Lead activates calmodulin sensitive processes

The effect of lead on two calcium sensitive processes was determined. Micromolar concentrations of lead successfully replaced calcium in the activation of calmodulin-sensitive phosphodiesterase and in the promotion of potassium loss from erythrocytes. Both actions of lead were blocked by trifluoperazine--an inhibitor of calmodulin function. We propose that some of the toxic effects of lead may be explained by its interaction with calmodulin.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25113/1/0000546.pd

Phosphoinositide metabolism and prostacyclin formation in retinal microvascular endothelium: Stimulation by adenine nucleotides

Phosphoinositide lipid metabolism and prostacyclin production are implicated in endothelium dependent vascular relaxation in large blood vessels. To determine if these biochemical pathways might be involved in the regulation of microvascular tone in the retina, we measured the formation of 6-keto-prostaglandin-F1[alpha], the stable end product of prostacyclin, and inositol phosphates from 3H-labeled phosphoinositide lipids, in endothelial cells prepared from bovine retinal microvessels and maintained in long-term culture. We found that adenosine 5'-triphosphate and adenosine 5'-diphosphate both stimulated a dose-dependent accumulation of inositol phosphates and of 6-keto-prostaglandin-F1[alpha] in these cells. The agonist specificity of the responses, with stimulation by adenosine 5'-triphosphate and adenosine 5'-diphosphate, and inactivity of adenosine 5'-monophosphate and adenosine, suggest that they are mediated through P2 purinergic receptors. The similar early time courses of 6-keto-prostaglandin-F1[alpha] and inositol triphosphate production support the hypothesis that prostacyclin formation could result from the mobilization of intracellular calcium by inositol triphosphate, which activates phospholipase A, and thereby releases arachidonic acid to form prostacyclin. These findings point to a role for these cells in the regulation of normal retinal vascular tone. Because phosphoinositide lipid metabolism is altered in diabetes, dysfunction of these biochemical pathways in retinal endothelium could underlie the pathophysiology of diabetic retinopathy.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28775/1/0000607.pd

Effect of synbiotic supplementation in children and adolescents with cystic fibrosis: a randomized controlled clinical trial

BACKGROUND/OBJECTIVES:Cystic fibrosis (CF) is characterized by excessive activation of immune processes. The aim of this study was to evaluate the effect of synbiotic supplementation on the inflammatory response in children/adolescents with CF. SUBJECTS/METHODS:A randomized, placebo-controlled, double-blind, clinical-trial was conducted with control group (CG, n = 17), placebo-CF-group (PCFG, n = 19), synbiotic CF-group (SCFG, n = 22), PCFG negative (n = 8) and positive (n = 11) bacteriology, and SCFG negative (n = 12) and positive (n = 10) bacteriology. Markers of lung function (FEV1), nutritional status [body mass index-for age (BMI/A), height-for-age (H/A), weight-for-age (W/A), upper-arm fat area (UFA), upper-arm muscle area (UMA), body fat (%BF)], and inflammation [interleukin (IL)-12, tumor necrosis factor-alpha (TNF-α), IL-10, IL-6, IL-1β, IL-8, myeloperoxidase (MPO), nitric oxide metabolites (NOx)] were evaluated before and after 90-day of supplementation with a synbiotic. RESULTS:No significance difference was found between the baseline and end evaluations of FEV1 and nutricional status markers. A significant interaction (time vs. group) was found for IL-12 (p = 0.010) and myeloperoxidase (p = 0.036) between PCFG and SCFG, however, the difference was not maintained after assessing the groups individually. NOx diminished significantly after supplementation in the SCFG (p = 0.030). In the SCFG with positive bacteriology, reductions were found in IL-6 (p = 0.033) and IL-8 (p = 0.009) after supplementation. CONCLUSIONS: Synbiotic supplementation shown promise at diminishing the pro-inflammatory markers IL-6, IL-8 in the SCFG with positive bacteriology and NOx in the SCFG in children/adolescents with CF

Abnormal joint torque patterns exhibited by chronic stroke subjects while walking with a prescribed physiological gait pattern

