Prevalence of augmented renal clearance and performance of glomerular filtration estimates in Indigenous Australian patients requiring intensive care admission.

Augmented renal clearance (ARC) refers to the enhanced renal excretion of circulating solute commonly demonstrated in numerous critically ill subgroups. This study aimed to describe the prevalence of ARC in critically ill Indigenous Australian patients and explore the accuracy of commonly employed mathematical estimates of glomerular filtration. We completed a single-centre, prospective, observational study in the intensive care unit (ICU), Alice Springs Hospital, Central Australia. Participants were critically ill adult Indigenous and non-Indigenous Australian patients with a urinary catheter in situ. Exclusion criteria were anuria, pregnancy or the requirement for renal replacement therapy. Daily eight-hour measured creatinine clearances (CrCLm) were collected throughout the ICU stay. ARC was defined by a CrCLm ≥130 ml/min/1.73 m2. The Cockcroft-Gault and Chronic Kidney Disease Epidemiology Collaboration equations were also used to calculate mathematical estimates for comparison. In total, 131 patients were recruited (97 Indigenous, 34 non-Indigenous) and 445 samples were collected. The median (range) CrCLm was 93.0 (5.14 to 205.2) and 90.4 (18.7 to 206.8) ml/min/1.73 m2 in Indigenous and non-Indigenous patients, respectively. Thirty-one of 97 (32%) Indigenous patients manifested ARC, compared to 7 of 34 (21%) non-Indigenous patients (P=0.21). Younger age, major surgery, higher baseline renal function and an absence of diabetes were all associated with ARC. Both mathematical estimates manifest limited accuracy. ARC was prevalent in critically ill Indigenous patients, which places them at significant risk of underdosing with renally excreted drugs. CrCLm should be obtained wherever possible to ensure accurate dosing.

Successful pharmacotherapy for the treatment of severe feeding aversion with mechanistic insights from cross-species neuronal remodeling.

Pediatric feeding disorders affect up to 5% of children, causing severe food intake problems that can result in serious medical and developmental outcomes. Behavioral intervention (BI) is effective in extinguishing feeding aversions, and also expert-dependent, time/labor-intensive and not well understood at a neurobiological level. Here we first conducted a double-blind, placebo-controlled trial comparing BI with BI plus d-cycloserine (DCS). DCS is a partial N-methyl-d-aspartate (NMDA) receptor agonist shown to augment extinction therapies in multiple anxiety disorders. We examined whether DCS enhanced extinction of feeding aversion in 15 children with avoidant/restrictive food intake disorder (ages 20-58 months). After five treatment days, BI improved feeding by 37%. By contrast, BI+DCS improved feeding by 76%. To gain insight into possible mechanisms of successful intervention, we next tested the neurobiological consequences of DCS in a murine model of feeding aversion and avoidance. In mice with conditioned food aversion, DCS enhanced avoidance extinction across a broad dose range. Confocal fluorescence microscopy and three-dimensional neuronal reconstruction indicated that DCS enlarged dendritic spine heads-the primary sites of excitatory plasticity in the brain-within the orbitofrontal prefrontal cortex, a sensory-cognition integration hub. DCS also increased phosphorylation of the plasticity-associated extracellular signal-regulated kinase 1/2. In summary, DCS successfully augments the extinction of food aversion in children and mice, an effect that may involve plasticity in the orbitofrontal cortex. These results warrant a larger-scale efficacy study of DCS for the treatment of pediatric feeding disorders and further investigations of neural mechanisms.

Adolescent cocaine self-administration induces habit behavior in adulthood: sex differences and structural consequences.

Adolescent cocaine use increases the likelihood of drug abuse and addiction in adulthood, and etiological factors may include a cocaine-induced bias towards so-called 'reward-seeking' habits. To determine whether adolescent cocaine exposure indeed impacts decision-making strategies in adulthood, we trained adolescent mice to orally self-administer cocaine. In adulthood, males with a history of escalating self-administration developed a bias towards habit-based behaviors. In contrast, escalating females did not develop habit biases; rather, low response rates were associated with later behavioral inflexibility, independent of cocaine dose. We focused the rest of our report on understanding how individual differences in young-adolescent females predicted long-term behavioral outcomes. Low, 'stable' cocaine-reinforced response rates during adolescence were associated with cocaine-conditioned object preference and enlarged dendritic spine head size in the medial (prelimbic) prefrontal cortex in adulthood. Meanwhile, cocaine resilience was associated with enlarged spine heads in deep-layer orbitofrontal cortex. Re-exposure to the cocaine-associated context in adulthood energized responding in 'stable responders', which could then be reduced by the GABAB agonist baclofen and the putative tyrosine receptor kinase B (trkB) agonist, 7,8-dihydroxyflavone. Together, our findings highlight resilience to cocaine-induced habits in females relative to males when intake escalates. However, failures in instrumental conditioning in adolescent females may precipitate reward-seeking behaviors in adulthood, particularly in the context of cocaine exposure.

