Health effects following subacute exposure to geogenic dust collected from active drainage surfaces (Nellis Dunes Recreation Area, Las Vegas, NV)

The specific health effects of direct inhalation of fine minerogenic dusts generated by natural soil surfaces remain poorly known and relatively little researched. To learn more about this exposure and its contri- bution to human health effects, we surveyed surface sediment and characterized dust from the Nellis Dunes Recreation Area (NDRA) in Clark County, Nevada, a popular off-road vehicle (ORV) recreational site. Dry drainage systems at NDRA are commonly used as natural trail systems for ORV recreation; these surfaces also are characterized by high concentrations of heavy metals. Geogenic dust with a median diameter of 4.05 ô°‚m, collected from drainage surfaces at NDRA contained a total elemental concentra- tion of aluminum (79,651 ô°‚g/g), vanadium (100 ô°‚g/g), chromium (54 ô°‚g/g), manganese (753 ô°‚g/g), iron (33,266 ô°‚g/g), cobalt (14 ô°‚g/g), copper (37 ô°‚g/g) zinc (135 ô°‚g/g), arsenic (71 ô°‚g/g), strontium (666 ô°‚g/g), cesium (15 ô°‚g/g), lead (34 ô°‚g/g), and uranium (54.9 ô°‚g/g). Adult female B6C3F1 mice exposed via oropha- ryngeal aspiration to 0.01--100mgdust/kg body weight, four times, a week apart, for 28-days, were evaluated for immuno- and neurotoxicological outcomes 24 h after the last exposure. Antigen-specific IgM responses were dose-responsively suppressed at 0.1, 1.0, 10 and 100 mg/kg. Splenic lymphocytic subpopulations, hematological and clinical chemistry parameters were affected. In brain tissue, antibod- ies against NF-68, and GFAP were not affected, whereas IgM antibodies against MBP were reduced by 26.6% only in the highest dose group. A lowest observed adverse effect level (LOAEL) of 0.1 mg/kg/day and a no observed adverse effect level (NOAEL) of 0.01 mg/kg/day were derived based on the antigen primary IgM responses after subacute exposure to this geogenic dust

Health effects from exposure to atmospheric mineral dust near Las Vegas, NV, USA

Desert areas are usually characterized by a continuous deposition of fine airborne particles. Over time, this process results in the accumulation of silt and clay on desert surfaces. We evaluated health effects associated with regional atmospheric dust, or geogenic dust, deposited on surfaces in the Nellis Dunes Recreation Area (NDRA) in Clark County, Nevada, a popular off-road vehicle (ORV) recreational site frequented daily by riders, families, and day campers. Because of atmospheric mixing and the mostly regional origin of the accumulated particles, the re-suspended airborne dust is composed of a complex mixture of minerals and metals including aluminum, vanadium, chromium, manganese, iron, cobalt, copper, zinc, arsenic, strontium, cesium, lead, uranium, and others. Geogenic dust with a median diameter of 4.1 μm was administered via oropharyngeal aspiration to female B6C3F1 mice at doses of 0.01 to 100 mg dust/kg body weight, four times, a week apart, for 28-days. Immuno- and neurotoxicological outcomes 24 h following the last exposure were evaluated. Antigen-specific IgM responses were dose-responsively suppressed at 0.1, 1.0, 10 and 100 mg/kg/day. Splenic and thymic lymphocytic subpopulations and natural killer cell activity also were significantly reduced. Antibodies against MBP, NF-68, and GFAP were not affected, while brain CD3+ T cells were decreased in number. A lowest observed adverse effect level (LOAEL) of 0.1 mg/kg/day and a no observed adverse effect level (NOAEL) of 0.01 mg/kg/day were derived based on the antigen-specific IgM responses

Health effects following subacute exposure to geogenic dust collected from active drainage surfaces (Nellis Dunes Recreation Area, Las Vegas, NV)

