Developmental vitamin D deficiency alters adult behaviour: An informative animal model of schizophrenia

Background: There is growing evidence that vitamin D is active in the brain but until recently there was a lack of evidence about its role during brain development. Guided by certain features of the epidemiology of schizophrenia, we have explored the role of vitamin D in the developing brain and behaviour using whole animal models. Methods: Sprague-Dawley rats were fed a vitamin D deficient diet (DVD) or control diet 6 weeks prior to mating and housed under UVB-free lighting conditions. On the day of birth all rats were fed a control diet for the remainder of the study. We observed behaviour at two timepoints; on the day of birth to study maternal behaviour, and at 10 weeks of age to study offspring behaviour in adulthood, under baseline and drug induced conditions (MK-801, haloperidol, amphetamine). Results: Prenatal vitamin D deficiency results in subtle alterations in maternal behaviour as well as long lasting effects on the adult offspring, despite a return to normal vitamin D levels during postnatal life. These affects were specific to transient prenatal vitamin D depletion as adult vitamin D depletion, combined prenatal and chronic postnatal vitamin D depletion, or ablation of the vitamin D receptor in mice led to markedly different outcomes. Conclusions: The developmental vitamin D (DVD) model now draws strength from epidemiological evidence of schizophrenia and animal experiments. Although the DVD model does not replicate every aspect of schizophrenia, it has several attractive features: (1) the exposure is based on clues from epidemiology; (2) it reproduces the increase in lateral ventricles; (3) it reproduces well-regarded behavioural phenotypes associated with schizophrenia (e.g. MK- 801 induced hyperlocomotion); and (4) it implicates a disturbance in dopamine signaling. In summary, low prenatal levels of vitamin D can influence critical components of orderly brain development and that this has a long lasting effect on behaviour.

Preparation of protein-loaded-PLGA microspheres by an emulsion/solvent evaporation process employing LTCC micromixers

This study presents the possibilities offered by microfluidic structures for the production of polymeric microspheres, using a process based upon the production of an emulsion. LTCC (Low Temperature Co-fired Ceramics) micromixers have been used for the preparation of polymeric microspheres. The effect of the geometry of the micromixers has been studied, with a specific focus on the size of the microspheres. as well as the control release properties of a model protein loaded within these microspheres. (C) 2008 Published by Elsevier B.V.

Use of AST platelet ratio index (APRI Score) as an alternative to liver biopsy for treatment indication in chronic hepatitis C

Chronic hepatitis C (CHC) is one of the most important causes of chronic liver disease in the world, potentially resulting in cirrhosis, hepatocellular carcinoma, and the need for liver transplantation. Liver biopsy is currently performed before therapy indication. Although, it is the golden standard there are many reasons to avoid or delay the procedure. APRI Score is an easy, low cost and practice alternative method which was described as an alternative for assessing structural changes in chronic hepatitis C (CHC). The rationale of this study was to observe the accuracy of APRI Score in comparison to liver biopsy in 400 patients divided into two groups of 200 carriers (Validation and Experimental groups respectively) selected at random or according to liver fibrosis staging (METAVIR). The ROC curves showed a concordance among these two methods of 92% and 88.5% when 1.05 was the cut off (F3 and F4), and 87% and 83%, on 0.75 cut offs (F2-F4). The discordance in advanced fibrosis staging (F3 and F4) was only 16 (8%) and 22 (11%) out of 200 patients in the experimental and validation groups, respectively. In 26 (13%) out of 200 patients in the experimental group and 34 (17%) out of 200 patients in the validation group, there was discordance between APRI Score and liver biopsy in moderate and advanced fibrosis (F2-F4). In conclusion APRI is a serological marker that has satisfactory sensitivity and specificity together with a high predictive value and it can be useful either in the absence of a biopsy or to reduce the frequency with which biopsies need to be carried out to monitor the evolution of chronic hepatitis C and the right moment for treatment indication.

Anxiety Disorders and Rheumatic Fever: Is There an Association?

