Oxidative stress, hyperlipidemia, neutrophil activation and endothelial cell dysfunction are characteristic of women with preeclampsia. We used in vitro experiments to test if a combination of oxidative stress and linoleic acid favors a mechanism for neutrophil transendothelial migration. We used linoleic acid because it is one of the fatty acids elevated in preeclampsia and the precursor for arachidonic acid and its inflammatory metabolites. For these studies, we developed a methodology for isolating and Culturing human vascular smooth muscle cells from placental chorionic plate arteries. Treatment of these cells with an oxidizing solution enriched with linoleic acid, but neither component alone, led to increased production of interleukin-8 (IL-8), a potent neutrophil chemotactic agent, This treatment solution also stimulated arachidonic acid metabolites, including leukotriene B4, another potent neutrophil chemotactic agent. The same treatment solution rapidly activated neutrophils to produce superoxide, These observations suggested there might be neutrophil transendothelial migration in women with preeclampsia because increased expression of IL-8 by vascular smooth muscle would attract neutrophils to the vasculature, and activation of neutrophils would prime them for transendothelial migration. These predictions were confirmed using immunohistochemical staining of systemic vascular tissue in preeclamptic women, as compared to normal pregnant and normal non-pregnant women, by demonstrating vascular smooth muscle cell expression of lL-8 coincident with neutrophil infiltration into systemic vessels. Endothelial cells and vascular smooth muscle cells also expressed ICAM-1, a cell adhesion molecule necessary for neutrophil infiltration. This investigation is the first to demonstrate vascular smooth muscle cell expression of IL-8 and ICAM-1 coincident with neutrophil transendothelial migration into systemic vascular tissue in women with preeclampsia. These observations provide evidence for total ‘Vascular cell dysfunction”, not only endothelial cell dysfunction, in women with preeclampsia. Together they link vascular cell dysfunction to a single mechanism, transendothelial migration of neutrophils, which could explain the clinical symptoms of hypertension, proteinuria, and pathological edema. These results bolster the use of antioxidants in preventing preeclampsia and suggest novel treatments for preeclampsia based on neutralizing antibodies to IL-8 or cell adhesion molecules.

Since the early 1800's, the basal ganglia have been recognized as an extrapyramidal subcortical motor area. Much of the knowledge of basal ganglia involvement in movement has been obtained through clinical symptomology. Consideration of the basal ganglia as a pure inhibitory influence upon motor regulation was a concept generated by early researchers (24,57,58). In spite of the fact that the basal ganglia was considered an inhibitory center, it was known that the basal ganglia produced fore limb flexion or contraversive head ‘turning. At the present, both facilitatory and inhibitory influences upon motor activity have been demonstrated (50). Physiological mechanisms underlying basal ganglia involvement in movement have been difficult to assess due to the fact that: (1) electrical stimulation and discrete surgical lesions within this subcortical area fail to produce as significant a change in locomotor activity as that observed in dysfunction; and (2) the basal ganglia are many synapses removed from sensory input and from lower motoneurons. Various approaches have been utilized to elucidate motor influences of the basal ganglia. These include: (1) ablation of one or more basal ganglia structures; (2) electrical stimulation of basal ganglia structures; (3) modulation of pre-existing motor activity by electrical stimulation of regions within the basal ganglia; (4) more recently, unit recording in basal ganglia structures in chronic preparations during a task related movement. Early investigators postulated that the basal ganglia exerted a steadying influence upon the pyramidal tract (86). Modulation of the gamma motoneuronal system by subcortical structures pertained to the alteration of background activity on a spinal level. Since some basal ganglia dysfunctions result in the alteration of tone as well as hyperactivity, one would suspect that they modulate the gamma motoneuronal system. Granit and Kaada (26) investigated basal ganglia influences upon gamma activity but did not determine the ‘pathway by which these influences were mediated. They did not investigate basal ganglia modulation of cortically induced increase in gamma discharge. Thus, the question was raised as to whether or not the basal ganglia actually modulated cortically induced increases in gamma activity. Two general mechanisms based on anatomical studies are possible for the modulation of motor activity by the basal ganglia. These mechanisms are: (l) modulation of the output of cortical neurons that exert motor influences and (2) modulation of subcortical neurons that exert motor influences. The former mechanism would occur via a well defined pathway from basal ganglia structures via the thalamus to the cortex (See Literature Review). Modulation could also occur via basal ganglia projections to subcortical areas which in turn project to the spinal level. Differentiation between these two mechanisms was accomplished in the present study by two experimental approaches. The first was an investigation of basal ganglia modulation of flexor responses of the anterior tibialis muscle elicited by electrical stimulation of the sensorimotor cortex and pyramidal tract. These investigations were carried out in intact and in decorticate cats. The anterior tibialis muscle is activated during the first phase, the flexion phase of movement (17). Therefore, this muscle was chosen for this study since a characteristic of some basal ganglia dysfunctions involves a slow onset or initiation of movement. The second approach was an analysis of modulation of cortically induced pyramidal tract responses by conditioning shock trains delivered to various loci within the basal ganglia. Both approaches were designed to determine whether inhibitory and facilitatory motor influences of the basal ganglia occurred at a cortical or subcortical level. A major hypothesis to be tested was whether facilitatory and inhibitory regions existed within the caudate nucleus and more specifically, whether the rostral region of the caudate nucleus was inhibitory and the caudal region facilitatory as proposed by Liles and Davis (50).

