Relaxin: a missing link in the pathomechanisms of Systemic Lupus Erythematosus?

Systemic Lupus Erythematosus (SLE) is an autoimmune rheumatic disease which predominantly affects women of reproductive age. Despite significant progress in recent years to elucidate many potential mechanisms involved in the generation of autoimmunity the factors behind the high incidence among women, the relapsing-remitting clinical course and pregnancy-related complications in SLE remain unclear. In this review, we hypothesize a potential role for uterine endometrium through its production of relaxin, a peptide hormone, as a "missing-link" to explain this female predominance, variable clinical course and obstetric complications operating in SLE.

HIV associated dementia: role for neurosteroids.

HIV associated dementia (HAD), is a neuronal complication of HIV infection and causes cognitive and motor impairment. The cognitive decline in HAD is due to widespread synaptic loss than neuronal loss. The neurotoxicity in HAD is caused by activation of NMDA receptors by HIV-proteins but the exact mechanism of the synaptic loss is yet to be determined. This article explores a novel pathomechanism for the observed synaptic loss. The HIV-proteins augment NMDA mediated increase of intracellular Ca(2+) in neurons which activates nNOs for Nitric Oxide (NO) synthesis. The NO activates MAPK and phosphorylates Microtubule-associated protein-2(MAP2) at specific sites causing conformational changes, microtubular disassembly and promote MAP2 degradation by the ubiquitin-proteosome pathway. Under physiological conditions Ca(2+) signaling increases cholesterol transport into mitochondria for steroidogenesis by the CYP11A1. The neurosteroid pregnenolone binds to MAP2 and causes inhibition of phosphorylation, increase in microtubule assembly and decrease MAP2 degradation. The NO can inhibits CYP11A1 in a concentration dependent manner and reduces steroidogeneisis. There is a upregulation of NO production in HAD from HIV infected microglia and astrocytes which cross neuronal membrane and increase intracellular NO. This can cause profound inhibition of steroidogenesis in the brain, increase MAP2 degradation and synaptic loss in presence of HIV-proteins.

Metabolic syndrome--psycho neuropathogenesis and human brain evolution.

AIM: Metabolic syndrome (MS) is a major risk factor for coronary artery disease. Heightened hypothalamo-pituitary-adrenal axis activity is associated with pathogenesis of MS. Life style, food habits and physical activity also play critical role in the pathogenesis of MS. However, the precise neurophysiology behind chronic stress leading on to such effects is unknown. MATERIALS AND METHODS: Review of recent animal and human studies have shown the subtle differences in morphological changes associated with chronic stress between medial prefrontal cortex and amygdaloid complex. RESULT: The loss of dendritic spines in pyramidal neurons of medial prefrontal cortex, dendritic hypertrophy in basolateral amygdala and dendritic loss in central nucleus of amygdala causes increased basal output from amygdaloid complex to HPA axis and other targets whose networks are evolutionarily well conserved. CONCLUSION: The increased HPA axis activity, elevated blood pressure and appetite for high calorie diet leads to MS. The evolution of isocortex in primates and associated regression in size of limbic structures predisposed to increased synaptic noise in amygdaloid complex which in turn cause heighetened output from amygdala during chronic stress.