Glucose and lipid effects of the ileal apical sodium-dependent bile acid transporter inhibitor GSK2330672: double-blind randomized trials with type 2 diabetes subjects taking metformin.

AIMS: To investigate the pharmacodynamics, pharmacokinetics and safety/tolerability of blocking reuptake of bile acids using the inhibitor GSK2330672 (GSK672) in patients with type 2 diabetes (T2D). METHODS: Subjects with T2D taking metformin were enrolled in two studies in which they took metformin 850 mg twice daily for 2 weeks prior to and during the randomized treatment periods. In the first crossover study (n = 15), subjects received GSK672 45 mg, escalating to 90 mg, twice daily, or placebo for 7 days. The second parallel-group study (n = 75) investigated GSK672 10-90 mg twice daily, placebo or sitagliptin for 14 days. RESULTS: In both studies, GSK672 reduced circulating bile acids and increased serum 7-α-hydroxy-4-cholesten-3-one (C4), an intermediate in the hepatic synthesis of bile acids. Compared with placebo, in the parallel-group study 90 mg GSK672 twice daily reduced fasting plasma glucose [FPG; -1.21 mmol/l; 95% confidence interval (CI) -2.14, -0.28] and weighted-mean glucose area under the curve (AUC)0-24 h (-1.33 mmol/l; 95% CI -2.30, -0.36), as well as fasting and weighted-mean insulin AUC0 -24 h . GSK672 also reduced cholesterol (LDL, non-HDL and total cholesterol) and apolipoprotein B concentrations; the maximum LDL cholesterol reduction was ∼40%. There was no change in HDL cholesterol but there was a trend towards increased fasting triglyceride levels in the GSK672 groups compared with placebo. In both studies, the most common adverse events associated with GSK672 were gastrointestinal, mostly diarrhoea (22-100%), which appeared to be independent of dose. CONCLUSIONS: In subjects with T2D on metformin, GSK672 improved glucose and lipids, but there was a high incidence of gastrointestinal adverse events.

Voxel-based morphometry predicts shifts in dendritic spine density and morphology with auditory fear conditioning.

Neuroimaging has provided compelling data about the brain. Yet the underlying mechanisms of many neuroimaging techniques have not been elucidated. Here we report a voxel-based morphometry (VBM) study of Thy1-YFP mice following auditory fear conditioning complemented by confocal microscopy analysis of cortical thickness, neuronal morphometric features and nuclei size/density. Significant VBM results included the nuclei of the amygdala, the insula and the auditory cortex. There were no significant VBM changes in a control brain area. Focusing on the auditory cortex, confocal analysis showed that fear conditioning led to a significantly increased density of shorter and wider dendritic spines, while there were no spine differences in the control area. Of all the morphology metrics studied, the spine density was the only one to show significant correlation with the VBM signal. These data demonstrate that learning-induced structural changes detected by VBM may be partially explained by increases in dendritic spine density.

Prelimbic BDNF and TrkB signaling regulates consolidation of both appetitive and aversive emotional learning.

The medial prefrontal cortex (mPFC) is known to regulate executive decisions and the expression of emotional memories. More specifically, the prelimbic cortex (PL) of the mPFC is implicated in driving emotional responses via downstream targets including the nucleus accumbens and amygdala, but mechanisms are yet to be fully understood. Therefore, we investigated whether prelimbic cortical brain-derived neurotrophic factor (BDNF) signaling through the high-affinity tyrosine kinase receptor B (TrkB) receptor may serve as a molecular mechanism underlying emotional memory encoding. Here, we utilized viral-mediated inducible bdnf deletion within the PL, as well as TrkB(F616A) mutant mice, wherein TrkB receptor point mutation results in its being highly sensitive to inhibition by small PP1-derivative molecules, serving as a specific TrkB inhibitor. The site-specific TrkB antagonism and viral-mediated bdnf deletion within the PL resulted in deficits in both cocaine-dependent associative learning and fear expression. Deficiencies were rescued by the novel TrkB agonist 7,8-dihydroxyflavone, indicating that PL BDNF expression and downstream signaling through the TrkB receptor are required for memory formation in both appetitive and aversive domains.

