Prenatal Excess Glucocorticoid Exposure and Adult Affective Disorders:A Role for Serotonergic and Catecholamine Pathways

Fetal glucocorticoid exposure is a key mechanism proposed to underlie prenatal ‘programming’ of adult affective behaviours such as depression and anxiety. Indeed, the glucocorticoid metabolising enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which is highly expressed in the placenta and the developing fetus, acts as a protective barrier from the high maternal glucocorticoids which may alter developmental trajectories. The programmed changes resulting from maternal stress or bypass or from the inhibition of 11β-HSD2 are frequently associated with alterations in the hypothalamic-pituitary-adrenal (HPA) axis. Hence, circulating glucocorticoid levels are increased either basally or in response to stress accompanied by CNS region-specific modulations in the expression of both corticosteroid receptors (mineralocorticoid and glucocorticoid receptors). Furthermore, early-life glucocorticoid exposure also affects serotonergic and catecholamine pathways within the brain, with changes in both associated neurotransmitters and receptors. Indeed, global removal of 11β-HSD2, an enzyme that inactivates glucocorticoids, increases anxiety‐ and depressive-like behaviour in mice; however, in this case the phenotype is not accompanied by overt perturbation in the HPA axis but, intriguingly, alterations in serotonergic and catecholamine pathways are maintained in this programming model. This review addresses one of the potential adverse effects of glucocorticoid overexposure in utero, i.e. increased incidence of affective behaviours, and the mechanisms underlying these behaviours including alteration of the HPA axis and serotonergic and catecholamine pathways

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Space-Time Joint Interference Cancellation Using Fuzzy-Inference-Based Adaptive Filtering Techniques in Frequency-Selective Multipath Channels

<p/> <p>An adaptive minimum mean-square error (MMSE) array receiver based on the fuzzy-logic recursive least-squares (RLS) algorithm is developed for asynchronous DS-CDMA interference suppression in the presence of frequency-selective multipath fading. This receiver employs a fuzzy-logic control mechanism to perform the nonlinear mapping of the squared error and squared error variation, denoted by ( <inline-formula><graphic file="1687-6180-2006-062052-i1.gif"/></inline-formula>, <inline-formula><graphic file="1687-6180-2006-062052-i2.gif"/></inline-formula>), into a forgetting factor <inline-formula><graphic file="1687-6180-2006-062052-i3.gif"/></inline-formula>. For the real-time applicability, a computationally efficient version of the proposed receiver is derived based on the least-mean-square (LMS) algorithm using the fuzzy-inference-controlled step-size <inline-formula><graphic file="1687-6180-2006-062052-i4.gif"/></inline-formula>. This receiver is capable of providing both fast convergence/tracking capability as well as small steady-state misadjustment as compared with conventional LMS- and RLS-based MMSE DS-CDMA receivers. Simulations show that the fuzzy-logic LMS and RLS algorithms outperform, respectively, other variable step-size LMS (VSS-LMS) and variable forgetting factor RLS (VFF-RLS) algorithms at least 3 dB and 1.5 dB in bit-error-rate (BER) for multipath fading channels.</p

Anemia falciforme alterações angiográficas cerebrais

São descritos dois casos de pacientes com anemia falciforme (AF) que desenvolveram complicações neurológicas. Os estudos angiográficos mostraram alterações semelhantes àquelas encontradas na doença moyamoya. Estes achados ocorrem também em outras patologias e são resultado de mecanismo de compensação a oclusão das artérias da base do cérebro. São comentados os riscos e as precauções para a realização da angiografia cerebral