Brain Aβ load association and sexual dimorphism of plasma BACE1 concentrations in cognitively normal individuals at risk for AD

IntroductionSuccessful development of effective β-site amyloid precursor protein cleaving enzyme 1 (BACE1)–targeted therapies for early stages of Alzheimer's disease requires biomarker-guided intervention strategies.MethodsWe investigated whether key biological factors such as sex, apolipoprotein E (APOE ε4) allele, and age affect longitudinal plasma BACE1 concentrations in a large monocenter cohort of individuals at risk for Alzheimer's disease. We explored the relationship between plasma BACE1 concentrations and levels of brain amyloid-β (Aβ) deposition, using positron emission tomography global standard uptake value ratios.ResultsBaseline and longitudinal mean concentrations of plasma BACE1 were significantly higher in women than men. We also found a positive significant impact of plasma BACE1 on baseline Aβ–positron emission tomography global standard uptake value ratios.DiscussionOur results suggest a sexual dimorphism in BACE1-related upstream mechanisms of brain Aβ production and deposition. We argue that plasma BACE1 should be considered in further biomarker validation and qualification studies as well as in BACE1 clinical trials.     

Congenital hydrocephalus – prevalence,prenatal diagnosis and outcome of pregnancy in four European regions

ObjectiveTo describe prevalence, prenatal diagnosis and outcome for fetuses and infants with congenital hydrocephalus.MethodsData were taken from four European registries of congenital malformations (EUROCAT). The registries included are based on multiple sources of information and include information about livebirths, fetal deaths with GA ≥ 20 weeks and terminations of pregnancy for fetal anomaly (TOPFA). All cases from the four registries diagnosed with congenital hydrocephalus and born in the period 1996–2003 were included in the study. Cases with hydrocephalus associated with neural tube defects were not included in the study.ResultsEighty-seven cases with congenital hydrocephalus were identified during the study period giving an overall prevalence of 4.65 per 10,000 births. There were 41 livebirths (47%), four fetal deaths (5%) and 42 TOPFA (48%). Nine percent of all cases were from a multiple pregnancy. Additional non-cerebral major malformations were diagnosed in 38 cases (44%) and karyotype anomalies in eight cases (9%). Median GA at TOPFA was 21 weeks. Among livebirths 61% were diagnosed prenatally at a median GA of 31 weeks (range 17–40 weeks) and median GA at birth was 37 weeks. Fourteen liveborn infants (34%) died within the first year of life with the majority of deaths during the first week after birth.ConclusionCongenital hydrocephalus is a severe congenital malformation often associated with other congenital anomalies. CH is often diagnosed prenatally, although sometimes late in pregnancy. A high proportion of affected pregnancies result in termination for severe fetal anomaly and there is a high mortality in livebirths.     

Evaluation of the Safety and Immunogenicity of Two Antigen Concentrations of the Mtb72F/AS02A Candidate Tuberculosis Vaccine in Purified Protein Derivative-Negative Adults

