Postsynaptic nigrostriatal dopamine receptors and their role in movement regulation

The article presents the hypothesis that nigrostriatal dopamine may regulate movement by modulation of tone and contraction in skeletal muscles through a concentration-dependent influence on the postsynaptic D1 and D2 receptors on the follow manner: nigrostriatal axons innervate both receptor types within the striatal locus somatotopically responsible for motor control in agonist/antagonist muscle pair around a given joint. D1 receptors interact with lower and D2 receptors with higher dopamine concentrations. Synaptic dopamine concentration increases immediately before movement starts. We hypothesize that increasing dopamine concentrations stimulate first the D1 receptors and reduce muscle tone in the antagonist muscle and than stimulate D2 receptors and induce contraction in the agonist muscle. The preceded muscle tone reduction in the antagonist muscle eases the efficient contraction of the agonist. Our hypothesis is applicable for an explanation of physiological movement regulation, different forms of movement pathology and therapeutic drug effects. Further, this hypothesis provides a theoretical basis for experimental investigation of dopaminergic motor control and development of new strategies for treatment of movement disorders

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

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Blockade of Thrombopoietin Reduces Organ Damage in Experimental Endotoxemia and Polymicrobial Sepsis

BACKGROUND AND PURPOSE:Thrombopoietin (TPO), a growth factor primarily involved in thrombopoiesis may also have a role in the pathophysiology of sepsis. In patients with sepsis, indeed, TPO levels are markedly increased, with disease severity being the major independent determinant of TPO concentrations. Moreover, TPO increases and correlates with ex vivo indices of platelet activation in patients with burn injury upon sepsis development, and may contribute to depress cardiac contractility in septic shock. Still, the role of TPO in sepsis pathophysiology remains controversial, given the protective role of TPO in other experimental disease models, for instance in doxorubicin-induced cardiotoxicity and myocardial ischemia/reperfusion injury. The aim of our study was to define the contribution of TPO in the development of organ damage induced by endotoxemia or sepsis, and to investigate the effects of inhibiting TPO in these conditions. METHODS:We synthesized a chimeric protein able to inhibit TPO, mTPOR-MBP, and studied its effect in two murine experimental models, acute endotoxemia and cecal ligation and puncture (CLP) model. RESULTS:In both models, TPO levels markedly increased, from 289.80±27.87 pg/mL to 465.60±45.92 pg/mL at 3 hours in the LPS model (P<0.01), and from 265.00±26.02 pg/mL to 373.70±26.20 pg/mL in the CLP model (P<0.05), respectively. Paralleling TPO levels, also platelet-monocyte aggregates increased, from 32.86±2.48% to 46.13±1.39% at 3 hours in the LPS model (P<0.01), and from 43.68±1.69% to 56.52±4.66% in the CLP model (P<0.05). Blockade of TPO by mTPOR-MBP administration reduced histological damage in target organs, namely lung, liver, and gut. In particular, neutrophil infiltration and lung septal thickening were reduced from a score of 1.86±0.34 to 0.60±0.27 (P<0.01) and from 1.43±0.37 to 0.40±0.16 (P<0.05), respectively, in the LPS model at 3 hours, and from a score of 1.75±0.37 to 0.38±0.18 (P<0.01) and from 1.25±0.31 to 0.13±0.13 (P<0.001), respectively, in the CLP model. Similarly, the number of hepatic microabscesses was decreased from 14.14±1.41 to 3.64±0.56 in the LPS model at 3 hours (P<0.001), and from 1.71±0.29 to 0.13±0.13 in the CLP model (P<0.001). Finally, the diameter of intestinal villi decreased from 90.69±3.95 μm to 70.74±3.60 μm in the LPS model at 3 hours (P<0.01), and from 74.29±4.29 μm to 57.50±1.89 μm in the CLP model (P<0.01). This protective effect was associated with the blunting of the increase in platelet-monocyte adhesion, and, on the contrary, with increased platelet-neutrophil aggregates in the circulation, which may be related to decreased neutrophil sequestration into the inflamed tissues. Conversely, circulating cytokine levels were not significantly changed, in both models, by mTPOR-MBP administration. CONCLUSION:Our results demonstrate that TPO participates in the development of organ damage induced by experimental endotoxemia or polymicrobial sepsis via a mechanism involving increased platelet-leukocyte adhesion, but not cytokine release, and suggest that blocking TPO may be useful in preventing organ damage in patients affected by systemic inflammatory response or sepsis

The maternal health study: Study design update for a prospective cohort of first-time mothers and their firstborn children from birth to age ten

BACKGROUND: Maternal health is critical to the health and well-being of children and families, but is rarely the primary focus of pregnancy and birth cohort studies. Globally, poor maternal health and the exposure of women and children to family violence contribute to the perpetuation and persistence of intergenerational health inequalities. OBJECTIVES: The Maternal Health Study was designed to investigate the contribution of social and obstetric risk factors to common maternal physical and psychological morbidities. Over time, our focus has expanded to include mother-child pairs and investigation of intergenerational trauma and family violence. POPULATION: A total of 1507 first-time mothers were recruited in early pregnancy from six public hospitals in Melbourne, Australia, in 2003-2005. METHODS: Women completed questionnaires or telephone interviews in early pregnancy (≤24 weeks); at 32 weeks' gestation; at three, six, nine, 12 and 18 months postpartum; and at four and ten years. At ten years, women and children were invited to participate in face-to-face interviews, which included direct assessment of children's cognitive and language development. A wide range of obstetric, social and contextual factors have been measured, including exposure to intimate partner violence (IPV) (1-year, 4-year and 10-year follow-up). RESULTS: 1507 eligible women were recruited at a mean gestation of 15 weeks. At one year, four years and ten years postpartum, 90.0%, 73.1% and 63.2% of the original cohort took part in follow-up. One in three women in the study (34.5%) reported exposure to IPV in the first ten years of motherhood: 19% in the first 12 months postpartum, 20% in the year prior to four-year follow-up and 18.3% in the year prior to ten-year follow-up. CONCLUSION: The study affords a unique opportunity to examine patterns of maternal and child health and health service use associated with exposure to IPV