<p>Abstract</p> <p>Background</p> <p>It is well documented that individuals with chronic stroke often exhibit considerable gait impairments that significantly impact their quality of life. While stroke subjects often walk asymmetrically, we sought to investigate whether prescribing near normal physiological gait patterns with the use of the Lokomat robotic gait-orthosis could help ameliorate asymmetries in gait, specifically, promote similar ankle, knee, and hip joint torques in both lower extremities. We hypothesized that hemiparetic stroke subjects would demonstrate significant differences in total joint torques in both the frontal and sagittal planes compared to non-disabled subjects despite walking under normal gait kinematic trajectories.</p> <p>Methods</p> <p>A motion analysis system was used to track the kinematic patterns of the pelvis and legs of 10 chronic hemiparetic stroke subjects and 5 age matched controls as they walked in the Lokomat. The subject's legs were attached to the Lokomat using instrumented shank and thigh cuffs while instrumented footlifters were applied to the impaired foot of stroke subjects to aid with foot clearance during swing. With minimal body-weight support, subjects walked at 2.5 km/hr on an instrumented treadmill capable of measuring ground reaction forces. Through a custom inverse dynamics model, the ankle, knee, and hip joint torques were calculated in both the frontal and sagittal planes. A single factor ANOVA was used to investigate differences in joint torques between control, unimpaired, and impaired legs at various points in the gait cycle.</p> <p>Results</p> <p>While the kinematic patterns of the stroke subjects were quite similar to those of the control subjects, the kinetic patterns were very different. During stance phase, the unimpaired limb of stroke subjects produced greater hip extension and knee flexion torques than the control group. At pre-swing, stroke subjects inappropriately extended their impaired knee, while during swing they tended to abduct their impaired leg, both being typical abnormal torque synergy patterns common to stroke gait.</p> <p>Conclusion</p> <p>Despite the Lokomat guiding stroke subjects through physiologically symmetric kinematic gait patterns, abnormal asymmetric joint torque patterns are still generated. These differences from the control group are characteristic of the hip hike and circumduction strategy employed by stroke subjects.</p

The Efficacy of Pharmacotherapy for Decreasing the Expansion Rate of Abdominal Aortic Aneurysms: A Systematic Review and Meta-Analysis

BACKGROUND: Pharmacotherapy may represent a potential means to limit the expansion rate of abdominal aortic aneurysms (AAAs). Studies evaluating the efficacy of different pharmacological agents to slow down human AAA-expansion rates have been performed, but they have never been systematically reviewed or summarized. METHODS AND FINDINGS: Two independent reviewers identified studies and selected randomized trials and prospective cohort studies comparing the growth rate of AAA in patients with pharmacotherapy vs. no pharmacotherapy. We extracted information on study interventions, baseline characteristics, methodological quality, and AAA growth rate differences (in mm/year). Fourteen prospective studies met eligibility criteria. Five cohort studies raised the possibility of benefit of beta-blockers [pooled growth rate difference: -0.62 mm/year, (95%CI, -1.00 to -0.24)], but this was not confirmed in three beta-blocker RCTs [pooled RCT growth rate difference: -0.05 mm/year (-0.16 to 0.05)]. Statins have been evaluated in two cohort studies that yield a pooled growth rate difference of -2.97 (-5.83 to -0.11). Doxycycline and roxithromycin have been evaluated in two RCTs that suggest possible benefit [pooled RCT growth rate difference: -1.32 mm/year (-2.89 to 0.25)]. Studies assessing NSAIDs, diuretics, calcium channel blockers and ACE inhibitors, meanwhile, did not find statistically significant differences. CONCLUSIONS: Beta-blockers do not appear to significantly reduce the growth rate of AAAs. Statins and other anti-inflammatory agents appear to hold promise for decreasing the expansion rate of AAA, but need further evaluation before definitive recommendations can be made

The spontaneous release of a high-molecular-weight aggregate containing immunoglobulin G from the surface of Ehrlich ascites tumor cells