Tuberculosis (TB) remains a major cause of illness and death worldwide, making a new TB vaccine an urgent public health priority. Purified protein derivative (PPD)-negative adults (n = 50) were equally randomized to receive 3 doses at 1-month intervals (at 0, 1, and 2 months) of one of the following vaccines: Mtb72F/AS02_A (10 or 40 μg antigen), Mtb72F/saline (10 or 40 μg antigen), or AS02_A. Mtb72F/AS02_A recipients received an additional dose 1 year after the first dose to evaluate if the elicited immune response could be boosted. Mtb72F/AS02_A vaccines were locally reactogenic but clinically well tolerated, with transient adverse events (usually lasting between 1 and 4 days) that resolved without sequelae being observed. No vaccine-related serious adverse events were reported. Vaccination with Mtb72F/AS02_A induced a strong Mtb72F-specific humoral response and a robust Mtb72F-specific CD4⁺ T-cell response, both of which persisted at 9 months after primary immunization and for 1 year after the booster immunization. There was no significant difference between the magnitude of the CD4⁺ T-cell response induced by the 10-μg and 40-μg Mtb72F/AS02_A vaccines. The Mtb72F-specific CD4⁺ T cells predominantly expressed CD40L; CD40L and interleukin-2 (IL-2); CD40L and tumor necrosis factor alpha (TNF-α); CD40L, IL-2, and TNF-α; and CD40L, IL-2, TNF-α, and gamma interferon (IFN-γ). Serum IFN-γ, but not TNF-α, was detected 1 day after doses 2 and 3 for the Mtb72F/AS02_A vaccine but did not persist. Vaccine-induced CD8⁺ T-cell responses were not detected, and no immune responses were elicited with AS02_A alone. In conclusion, Mtb72F/AS02_A is clinically well tolerated and is highly immunogenic in TB-naïve adults. The 10- and 40-μg Mtb72F/AS02_A vaccines show comparable safety and immunogenicity profiles.Tuberculosis (TB) is a major cause of illness and death worldwide, causing approximately 1.7 million deaths a year (43). Despite global efforts to control or eradicate the disease, the WHO estimates that in 2008 an estimated 8.9 million to 9.9 million people became infected with Mycobacterium tuberculosis. The situation is compounded by the emergence of multidrug-resistant TB. Since one-third of the world''s population is estimated to be latently infected with M. tuberculosis and at possible risk of disease, TB prevention remains one of today''s greatest public health challenges. An efficacious vaccination strategy is an essential tool to control TB.M. bovis bacillus Calmette-Guérin (BCG), consisting of attenuated strains of M. bovis, is the only TB vaccine currently available. It effectively prevents meningeal and miliary TB in young children (8) but appears to be ineffective in preventing adult-onset TB (protection rates, 0 to 80%) (10) and pulmonary TB in children.GlaxoSmithKline (GSK) Biologicals'' candidate TB vaccine antigen, Mtb72F, is composed of a fusion protein derived from two highly immunogenic M. tuberculosis antigens: Mtb39A (Rv0125 encoding PepA) and Mtb32A (Rv1196 encoding PPE18) (34, 35). Mtb72F, formulated with GSK Biologicals'' proprietary AS02_A adjuvant system, was shown to be well tolerated in animal models and protected against M. tuberculosis challenge in nonhuman primates, where Mtb72F/AS02_A was shown to be capable of inducing long-term protection against tuberculosis, as determined by protection against severe disease and death and by other clinical and histopathological parameters (6, 30, 34, 39). A first-time-in-human study evaluated Mtb72F/AS02_A (10 μg) in purified protein derivative (PPD)-negative TB-naïve, healthy adults in the United States given according to a 0-, 1-, and 2-month schedule and was found to be clinically well tolerated and highly immunogenic (42).This study assessed whether a larger amount of the Mtb72F/AS02_A vaccine antigen (40 μg) could improve the elicited immune response compared with the response elicited by the previously tested 10-μg antigen dose (42). In addition, a fourth vaccine dose was given to the vaccine recipients to evaluate whether the immune response could be boosted approximately 1 year after the primary vaccination course.     

Renewal of mural thrombus releases plasma markers and is involved in aortic abdominal aneurysm evolution

Human abdominal aortic aneurysm (AAA) expansion has been linked to the presence of a mural thrombus. Here we explored the mechanism of the continual luminal renewal of this thrombus and its ability to release biological markers potentially detectable in plasma. We also explored the ability of platelet inhibition to pacify the thrombus and to limit aneurysm progression in an experimental model. Blood samples and mural thrombi were collected in 20 AAA patients. In parallel, segments of sodium dodecyl sulfate-decellularized guinea pig aorta were xenografted onto the abdominal aorta of 30 rats to induce aneurysms. Fifteen rats received abciximab treatment and fifteen received irrelevant immunoglobulins. Procoagulant activity and platelet activation markers (microparticles, sP-selectin, sGPV, sCD40L) were increased threefold to fivefold in eluates from the luminal thrombus layer compared to other layers. All these markers were increased twofold to fivefold in patients' plasma compared to matched controls (P < 0.005). In the rat model, abciximab reduced both thrombus area and aneurysmal enlargement (P < 0.05). Platelet aggregation is probably responsible for the renewal of the thrombus in AAA. The luminal thrombus released markers of platelet activation that could easily be detected in plasma. Platelet inhibition limited aortic aneurysm expansion in a rat model, providing new therapeutic perspectives in the prevention of AAA enlargement.     