That alcohol affects human behavior has been known for centuries. However, how and why it affects behavior has not been precisely established despite extensive research and study. The inconsistent action of alcohol at different doses on different tissue systems and on different response systems has been well documented (Kalant 1 referenced in 39). The exact sites of action of alcohol in the central nervous system and the relative influence of each of these sites in cognitive and motor behavior are not known. The primary purpose of this experiment was to study the effects of blood alcohol concentrations below 0.100 percent on the motor and cognitive components of complex human behavior using replicable and quantifiable measures.

The Nb2 lymphoma cell line is susceptible to glucocorticoid (GC)-induced apoptosis in the absence of mitogen and this effect is inhibited by the mitogen prolactin (PRL). This process is believed to be mediated by the glucocorticoid receptor (GR) and various downstream signals. The purpose of this study was to use the limiting dilution method to isolate subsets of Nb2 clones which expressed either highly enriched amounts of GR or an absence of GR and to relate the amount of GR to the magnitude of GC induced cytolysis. The presence of GR in these clones was determined by immunocytochemistry (ICC) using an affinity purified polyclonal rabbit antibody directed towards the GR. The presence of GR was then correlated to cytolysis in these cells produced by incubation with dexamethasone (Dex), a synthetic GC, in the presence and absence of PRL. Cytolysis was measured by two different methods, Trypan Blue exclusion counts, to determine the percentage of dead and the TUNEL (TdT-dependent dUTP-biotin Nick End Labeling) assay used to label apoptotic cells. The limiting dilution produced 28 clones with varying amounts of GR and all were responsive to Dex and this response was inhibited by PRL. A significant correlation (r2=0.419 and p

