wall to be 82% +/- 3% in exponential phase and 80% +/- 3% in stationary phase, This finding provides a failure criterion that can be used to predict when applied stresses (e,g,, because of fluid flow) will lead to wall rupture, This work analyzes yeast compression experiments in different growth phases by using engineering methodology.

The interaction between the equity premium and the risk-free rate

The equity premium arises from the interaction between the atemporal risk premium for equity, the risk-free rate of intertemporal substitution and the impact of risk on the precautionary motive for saving. Depending on parameter values, the equity premium may either be increased or reduced by the presence of undiversifiable background risk. (C) 2000 Elsevier Science S.A. All rights reserved.

Exposure of rats to a high but not low dose of ethanol during early postnatal life increases the rate of loss of optic nerve axons and decreases the rate of myelination

Visual system abnormalities are commonly encountered in the fetal alcohol syndrome although the level of exposure at which they become manifest is uncertain. In this study we have examined the effects of either low (ETLD) or high dose (ETHD) ethanol, given between postnatal days 4-9, on the axons of the rat optic nerve. Rats were exposed to ethanol vapour in a special chamber for a period of 3 h per day during the treatment period. The blood alcohol concentration in the ETLD animals averaged similar to 171 mg/dl and in the ETHD animals similar to 430 mg/dl at the end of the treatment on any given day. Groups of 10 and 30-d-old mother-reared control (MRC), separation control (SC), ETLD and ETHD rats were anaesthetised with an intraperitoneal injection or ketamine and xylazine, and killed by intracardiac perfusion with phosphate-buffered glutaraldehyde. In the 10-d-old rat optic nerves there was a total of similar to 145000-165000 axons in MRC, SC and ETLD animals. About 4 % of these fibres were myelinated. The differences between these groups were not statistically significant. However, the 10-d-old ETHD animals had only about 75000 optic nerve axone (P < 0.05) of which about 2.8 % were myelinated. By 30 d of age there was a total of between 75000 90000 optic nerve axons, irrespective of the group examined. The proportion of axons which were myelinated at this age was still significantly lower (P < 0.001) in the ETHD animals (similar to 77 %) than in the other groups (about 98 %). It is concluded that the normal stages of development and maturation of the rat optic nerve axons, as assessed in this study, can be severely compromised by exposure to a relatively high (but not low) dose of ethanol between postnatal d 4 and 9.

Impact of increasing the re-supply interval on the seasonality of subsidised prescription use in Australia

Objective: To evaluate the impact of increasing the minimum resupply period for prescriptions on the Pharmaceutical Benefits Scheme (PBS) in November 1994. The intervention was designed to reduce the stockpiling of medicines used for chronic medical conditions under the PBS safety net. Methods: Interrupted times series regression analyses were performed on 114 months of PBS drug utilisation data from January 1991 to June 2000. These analyses assessed whether there had been a significant interaction between the onset of the intervention in November 1994 and the extreme levels of drug utilisation in the months of December (peak utilisation) and January (lowest utilisation) respectively. Both serial and 12-month lag autocorrelations were controlled for. Results: The onset of the intervention was associated with a significant reduction in the December peak in drug utilisation; after the introduction of the policy there were 1,150,196 fewer proscriptions on average or that month (95% Cl 708,333-1,592,059). There was, however, no significant change in the low level of utilisation in January. The effect of the policy appears to be decreasing across successive postintervention years. though the odds of a prescription being dispensed in December remained significantly lower in 1999 compared to each of the pre-intervention years (11% vs. 14%) Conclusion: Analysis of the impact of increasing the re-supply period for PBS prescriptions showed that the magnitude of peak utilisation in December had been markedly reduced by the policy, though this effect appears to be decreasing over time. Continued monitoring and policy review is warranted in order to ensure that the initial effect of the intervention be maintained.