Introduction: Findings suggest that obsessive-compulsi e disorder (OCD) and related disorders, referred to as obsessive-compulsive spectrum disorders (OCSDs), are more common in patients with rheumatic fever (RF). Objectives: To determine whether RF or Sydenham`s chorea increases the probability of anxiety disorders in the relatives of individuals with RF with and without SC. Methods: This was a case-Control family study in which 98 probands and 389 first-degree relatives (FDRs) were assessed using structured psychiatric interviews. A Poisson regression model was used to determine whether the presence of any disorder in one family member influences the rate of disorders in the remaining family members. Results: Generalized anxiety disorder (GAD) occurred more frequently in the FDRs of RF probands than in those of control probands (P=.018). The presence of RF,GAD, or separation anxiety disorder in one family member significantly increased the chance of OCSDs in another member of the family.

An 18-Week, Prospective, Randomized, Double-Blind, Multicenter Study of Amlodipine/Ramipril Combination Versus Amlodipine Monotherapy in the Treatment of Hypertension: The Assessment of Combination Therapy of Amlodipine/Ramipril (ATAR) Study

Background: A combination of antihypertensive agents of different drug classes in a fixed-dose combination (FDC) may offer advantages in terms of efficacy, tolerability, and treatment compliance. Combination of a calcium channel blocker with an angiotensin-converting enzyme inhibitor may act synergistically to reduce blood pressure (BP). Objective: The aim of this study was to compare the efficacy and tolerability of an amlodipine/ramipril FDC with those of amlodipine monotherapy. Methods: This 18-week, prospective, randomized, double-blind study was conducted at 8 centers across Brazil. Patients with stage 1 or 2 essential hypertension were enrolled. After a 2-week placebo run-in phase, patients received amlodipine/ramipril 2.5/2.5 mg or amlodipine 2.5 mg, after which the doses were titrated, based on BP, to 515 then 10/10 mg (amlodipme/ramipril) and 5 then 10 mg (amiodipine). The primary end point was BP measured in the intent-to-treat (ITT) population. Hematology and serum biochemistry were assessed at baseline and study end. Tolerability was assessed using patient interview, laboratory analysis, and physical examination, including measurement of ankle circumference to assess peripheral edema. Results: A total of 222 patients completed the study (age range, 40-79 years; FDC group, 117 patients [mean dose, 7.60/7.60 mg]; monotherapy, 105 patients [mean dose, 7.97 mg]). The mean (SD) changes in systolic BP (SBP) and diastolic BP (DBP), as measured using 24-hour ambulatory blood pressure monitoring (ABPM) and in the physician`s office, were significantly greater with combination therapy than monotherapy, with the exception of office DBP (ABPM, -20.76 [1.25] vs -15.80 [1.18] mm Hg and -11.71 [0.78] vs -8.61 [0.74] mm Hg, respectively [both, P = 0.004]; office, -27.51 [1.40] vs -22.84 [1.33] min Hg [P = 0.012] and -16.41 [0.79] vs -14.64 [0.75] mm Hg [P = NS], respectively). In the ITT analysis, the mean changes in ambulatory, but not office-based, BP were statistically significant (ABPM: SBP, -20.21 [1.14] vs -15.31 [1.12] mm Hg and DBP, -11.61 [0.72] vs -8.42 [0.70] mm Hg, respectively [both, P = 0.002]; office: SBP, -26.60 [1.34] vs -22.97 [1.30] mm Hg and DBP, -16.48 [0.78] vs -14.48 [0.75] mm Hg [both, P = NS]). Twenty-nine patients (22.1%) treated with combination therapy and 41 patients (30.6%) treated with monotherapy experienced >= 1 adverse event considered possibly related to study drug. The combmation-therapy group had lower prevalence of edema (7.6% vs 18.7%; P = 0.011) and a similar prevalence of dry cough (3.8% vs 0.8%; P = NS). No clinically significant changes in laboratory values were found in either group. Conclusions: In this population of patients with essential hypertension, the amlodipine/ramipril FDC was associated with significantly reduced ambulatory and office-measured BP compared with amlodipine monotherapy, with the exception of office DBP. Both treatments were well tolerated. (Clin Ther. 2008;30: 1618-1628) (C) 2008 Excerpta Medica Inc.

