Impaired protein stability of 11beta-hydroxysteroid dehydrogenase type 2: a novel mechanism of apparent mineralocorticoid excess

Apparent mineralocorticoid excess (AME) is a severe form of hypertension that is caused by impaired activity of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), which converts biologically active cortisol into inactive cortisone. Mutations in HSD11B2 result in cortisol-induced activation of mineralocorticoid receptors and cause hypertension with hypokalemia, metabolic alkalosis, and suppressed circulating renin and aldosterone concentrations. This study uncovered the first patient with AME who was described in the literature, identified the genetic defect in HSD11B2, and provided evidence for a novel mechanism of reduced 11beta-HSD2 activity. This study identified a cluster of amino acids (335 to 339) in the C-terminus of 11beta-HSD2 that are essential for protein stability. The cluster includes Tyr(338), which is mutated in the index patient, and Arg(335) and Arg(337), previously reported to be mutated in hypertensive patients. It was found that wild-type 11beta-HSD2 is a relatively stable enzyme with a half-life of 21 h, whereas that of Tyr(338)His and Arg(337)His was 3 and 4 h, respectively. Enzymatic activity of Tyr(338)His was partially retained at 26 degrees C or in the presence of the chemical chaperones glycerol and dexamethasone, indicating thermodynamic instability and misfolding. The results provide evidence that the degradation of both misfolded mutant Tyr(338)His and wild-type 11beta-HSD2 occurs through the proteasome pathway. Therefore, impaired 11beta-HSD2 protein stability rather than reduced gene expression or loss of catalytic activity seems to be responsible for the development of hypertension in some individuals with AME.

Steroid disorders in children: Congenital adrenal hyperplasia and apparent mineralocorticoid excess

Our research team and laboratories have concentrated on two inherited endocrine disorders, congenital adrenal hyperplasia (CAH) and apparent mineralocorticoid excess, in thier investigations of the pathophysiology of adrenal steroid hormone disorders in children. CAH refers to a family of inherited disorders in which defects occur in one of the enzymatic steps required to synthesize cortisol from cholesterol in the adrenal gland. Because of the impaired cortisol secretion, adrenocorticotropic hormone levels rise due to impairment of a negative feedback system, which results in hyperplasia of the adrenal cortex. The majority of cases is due to 21-hydroxylase deficiency (21-OHD). Owing to the blocked enzymatic step, cortisol precursors accumulate in excess and are converted to potent androgens, which are secreted and cause in utero virilization of the affected female fetus genitalia in the classical form of CAH. A mild form of the 21-OHD, termed nonclassical 21-OHD, is the most common autosomal recessive disorder in humans, and occurs in 1/27 Ashkenazic Jews. Mutations in the CYP21 gene have been identified that cause both classical and nonclassical CAH. Apparent mineralocorticoid excess is a potentially fatal genetic disorder causing severe juvenile hypertension, pre- and postnatal growth failure, and low to undetectable levels of potassium, renin, and aldosterone. It is caused by autosomal recessive mutations in the HSD11B2 gene, which result in a deficiency of 11β-hydroxysteroid dehydrogenase type 2. In 1998, we reported a mild form of this disease, which may represent an important cause of low-renin hypertension.

Excess deaths during the 2004 heatwave in Brisbane, Australia

The paper examines whether there was an excess of deaths and the relative role of temperature and ozone in a heatwave during 7–26 February 2004 in Brisbane, Australia, a subtropical city accustomed to warm weather. The data on daily counts of deaths from cardiovascular disease and non-external causes, meteorological conditions, and air pollution in Brisbane from 1 January 2001 to 31 October 2004 were supplied by the Australian Bureau of Statistics, Australian Bureau of Meteorology, and Queensland Environmental Protection Agency, respectively. The relationship between temperature and mortality was analysed using a Poisson time series regression model with smoothing splines to control for nonlinear effects of confounding factors. The highest temperature recorded in the 2004 heatwave was 42°C compared with the highest recorded temperature of 34°C during the same periods of 2001–2003. There was a significant relationship between exposure to heat and excess deaths in the 2004 heatwave estimated increase in non-external deaths: 75 [(95% confidence interval, CI: 11–138; cardiovascular deaths: 41 (95% CI: −2 to 84)]. There was no apparent evidence of substantial short-term mortality displacement. The excess deaths were mainly attributed to temperature but exposure to ozone also contributed to these deaths.

Excess length of stay due to central line–associated bloodstream infection in intensive care units in Argentina, Brazil, and Mexico

Objective.To estimate the excess length of stay in an intensive care unit (ICU) due to a central line–associated bloodstream infection (CLABSI), using a multistate model that accounts for the timing of infection. Design.A cohort of 3,560 patients followed up for 36,806 days in ICUs. Setting.Eleven ICUs in 3 Latin American countries: Argentina, Brazil, and Mexico. Patients.All patients admitted to the ICU during a defined time period with a central line in place for more than 24 hours. Results.The average excess length of stay due to a CLABSI increased in 10 of 11 ICUs and varied from −1.23 days to 4.69 days. A reduction in length of stay in Mexico was probably caused by an increased risk of death due to CLABSI, leading to shorter times to death. Adjusting for patient age and Average Severity of Illness Score tended to increase the estimated excess length of stays due to CLABSI. Conclusions.CLABSIs are associated with an excess length of ICU stay. The average excess length of stay varies between ICUs, most likely because of the case‐mix of admissions and differences in the ways that hospitals deal with infections.