The specific health effects of direct inhalation of fine minerogenic dusts generated by natural soil surfaces remain poorly known and relatively little researched. To learn more about this exposure and its contri- bution to human health effects, we surveyed surface sediment and characterized dust from the Nellis Dunes Recreation Area (NDRA) in Clark County, Nevada, a popular off-road vehicle (ORV) recreational site. Dry drainage systems at NDRA are commonly used as natural trail systems for ORV recreation; these surfaces also are characterized by high concentrations of heavy metals. Geogenic dust with a median diameter of 4.05 �m, collected from drainage surfaces at NDRA contained a total elemental concentra- tion of aluminum (79,651 �g/g), vanadium (100 �g/g), chromium (54 �g/g), manganese (753 �g/g), iron (33,266 �g/g), cobalt (14 �g/g), copper (37 �g/g) zinc (135 �g/g), arsenic (71 �g/g), strontium (666 �g/g), cesium (15 �g/g), lead (34 �g/g), and uranium (54.9 �g/g). Adult female B6C3F1 mice exposed via oropha- ryngeal aspiration to 0.01–100mgdust/kg body weight, four times, a week apart, for 28-days, were evaluated for immuno- and neurotoxicological outcomes 24 h after the last exposure. Antigen-specific IgM responses were dose-responsively suppressed at 0.1, 1.0, 10 and 100 mg/kg. Splenic lymphocytic subpopulations, hematological and clinical chemistry parameters were affected. In brain tissue, antibod- ies against NF-68, and GFAP were not affected, whereas IgM antibodies against MBP were reduced by 26.6% only in the highest dose group. A lowest observed adverse effect level (LOAEL) of 0.1 mg/kg/day and a no observed adverse effect level (NOAEL) of 0.01 mg/kg/day were derived based on the antigen primary IgM responses after subacute exposure to this geogenic dust

Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis

BackgroundThere are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood-brain barrier, with potential salutary effects in progressive multiple sclerosis.MethodsWe enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (≤100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis.ResultsOf 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression.ConclusionsIn a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942 .)

Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis

BackgroundThere are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood-brain barrier, with potential salutary effects in progressive multiple sclerosis.MethodsWe enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (≤100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis.ResultsOf 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression.ConclusionsIn a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942 .)

Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis

BACKGROUND: Primary and secondary progressive multiple sclerosis (MS), collectively called progressive multiple sclerosis (PMS), is characterized by gradual progression of disability. The current anti-inflammatory treatments for MS have little or no efficacy in PMS in the absence of obvious active inflammation. Optimal biomarkers for phase II PMS trials is unknown. Ibudilast is an inhibitor of macrophage migration inhibitor factor and phosphodiesterases-4 and -10 and exhibits possible neuroprotective properties. The goals of SPRINT-MS study are to evaluate the safety and efficacy of ibudilast in PMS and to directly compare several imaging metrics for utility in PMS trials. METHODS: SPRINT-MS is a randomized, placebo-controlled, phase II trial of ibudilast in patients with PMS. Eligible subjects were randomized 1:1 to receive either ibudilast (100 mg/day) or placebo for 96 weeks. Imaging is conducted every 24 weeks for whole brain atrophy, magnetization transfer ratio, diffusion tensor imaging, cortical brain atrophy, and retinal nerve fiber layer thickness. Clinical outcomes include neurologic disability and patient reported quality of life. Safety assessments include laboratory testing, electrocardiography, and suicidality screening. RESULTS: A total of 331 subjects were enrolled, of which 255 were randomized onto active study treatment. Randomized subjects were 53.7% female and mean age 55.7 (SD 7.3) years. The last subject is projected to complete the study in May 2017. CONCLUSION: SPRINT-MS is designed to evaluate the safety and efficacy of ibudilast as a treatment for PMS while simultaneously validating five different imaging biomarkers as outcome metrics for use in future phase II proof-of-concept PMS trials