The actual incidence of congenital adrenal hyperplasia in Brazil may not be as high as inferred - An estimate based on a public neonatal screening program in the state of Goias

The incidence of 21-hydroxylase deficiency (CYP21 D) congenital adrenal hyperplasia (CAH) in Brazil is purportedly one of the highest in the world (1:7,533). However, this information is not based on official data. The aim of this study was to determine the incidence of CYP21 D CAH in the state of Goias, Brazil, based on the 2005 results of government-funded mandatory screening. Of the live births during this period, 92.95% were screened by heel-prick capillary 17 alpha-hydroxyprogesterone (17-OHP). Of these, 82,343 were normal, 28 were at high risk for CAH and 232 at low risk for CAH. Eight cases, all from the high risk group, were confirmed. Eight asymptomatic children at 6-18 months of age still have high 17-OHP levels and await diagnostic definition. Based on the number of confirmed CYP21 D CAH cases among the 82,603 screened, the estimated annual incidence of the disease was 1:10,325, lower than the previously reported rate in Brazil.

Copper-mediated amyloid-beta toxicity is associated with an intermolecular histidine bridge

Amyloid-beta peptide (A beta) is pivotal to the pathogenesis of Alzheimer disease. Here we report the formation of a toxic A beta-Cu2+ complex formed via a histidine-bridged dimer, as observed at Cu2+/ peptide ratios of > 0.6:1 by EPR spectroscopy. The toxicity of the A beta-Cu2+ complex to cultured primary cortical neurons was attenuated when either the pi- or tau-nitrogen of the imidazole side chains of His were methylated, thereby inhibiting formation of the His bridge. Toxicity did not correlate with the ability to form amyloid or perturb the acyl-chain region of a lipid membrane as measured by diphenyl- 1,3,5-hexatriene anisotropy, but did correlate with lipid peroxidation and dityrosine formation. P-31 magic angle spinning solid-state NMR showed that A beta and A beta-Cu2+ complexes interacted at the surface of a lipid membrane. These findings indicate that the generation of the A beta toxic species is modulated by the Cu2+ concentration and the ability to form an intermolecular His bridge.

Ferromagnetism, paramagnetism, and a Curie-Weiss metal in an electron-doped Hubbard model on a triangular lattice

Motivated by the unconventional properties and rich phase diagram of NaxCoO2 we consider the electronic and magnetic properties of a two-dimensional Hubbard model on an isotropic triangular lattice doped with electrons away from half-filling. Dynamical mean-field theory (DMFT) calculations predict that for negative intersite hopping amplitudes (t < 0) and an on-site Coulomb repulsion, U, comparable to the bandwidth, the system displays properties typical of a weakly correlated metal. In contrast, for t > 0 a large enhancement of the effective mass, itinerant ferromagnetism, and a metallic phase with a Curie-Weiss magnetic susceptibility are found in a broad electron doping range. The different behavior encountered is a consequence of the larger noninteracting density of states (DOS) at the Fermi level for t > 0 than for t < 0, which effectively enhances the mass and the scattering amplitude of the quasiparticles. The shape of the DOS is crucial for the occurrence of ferromagnetism as for t > 0 the energy cost of polarizing the system is much smaller than for t < 0. Our observation of Nagaoka ferromagnetism is consistent with the A-type antiferromagnetism (i.e., ferromagnetic layers stacked antiferromagnetically) observed in neutron scattering experiments on NaxCoO2. The transport and magnetic properties measured in NaxCoO2 are consistent with DMFT predictions of a metal close to the Mott insulator and we discuss the role of Na ordering in driving the system towards the Mott transition. We propose that the Curie-Weiss metal phase observed in NaxCoO2 is a consequence of the crossover from a bad metal with incoherent quasiparticles at temperatures T > T-* and Fermi liquid behavior with enhanced parameters below T-*, where T-* is a low energy coherence scale induced by strong local Coulomb electron correlations. Our analysis also shows that the one band Hubbard model on a triangular lattice is not enough to describe the unusual properties of NaxCoO2 and is used to identify the simplest relevant model that captures the essential physics in NaxCoO2. We propose a model which allows for the Na ordering phenomena observed in the system which, we propose, drives the system close to the Mott insulating phase even at large dopings.

