Developmental regulation of expression of schizophrenia susceptibility genes in the primate hippocampal formation

The hippocampal formation is essential for normal memory function and is implicated in many neurodevelopmental, neurodegenerative and neuropsychiatric disorders. In particular, abnormalities in hippocampal structure and function have been identified in schizophrenic subjects. Schizophrenia has a strong polygenic component, but the role of numerous susceptibility genes in normal brain development and function has yet to be investigated. Here we described the expression of schizophrenia susceptibility genes in distinct regions of the monkey hippocampal formation during early postnatal development. We found that, as compared with other genes, schizophrenia susceptibility genes exhibit a differential regulation of expression in the dentate gyrus, CA3 and CA1, over the course of postnatal development. A number of these genes involved in synaptic transmission and dendritic morphology exhibit a developmental decrease of expression in CA3. Abnormal CA3 synaptic organization observed in schizophrenics might be related to some specific symptoms, such as loosening of association. Interestingly, changes in gene expression in CA3 might occur at a time possibly corresponding to the late appearance of the first clinical symptoms. We also found earlier changes in expression of schizophrenia susceptibility genes in CA1, which might be linked to prodromal psychotic symptoms. A number of schizophrenia susceptibility genes including APOE, BDNF, MTHFR and SLC6A4 are involved in other disorders, and thus likely contribute to nonspecific changes in hippocampal structure and function that must be combined with the dysregulation of other genes in order to lead to schizophrenia pathogenesis

Effects of digoxin on muscle reflexes in normal humans.

Blockade of the skeletal muscle Na(+)-K(+)-ATPase pump by digoxin could result in a more marked hyperkaliema during a forearm exercise, which in turn could stimulate the mechano- and metaboreceptors. In a randomized, double-blinded, placebo-controlled, and cross-over-design study, we measured mean blood pressure (MBP), heart rate (HR), ventilation (V(E)), oxygen saturation (SpO(2)), muscle sympathetic nerve activity (MSNA), venous plasma potassium and lactic acid during dynamic handgrip exercises, and local circulatory arrest in 11 healthy subjects. Digoxin enhanced MBP during exercise but not during the post-handgrip ischemia and had no effect on HR, V(E), SpO(2), and MSNA. Venous plasma potassium and lactic acid were also not affected by digoxin-induced skeletal muscle Na(+)-K(+)-ATPase blockade. We conclude that digoxin increased MBP during dynamic exercise in healthy humans, independently of changes in potassium and lactic acid. A modest direct sensitization of the muscle mechanoreceptors is unlikely and other mechanisms, independent of muscle reflexes and related to the inotropic effects of digoxin, might be implicated.Journal ArticleRandomized Controlled TrialResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Cardiovascular Sequels During and After Preeclampsia

Preeclampsia is a pregnancy-specific disorder complicating 2%-8% of pregnancies worldwide and characterized by de novo development of hypertension and proteinuria. Current understanding of the pathophysiology of preeclampsia is limited. A main feature is disrupted spiral artery remodeling in the placenta, which restricts the blood flow to the placenta, which in turn leads to decreased uteroplacental perfusion. Impaired blood flow through the placenta might result in fetal growth restriction and secretion of several factors by the placenta-mainly pro-inflammatory cytokines and anti-angiogenic factors-which spread into the maternal circulation, leading to endothelial dysfunction, which subsequently results in disrupted maternal hemodynamics. To date, no treatment options are available apart from termination of pregnancy. Despite normalization of the maternal vascular disturbances after birth, it has become apparent that formerly preeclamptic women experience an increased risk to develop cardiovascular and kidney disease later in life. One well-accepted concept is that the development of preeclampsia is an indicator of maternal susceptibility to develop future cardiovascular conditions, although the increased risk might also be the result of organ damage caused during preeclampsia. Given the associations between preeclampsia and long-term complications, preeclampsia is acknowledged as woman-specific risk factor for cardiovascular disease. Current research focuses on finding effective screening and prevention strategies for the reduction of cardiovascular disease in women with a history of preeclampsia