Monotone travelling fronts in an age-structured reaction-diffusion model of a single species.

We consider a partially coupled diffusive population model in which the state variables represent the densities of the immature and mature population of a single species. The equation for the mature population can be considered on its own, and is a delay differential equation with a delay-dependent coefficient. For the case when the immatures are immobile, we prove that travelling wavefront solutions exist connecting the zero solution of the equation for the matures with the delay-dependent positive equilibrium state. As a perturbation of this case we then consider the case of low immature diffusivity showing that the travelling front solutions continue to persist. Our findings are contrasted with recent studies of the delayed Fisher equation. Travelling fronts of the latter are known to lose monotonicity for sufficiently large delays. In contrast, travelling fronts of our equation appear to remain monotone for all values of the delay.

Dynamics of a food-limited population model incorporating nonlocal delays on a finite domain.

In this paper we model and analyse nonlocal spatial effects, induced by time delays, in a diffusion model for a single species confined to a finite domain. The nonlocality, a weighted average in space, arises when account is taken of the fact that individuals have been at different points in space at previous times. We show how to correctly derive the spatial averaging kernels for finite domain problems, generalising the ideas of other investigators who restricted attention to the simpler case of an infinite domain. The resulting model is then analysed and results established on linear stability, boundedness, global convergence of solutions and bifurcations.

Travelling front solutions of a nonlocal Fisher equation.

We consider a scalar reaction-diffusion equation containing a nonlocal term (an integral convolution in space) of which Fisher's equation is a particular case. We consider travelling wavefront solutions connecting the two uniform states of the equation. We show that if the nonlocality is sufficiently weak in a certain sense then such travelling fronts exist. We also construct expressions for the front and its evolution from initial data, showing that the main difference between our front and that of Fisher's equation is that for sufficiently strong nonlocality our front is non-monotone and has a very prominent hump.

Efficacy and safety of cerivastatin and pravastatin in the treatment of primary hypercholesterolemia.

In this randomized, double-blind, parallel group study, the efficacy and safety of cerivastatin (0.3 mg) and pravastatin (20 mg) were compared in 402 patients with primary hypercholesterolemia with and without documented coronary heart disease or peripheral vascular disease. After 8 weeks of treatment, cerivastatin provided significantly greater reductions than pravastatin in low-density lipoprotein (LDL)-cholesterol (31.1% vs. 26.0%; p < 0.0001) and total cholesterol (21.1% vs. 17.8%; p < 0.0001). A greater proportion of patients treated with cerivastatin than pravastatin achieved > 30% and > 40% reductions from baseline in LDL-cholesterol. Both agents also increased high density lipoprotein-cholesterol and reduced triglycerides. Overall, 65.1% of patients treated with cerivastatin and 63.3% of patients with pravastatin achieved LDL-cholesterol goals defined by the National Cholesterol Education Program. Both drugs were well tolerated, with most adverse events being mild. These results demonstrate that cerivastatin (0.3 mg) is a highly effective 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, which enables a large proportion of patients to achieve clinically meaningful reductions in LDL-cholesterol.

Linear stability criteria for population models with periodically perturbed delays.

We examine some simple population models that incorporate a time delay which is not a constant but is instead a known periodic function of time. We examine what effect this periodic variation has on the linear stability of the equilibrium states of scalar population models and of a simple predator prey system. The case when the delay differs from a constant by a small amplitude periodic perturbation can be treated analytically by using two-timing methods. Of particular interest is the case when the system is initially marginally stable. The introduction of variation in the delay can then have either a stabilising effect or a destabilizing one, depending on the frequency of the periodic perturbation. The case when the periodic perturbation has large amplitude is studied numerically. If the fluctuation is large enough the effect can be stabilising.

Genetic analysis of multiplex rheumatoid arthritis families.