Modeling random effect and excess zeros in road traffic accident prediction

Poisson distribution has often been used for count like accident data. Negative Binomial (NB) distribution has been adopted in the count data to take care of the over-dispersion problem. However, Poisson and NB distributions are incapable of taking into account some unobserved heterogeneities due to spatial and temporal effects of accident data. To overcome this problem, Random Effect models have been developed. Again another challenge with existing traffic accident prediction models is the distribution of excess zero accident observations in some accident data. Although Zero-Inflated Poisson (ZIP) model is capable of handling the dual-state system in accident data with excess zero observations, it does not accommodate the within-location correlation and between-location correlation heterogeneities which are the basic motivations for the need of the Random Effect models. This paper proposes an effective way of fitting ZIP model with location specific random effects and for model calibration and assessment the Bayesian analysis is recommended.

Excess power circulation in distribution networks containing distributed energy resources

The presence of large number of single-phase distributed energy resources (DERs) can cause severe power quality problems in distribution networks. The DERs can be installed in random locations. This may cause the generation in a particular phase exceeds the load demand in that phase. Therefore the excess power in that phase will be fed back to the transmission network. To avoid this problem, the paper proposes the use of distribution static compensator (DSTATCOM) that needs to be connected at the first bus following a substation. When operated properly, the DSTATCOM can facilitate a set of balanced current flow from the substation, even when excess power is generated by DERs. The proposals are validated through extensive digital computer simulation studies using PSCAD and MATLAB.

Review Essay: John Pratt and Anna Eriksson (2013) 'Contrasts in Punishment: An Explanation of Anglophone Excess and Nordic Exceptionalism'

This review essay combines the comments made by David Brown, Russell Hogg and Mark Finanne at the Crime, Justice and Social Democracy: 2nd International Conference July 2013. It is followed by a rejoinder by the two authors John Pratt and Anna Eriksson.

Calculate excess mortality during heatwaves using Hilbert-Huang transform algorithm

Background Heatwaves could cause the population excess death numbers to be ranged from tens to thousands within a couple of weeks in a local area. An excess mortality due to a special event (e.g., a heatwave or an epidemic outbreak) is estimated by subtracting the mortality figure under ‘normal’ conditions from the historical daily mortality records. The calculation of the excess mortality is a scientific challenge because of the stochastic temporal pattern of the daily mortality data which is characterised by (a) the long-term changing mean levels (i.e., non-stationarity); (b) the non-linear temperature-mortality association. The Hilbert-Huang Transform (HHT) algorithm is a novel method originally developed for analysing the non-linear and non-stationary time series data in the field of signal processing, however, it has not been applied in public health research. This paper aimed to demonstrate the applicability and strength of the HHT algorithm in analysing health data. Methods Special R functions were developed to implement the HHT algorithm to decompose the daily mortality time series into trend and non-trend components in terms of the underlying physical mechanism. The excess mortality is calculated directly from the resulting non-trend component series. Results The Brisbane (Queensland, Australia) and the Chicago (United States) daily mortality time series data were utilized for calculating the excess mortality associated with heatwaves. The HHT algorithm estimated 62 excess deaths related to the February 2004 Brisbane heatwave. To calculate the excess mortality associated with the July 1995 Chicago heatwave, the HHT algorithm needed to handle the mode mixing issue. The HHT algorithm estimated 510 excess deaths for the 1995 Chicago heatwave event. To exemplify potential applications, the HHT decomposition results were used as the input data for a subsequent regression analysis, using the Brisbane data, to investigate the association between excess mortality and different risk factors. Conclusions The HHT algorithm is a novel and powerful analytical tool in time series data analysis. It has a real potential to have a wide range of applications in public health research because of its ability to decompose a nonlinear and non-stationary time series into trend and non-trend components consistently and efficiently.

Costs - solicitor's retainer on 'no win, no fee' basis - meaning of 'win' - solicitor not entitled to recover excess of costs over amount paid on settlement - no consideration for variation of oral retainer.

In Baker Johnson Lawyers v Jorgensen [2002] QDC 205 McGill DCJ considered the meaning of a 'no win, no fee' retainer and concluded that, in the absence of qualification by agreement, solicitors retained on that basis were not entitled to recover costs exceeding the amount of any judgment or settlement.

Estimating the burden of disease attributable to excess body weight in South Africa in 2000

Objective. To estimate the burden of disease attributable to excess body weight using the body mass index (BMI), by age and sex, in South Africa in 2000. Design. World Health Organization comparative risk assessment (CRA) methodology was followed. Re-analysis of the 1998 South Africa Demographic and Health Survey data provided mean BMI estimates by age and sex. Populationattributable fractions were calculated and applied to revised burden of disease estimates. Monte Carlo simulation-modelling techniques were used for the uncertainty analysis. Setting. South Africa. Subjects. Adults 30 years of age. Outcome measures. Deaths and disability-adjusted life years (DALYs) from ischaemic heart disease, ischaemic stroke, hypertensive disease, osteoarthritis, type 2 diabetes mellitus, and selected cancers. Results. Overall, 87% of type 2 diabetes, 68% of hypertensive disease, 61% of endometrial cancer, 45% of ischaemic stroke, 38% of ischaemic heart disease, 31% of kidney cancer, 24% of osteoarthritis, 17% of colon cancer, and 13% of postmenopausal breast cancer were attributable to a BMI 21 kg/m2. Excess body weight is estimated to have caused 36 504 deaths (95% uncertainty interval 31 018 - 38 637) or 7% (95% uncertainty interval 6.0 - 7.4%) of all deaths in 2000, and 462 338 DALYs (95% uncertainty interval 396 512 - 478 847) or 2.9% of all DALYs (95% uncertainty interval 2.4 - 3.0%). The burden in females was approximately double that in males. Conclusions. This study shows the importance of recognising excess body weight as a major risk to health, particularly among females, highlighting the need to develop, implement and evaluate comprehensive interventions to achieve lasting change in the determinants and impact of excess body weight.