Hypertension, defined as systolic blood pressure (SBP) greater than or equal to 140 mmHg, or diastolic blood pressure (DBP) of 90 mmHg or greater, is a prevalent risk factor for cardiovascular disease that affects more than 75 million people in the United States. It is also estimated that 1 out of 3 Americans have prehypertension, which is classified as SBP ranging from 120-139 mmHg, or DBP from 80-89 mmHg. As aging occurs, there is a significant increase in the risk for development of elevated blood pressures (BP) at rest or during stress related activities. Measurements of BP response to stress are used to predict individuals at greater risk of developing prehypertension or hypertension. There are many theories as to why BP increases with age such as baroreflex dysfunction, increased sympathetic nervous system activity, and vascular dysfunction. Additionally with aging, there is a decrease in the important molecule nitric oxide (NO), which plays a critical role in the regulation of vasomotor tone as well as in the tonic restraint of central sympathetic outflow, both of which are integral for BP regulation. Consumption of exogenous nitrate/nitrite can increase NO bioavailability resulting in beneficial attenuating effects on BP at rest. However, to our knowledge, no data exists as to whether improvements in spontaneous cardiovagal baroreceptor sensitivity (BRS) occur following nitrate supplementation, and if this contributes to improvements in resting BP. Furthermore, the beneficial effects of dietary nitrate supplementation on BP responsiveness to stress in older adults are unclear. Therefore, we examined whether baroreflex sensitivity is improved in older adults following 4-weeks of dietary nitrate supplementation and whether this improvement is associated with reductions in resting BP. Additionally, we investigated whether dietary nitrate supplementation attenuates BP responses to stress in older adults. Ten young (26 ± 2 years; 5 male, 5 female) and ten older (67 ± 1 years; 6 male, 4 female) adults volunteered to participate in this study. Young subjects served as a control study group to assess age-related changes in all outcome measures and did not participate in the intervention portion (dietary nitrate supplementation) of the study. Older subjects participated in a randomized placebo controlled cross-over study over a 3 month period consisting of four separate visits (each separated by 4 weeks) comprised of identical testing procedures. Each older subject was randomized to receive either a beetroot powder containing nitrate and nitrite (active) or beetroot powder devoid of nitrate and nitrite (placebo) for 4 weeks. During each study visit, subjects underwent the same battery of tests to assess spontaneous cardiovagal baroreflex sensitivity (BRS), the metaboreflex arm of the exercise pressor reflex and blood pressure responsiveness to cold induced stress (cold pressor testing, CPT). Venous blood samples were obtained each visit to measure plasma levels of nitrate and nitrite. Despite similar resting BP values between age groups, older adults demonstrated decreases in overall, up, and down spontaneous cardiovagal BRS (64%, 66%, and 61% respectively; P< 0.01 for all) compared to the young adults. During metaboreflex testing, older adults demonstrated a greater increase in SBP than the young during post exercise ischemia (PEI) (P< 0.05). SBP and mean arterial pressure (MAP) responses were similar between young and older adults during CPT, however, young adults demonstrated a greater increase in DBP vs. older adults (P< 0.05). In the older adults, nitrate supplementation increased plasma levels of nitrate and nitrite (P< 0.01 for both) compared to pre-supplementation as well as in comparison to placebo (P< 0.05 for both). Additionally, resting SBP and MAP were reduced following nitrate supplementation (P< 0.05 for both). However, changes in resting BP were not associated with improvements in spontaneous cardiovagal BRS. The magnitudes of change in DBP, SBP, and MAP in response to isometric handgrip exercise (IHG) did not change following nitrate supplementation. However, during the PEI portion of the metaboreflex the magnitudes of change in DBP (P< 0.05), SBP (P< 0.01), and MAP (P< 0.01) were attenuated following active supplementation but not for the placebo group (P=0.25, P=0.99, P=0.45 respectively). In response to cold induced stress, the magnitudes of change in in DBP (P< 0.05), SBP (P< 0.01), and MAP (P< 0.01) were reduced following active supplementation versus no change in the placebo group (P=0.13, P= 0.97, P=0.28 respectively). Our results suggest that there is a beneficial effect of dietary nitrate supplementation on the metaboreflex-mediated increases in BP during exercise in older adults. Additionally, dietary nitrate reduces BP responsiveness to cold induced stress (via CPT) in older adults. In conclusion, we suggest that dietary nitrate supplementation has beneficial antihypertensive properties, and its consideration as an alternative to pharmacological intervention could prove to be therapeutic and cost effective.

No description available.

No description available.

No description available.

No description available.

No description available.