To examine the genetic contribution of HLA and non-HLA genes in the etiopathogenesis of rheumatoid arthritis (RA), 60 Caucasian multiplex families were identified and DNA analyzed for over 52 markers including DRB1, DQA1 and DQB1 alleles. Many of the markers were chosen because of close proximity to candidate genes suggested by previous studies or models of pathogenesis. Sibling pair analysis (SIBPAL), relative pair analysis (RELPAL) and linkage studies using two different models of inheritance suggested linkage for the MHC and two additional chromosomal regions: chromosome 2 (D2S443 near CD8 and IGk; 2p13-2p11.1), and chromosome 15 (CYP19-estrogen synthase; 15q15). No support was found for two chromosomal regions, 1p36 and 3q13, recently suggested by other studies. We used transmission disequilibrium testing (TDT), conditional logistic regression, and segregation analysis to study the contributions that the shared epitope and TNF-c have in contributing to risk for RA. These studies provide additional evidence that the association of HLA alleles in RA patients from multiplex families is similar to that observed in sporadic disease, suggest candidate regions for further analysis and find additional support for an association of TNF-c alleles with RA susceptibility.

On the problem of asymptotic positivity of solutions for dissipative partial differential equations.

The objective of this paper aims to prove positivity of solutions for the following semilinear partial differential equationu[Formula: see text]. This equation represents a generalised model of the so-called porous medium equation. It arises in a variety of meaningful physical situations including gas flows, diffusion of an electron-ion plasma and the dynamics of biological populations whose mobility is density dependent. In all these situations the solutions of the equation must be positive functions.

Effectiveness of three different doses of carvedilol for exertional angina. Carvedilol-Angina Study Group.

Carvedilol is a nonselective beta-receptor antagonist with vasodilating properties primarily due to selective alpha-1 antagonism. This 4-treatment, 5-period, double-blind, crossover study evaluated the efficacy and safety of 3 doses of carvedilol (12.5, 25, and 50 mg given twice daily) versus placebo in 122 patients with chronic stable angina. Carvedilol in doses of 25 mg twice daily and 50 mg twice daily was statistically superior to placebo with respect to time to angina (placebo: 316 seconds; 25 mg carvedilol: 337 seconds, p = 0.0039; 50 mg: 345 seconds, p <0.0001) and time to 1-mm ST-segment depression (placebo: 301 seconds; 25 mg: 313 seconds; 50 mg: 323 seconds; p <0.0001). The percentage of patients reporting any adverse experience was slightly less in those receiving placebo (placebo: 28.4%; 12.5 mg: 33.1%; 25 mg: 34.5%; 50 mg: 31.9%). Carvedilol is effective and safe in treating patients with chronic stable angina.

Effects of carvedilol during exercise.

The effect of carvedilol on cardiovascular and physical performance parameters at rest and during exercise was evaluated in an open, uncontrolled study. Assessments were made at rest, at one-half anaerobic threshold (1/2AT), at AT, and at maximal work load (WLmax) before and after 3 weeks of treatment with 12.5 mg carvedilol once daily for 1 week, followed by 25 mg carvedilol once daily for 2 weeks. Ten well-conditioned healthy male volunteers maintained their regular training program during the study, and all completed the study. End-of-study measures of physical performance (time to WLmax, WLmax, and VO2/kg) and behavioral measures (Borg scale) of perceived exertion were unchanged from prestudy values. End-of-study diastolic BP (DBP) at rest and at WLmax was unchanged compared with prestudy values (mean +/- SD; 81.0 +/- 7.38 and 84.4 +/- 4.95 mm Hg, respectively, compared with 82.0 +/- 8.88 and 85.0 +/- 7.07 mm Hg, respectively). Mean +/- SD change from prestudy to end-of-study baseline resting systolic BP (SBP) was a reduction of 11.5 +/- 8.83 mm Hg, and mean +/- SD change from prestudy to end-of-study SBP at WLmax was a reduction of 20.0 +/- 12.25 mm Hg. Mean +/- SD change from prestudy to end-of-study resting heart rate (HR) a reduction of 7.8 +/- 18.45 beats/min, and mean +/- SD change from prestudy to end-of-study HR at WLmax was a reduction of 19.7 +/- 9.24 beats/min. The effect of carvedilol thus represents a combination of reduction in resting systolic BP and HR and attenuation of the exercise-induced changes in these parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Motor point blocks in children. A technique to relieve spasticity using phenol injections.

The careful attention that the day-surgery staff provides to the child who undergoes a motor point block procedure can reduce the anxiety of the parents and child and significantly contribute to the overall interdisciplinary care of the patient. The experience should be a positive one for the family and for the surgical staff.