Accelerating seismic energy release and evolution of event time and size statistics: Results from two heterogeneous cellular automaton models

The evolution of event time and size statistics in two heterogeneous cellular automaton models of earthquake behavior are studied and compared to the evolution of these quantities during observed periods of accelerating seismic energy release Drier to large earthquakes. The two automata have different nearest neighbor laws, one of which produces self-organized critical (SOC) behavior (PSD model) and the other which produces quasi-periodic large events (crack model). In the PSD model periods of accelerating energy release before large events are rare. In the crack model, many large events are preceded by periods of accelerating energy release. When compared to randomized event catalogs, accelerating energy release before large events occurs more often than random in the crack model but less often than random in the PSD model; it is easier to tell the crack and PSD model results apart from each other than to tell either model apart from a random catalog. The evolution of event sizes during the accelerating energy release sequences in all models is compared to that of observed sequences. The accelerating energy release sequences in the crack model consist of an increase in the rate of events of all sizes, consistent with observations from a small number of natural cases, however inconsistent with a larger number of cases in which there is an increase in the rate of only moderate-sized events. On average, no increase in the rate of events of any size is seen before large events in the PSD model.

Increasingly inequitable distribution of general practitioners in Australia, 1986-96

Objective: To document trends in the distribution of general practitioners (GPs) in Australia between 1986 and 1996, adjusted for community need. Methods: Data on the location of GPs, population size and crude mortality in statistical divisions (SD) were obtained from the Australian Bureau of Statistics Census of Population and Housing in 1986 and 1996. From these data, we calculated measures of distribution equality (number of people sharing each GP in each SD) and distribution equity (number of people sharing each GP divided by the crude mortality rate; the Robin Hood Index), and analysed temporal changes in the distribution of GPs. Results: Nationally the number of people sharing each GP fell 11% from 1,038 in 1986 to 921 in 1996. However, in 41 of 57 SDs (72%, p=0.01) the number of people sharing a GP actually increased over this time, and the average Robin Hood Index across SDs fell from 0.943 to 0.783 (p=0.004), indicating increasingly inequitable distribution. Comparing the Robin Hood index values of all SDs ranked in pairs, the value fell in 53 of 57 (93%, p<0.001) paired SDs over the decade. These patterns demonstrate increasing inequity over the decade. The number of people sharing each GP was consistently and substantially lower in the capital city SDs and the Robin Hood Index values were consistently and substantially higher (overserved) compared with country SDs. Conclusions: Despite there being more GPs per capita in Australia, their distribution became increasingly unequal and inequitable between 1986 and 1996, such that rural and remote areas became increasingly poorly served.

Identifying rate-limiting nodes in large-scale cortical networks for visuospatial processing: an illustration using fMRI

With the advent of functional neuroimaging techniques, in particular functional magnetic resonance imaging (fMRI), we have gained greater insight into the neural correlates of visuospatial function. However, it may not always be easy to identify the cerebral regions most specifically associated with performance on a given task. One approach is to examine the quantitative relationships between regional activation and behavioral performance measures. In the present study, we investigated the functional neuroanatomy of two different visuospatial processing tasks, judgement of line orientation and mental rotation. Twenty-four normal participants were scanned with fMRI using blocked periodic designs for experimental task presentation. Accuracy and reaction time (RT) to each trial of both activation and baseline conditions in each experiment was recorded. Both experiments activated dorsal and ventral visual cortical areas as well as dorsolateral prefrontal cortex. More regionally specific associations with task performance were identified by estimating the association between (sinusoidal) power of functional response and mean RT to the activation condition; a permutation test based on spatial statistics was used for inference. There was significant behavioral-physiological association in right ventral extrastriate cortex for the line orientation task and in bilateral (predominantly right) superior parietal lobule for the mental rotation task. Comparable associations were not found between power of response and RT to the baseline conditions of the tasks. These data suggest that one region in a neurocognitive network may be most strongly associated with behavioral performance and this may be regarded as the computationally least efficient or rate-limiting node of the network.