The spontaneous release of tumor cell antigens from the cell surface into the circulation has been proposed as a mechanism whereby tumors may escape the immune response of the host. In this study we have found that Ehrlich ascites tumor cells after removal from the host (mouse) spontaneously release significant amounts of cell surface components during incubation for 1 h in cold isotonic buffer. Immunodiffusion studies revealed that immunoglobulin G (IgG) and a complement component (C3) are included in this spontaneously released material. These surface-bound humoral immune components are apparently released in the form of a high-molecular-weight aggregate (cell coat particle) as shown by ultracentrifugation and ultrafiltration experiments. Precipitation of IgG from the cell coat particle preparation with antibodies directed against mouse IgG followed by detergent gel electrophoresis of the immune precipitate revealed five major bands in addition to the heavy and light chains of IgG. These results suggest that host IgG is tightly bound to several other components at the cell surface, perhaps in the form of immune complexes. IgG is localized on the tumor cell surface in a highly heterogeneous pattern with the appearance of patches and caps in some cells as shown by immuno-fluorescence analysis. The possibility that humoral immune components bind to the tumor cell surface and result in the shedding of high-molecular-weight aggregates of cell surface antigens into extracellular fluids is discussed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38207/1/400090311_ftp.pd

CTCF cis-Regulates Trinucleotide Repeat Instability in an Epigenetic Manner: A Novel Basis for Mutational Hot Spot Determination

At least 25 inherited disorders in humans result from microsatellite repeat expansion. Dramatic variation in repeat instability occurs at different disease loci and between different tissues; however, cis-elements and trans-factors regulating the instability process remain undefined. Genomic fragments from the human spinocerebellar ataxia type 7 (SCA7) locus, containing a highly unstable CAG tract, were previously introduced into mice to localize cis-acting “instability elements,” and revealed that genomic context is required for repeat instability. The critical instability-inducing region contained binding sites for CTCF—a regulatory factor implicated in genomic imprinting, chromatin remodeling, and DNA conformation change. To evaluate the role of CTCF in repeat instability, we derived transgenic mice carrying SCA7 genomic fragments with CTCF binding-site mutations. We found that CTCF binding-site mutation promotes triplet repeat instability both in the germ line and in somatic tissues, and that CpG methylation of CTCF binding sites can further destabilize triplet repeat expansions. As CTCF binding sites are associated with a number of highly unstable repeat loci, our findings suggest a novel basis for demarcation and regulation of mutational hot spots and implicate CTCF in the modulation of genetic repeat instability

Logistics of community smallpox control through contact tracing and ring vaccination: a stochastic network model

BACKGROUND: Previous smallpox ring vaccination models based on contact tracing over a network suggest that ring vaccination would be effective, but have not explicitly included response logistics and limited numbers of vaccinators. METHODS: We developed a continuous-time stochastic simulation of smallpox transmission, including network structure, post-exposure vaccination, vaccination of contacts of contacts, limited response capacity, heterogeneity in symptoms and infectiousness, vaccination prior to the discontinuation of routine vaccination, more rapid diagnosis due to public awareness, surveillance of asymptomatic contacts, and isolation of cases. RESULTS: We found that even in cases of very rapidly spreading smallpox, ring vaccination (when coupled with surveillance) is sufficient in most cases to eliminate smallpox quickly, assuming that 95% of household contacts are traced, 80% of workplace or social contacts are traced, and no casual contacts are traced, and that in most cases the ability to trace 1–5 individuals per day per index case is sufficient. If smallpox is assumed to be transmitted very quickly to contacts, it may at times escape containment by ring vaccination, but could be controlled in these circumstances by mass vaccination. CONCLUSIONS: Small introductions of smallpox are likely to be easily contained by ring vaccination, provided contact tracing is feasible. Uncertainties in the nature of bioterrorist smallpox (infectiousness, vaccine efficacy) support continued planning for ring vaccination as well as mass vaccination. If initiated, ring vaccination should be conducted without delays in vaccination, should include contacts of contacts (whenever there is sufficient capacity) and should be accompanied by increased public awareness and surveillance