Reproducibility of primary motor cortex somatotopy under controlled conditions

BACKGROUND AND PURPOSE: The somatotopic organization of the contralateral primary motor cortex (M1) and its intra- and intersubject reproducibility has been the subject of many investigations and controversies. A potential explanation for a least some of the conflicting results could be the lack of movement control in the studies performed. The purpose of this study was to investigate these issues under controlled experimental conditions. METHODS: Functional MR imaging was performed in 12 healthy volunteers performing hand, finger, wrist, elbow, foot, and tongue movements. Two experimental sessions were separated by 2 weeks. Controlled conditions were achieved by means of a custom-designed arm and hand manipulandum providing standardization of the movements within and across subjects. RESULTS: The experiments revealed a clear large-scale somatotopy of the contralateral M1 with distinct subregions controlling the foot, arm, and tongue. Despite considerable overlap of the volumes, geometric centers of gravity (COGs) showed statistically significant differences in coordinates between the elbow, wrist, fingers, and hand. COGs showed a high degree of intra- and interindividual reproducibility, particularly for the upper limb movements, in contrast to the activation volumes that proved to be unreliable parameters, despite the controlled conditions. CONCLUSION: These findings support the existence of a gross-scale somatotopic organization yet also demonstrate a clear, fine-scale somatotopy of the within-arm representations. Furthermore, they reveal high reproducibility of the COGs when standardized conditions are applied. This observation highlights the need for movement control to allow for intra- and intersubject comparison.     

Randomized calcineurin inhibitor cross over study to measure the pharmacokinetics of co-administered enteric-coated mycophenolate sodium

Enteric-coated mycophenolate sodium (EC-MPS) (myfortic) is an advanced formulation delivering mycophenolic acid (MPA), designed to improve MPA-related upper gastrointestinal adverse events by delaying the release of MPA until the small intestine. A randomized, calcineurin inhibitor crossover, steady-state pharmacokinetic study in stable renal transplant patients receiving EC-MPS demonstrated increased MPA exposure of 19% higher, MPA C(max,ss) 19% lower and MPA C(min,ss) approximately twofold higher with tacrolimus, than cyclosporine microemulsion. No study drug-related adverse events were recorded, but mean blood glucose concentration was higher in patients receiving tacrolimus (p = 0.031). The dose changes in relation to MPA exposure in patients is dependent on the clinical situation and may not always be warranted. These observations should be taken into consideration when switching from one calcineurin inhibitor to another, but the final dosage should be based on both this pharmacokinetic data and the clinical situation.     

Neuroendocrine predictors of the evolution of depression

Depression is both clinically and biologically a heterogeneous entity. Despite advances in psychopharmacology, a significant proportion of depressed patients either continue to have residual symptoms or do not respond to antidepressants. It has therefore become essential to determine parameters (or predictors) that would rationalize the therapeutic choice, taking into account not only the clinical features, but also the "biological state," which is a major determinant in the antidepressant response. Such predictors can derive from bioclinical correlates and, in this context, the neuroendocrine strategy appears particularly suited. Numerous studies have investigated neuroendocrine parameters--derived mainly from dynamic challenge tests--in order to (i) determine the predictive profiles of good clinical responders to given antidepressants; (ii) monitor the progression of markers in parallel with the clinical outcome; and (iii) evaluate "in vivo" in humans the mechanisms of action of antidepressant compounds (before, during, and after treatment). This article does not attempt to be exhaustive, but rather uses selected examples to illustrate the usefulness of the investigation of the adrenal and thyroid axes and the assessment of central serotonergic, noradrenergic, and dopaminergic systems by means of neuroendocrine tests. Given methodological constraints, most of these investigations--except for baseline hormone values and the dexamethasone suppression test--cannot be used routinely in psychiatry. Despite these limitations, the neuroendocrine strategy still offers new insights in biology and the treatment of depression. Its possible expansion depends mainly on the development of specific agonists or antagonists for better investigation of the receptors supposedly involved in the pathophysiology of depression. These investigations will help define more homogeneous subgroups from a bioclinical and therapeutic viewpoint.