An examination of movement kinematics in young people with high-functioning autism and Asperger's disorder: Further evidence for a motor planning deficit

This paper examines upper-body movement kinematics in individuals with high-functioning autism (HFA) and Asperger's disorder (AD). In general, the results indicate that HFA is more consistently associated with impaired motoric preparation/initiation than AD. The data further suggest that this quantitative difference in motor impairment is not necessarily underpinned by greater executive dysfunction vulnerability in autism relative to AD. Quantitative motoric dissociation between autism and AD may have down-stream effects on later stages of movement resulting in qualitative differences between these disorder groups, e.g. motor clumsiness in AD versus abnormal posturing in autism. It will be important for future research to map the developmental trajectory of motor abnormalities in these disorder groups.

Improved VDC casting of aluminium alloys through an understanding of the surface properties of the molten metal

Vertical direct chill (VDC) casting of aluminium alloys is a mature process that has evolved over many decades through gradual change to both equipment design and casting practice. Today, air-pressurised, continuous lubrication, hot top mould systems with advanced station automation are selected as the process of choice for producing extrusion billet. Specific sets of operating parameters are employed on these stations for each alloy and size combination to produce optimal billet quality. The designs and parameters are largely derived from past experience and accumulated know-how. Recent experimental work at the University of Queensland has concentrated on understanding the way in which the surface properties of liquid aluminium alloys, e.g., surface tension, wetting angle and oxide skin strength, influence the size and shape of the naturally-stab le meniscus for a given alloy, temperature and atmosphere. The wide range of alloy-and condition-dependent values measured has led to the consideration of how these properties impact the stability of the enforced molten metal meniscus within the hot top mould cavity. The actual shape and position of the enforced meniscus is controlled by parameters such as the upstream conduction distance (UCD) from sub-mould cooling and the molten metal head. The degree of deviation of this actual meniscus from the predicted stable meniscus is considered to be a key driver in surface defect formation. This paper reports on liquid alloy property results and proposes how this knowledge might be used to better design VDC mould systems and casting practices.

An optimized model for rat liver perfusion studies

Conditions which influence the viability, integrity, and extraction efficiency of the isolated perfused rat liver were examined to establish optimal conditions for subsequent work in reperfusion injury studies including the choice of buffer, use of oncotic agents, hematocrit, perfusion flow rate, and pressure. Rat livers were perfused with MOPS-buffered Ringer solution with or without erythrocytes. Perfusates were collected and analyzed for blood gases, electrolytes, enzymes, radioactivity in MID studies, and lignocaine in extraction studies. Liver tissue was sampled for histological examinations, and wet:dry weight of the liver was also determined. MOPS-buffered Ringer solution was found to be superior to Krebs bicarbonate buffer, in terms of pH control and buffering capacity, especially during any prolonged period of liver perfusion. A pH of 7.2 is chosen for perfusion since this is the physiological pH of the portal blood. The presence of albumin was important as an oncotic agent, particularly when erythrocytes were used in the perfusate. Perfusion pressure, resistance, and vascular volume are how-dependent and the inclusion of erythrocytes in the perfusate substantially altered the flow characteristics for perfusion pressure and resistance but not vascular volume. Lignocaine extraction was relatively flow-independent. Perfusion injury as defined by enzyme release and tissue fine structure was closely related to the supply of O-2. The optimal conditions for liver perfusion depend upon an adequate supply of oxygen. This can be achieved by using either erythrocyte-free perfusate at a how rate greater than 6 ml/min/g liver or a 20% erythrocyte-containing perfusate at 2 ml/min/g. (C) 1996 Academic Press, Inc.