cAMP signaling in brain is decreased in unmedicated depressed patients and increased by treatment with a selective serotonin reuptake inhibitor.

Basic studies exploring the importance of the cyclic adenosine monophosphate (cAMP) cascade in major depressive disorder (MDD) have noted that the cAMP cascade is downregulated in MDD and upregulated by antidepressant treatment. We investigated cAMP cascade activity by using 11C-(R)-rolipram to image phosphodiesterase-4 (PDE4) in unmedicated MDD patients and after ~8 weeks of treatment with a selective serotonin reuptake inhibitor (SSRI). 11C-(R)-rolipram positron emission tomographic (PET) scans were performed in 44 unmedicated patients during a major depressive episode and 35 healthy controls. Twenty-three of the 44 patients had a follow-up 11C-(R)-rolipram PET scan ~8 weeks after treatment with an SSRI. Patients were moderately depressed (Montgomery-Åsberg Depression Rating Scale=30±6) and about half were treatment naïve. 11C-(R)-rolipram binding was measured using arterial sampling to correct for individual differences in radioligand metabolism. We found in unmedicated MDD patients widespread, ~20% reductions in 11C-(R)-rolipram binding compared with controls (P=0.001). SSRI treatment significantly increased rolipram binding (12%, P<0.001), with significantly greater increases observed in older patients (P<0.001). Rolipram binding did not correlate with severity of baseline symptoms, and increased rolipram binding during treatment did not correlate with symptom improvement. In brief, consistent with the results of basic studies, PDE4 was decreased in unmedicated MDD patients and increased after SSRI treatment. The lack of correlation between PDE4 binding and depressive symptoms could reflect the heterogeneity of the disease and/or the heterogeneity of the target, given that PDE4 has four subtypes. These results suggest that PDE4 inhibitors, which increase cAMP cascade activity, may have antidepressant effects.

Does the effect of smoking on fractional exhaled nitric oxide vary by race in adults in a US National Survey?

No disponible

Magnetic resonance imaging assessment of the ventricular system in the brains of adult and juvenile beagle dogs treated with posaconazole IV Solution.

INTRODUCTION: Noxafil® (posaconazole; POS) is a potent, selective triazole antifungal approved for use in adults as an oral suspension, oral tablet and intravenous (IV) Solution. In support of pediatric administration of POS IV Solution to childrentwo years of age, two studies were undertaken using magnetic resonance imaging (MRI) to monitor brain ventricle size longitudinally during three months administration of POS IV in adult and juvenile dogs. Necropsy was performed on all animals at the end of the studies. From the baseline MRI images, great variability in ventricle size was noted in both the adult and juvenile dogs; these images were used to distribute differently sized ventricles between treatment and vehicle groups as to not skew group means during the course of the study. RESULTS: POS IV Solution had no effect on ventricle volume at any timepoint during dosing in either the adult or the juvenile dogs. Further, no gross or histomorphologic differences between groups were observed in either study. Compared to juvenile dogs, MRI analysis showed that adult dogs had larger ventricles, lower variability in all ventricle volumes, and a greater rate of increase in total ventricle volume. DISCUSSION: Information on growth and development of brains is one of the few areas in which more detailed information is available about humans than about the standard laboratory animals used to model disease and predict toxicities. The use of MRI helped elucidate large natural variabilities in the dog brain, which could have altered the interpretation of this de-risking study, and provided a valuable noninvasive means to monitor the brain ventricles longitudinally.

Investing in prospective cohorts for etiologic study of occupational exposures.

Prospective cohorts have played a major role in understanding the contribution of diet, physical activity, medical conditions, and genes to the development of many diseases, but have not been widely used for occupational exposures. Studies in agriculture are an exception. We draw upon our experience using this design to study agricultural workers to identify conditions that might foster use of prospective cohorts to study other occupational settings. Prospective cohort studies are perceived by many as the strongest epidemiologic design. It allows updating of information on exposure and other factors, collection of biologic samples before disease diagnosis for biomarker studies, assessment of effect modification by genes, lifestyle, and other occupational exposures, and evaluation of a wide range of health outcomes. Increased use of prospective cohorts would be beneficial in identifying hazardous exposures in the workplace. Occupational epidemiologists should seek opportunities to initiate prospective cohorts to investigate high priority, occupational exposures.

Reduced cannabinoid CB1 receptor binding in alcohol dependence measured with positron emission tomography.

Brain cannabinoid CB1 receptors contribute to alcohol-related behaviors in experimental animals, but their potential role in humans with alcohol dependence is poorly understood. We measured CB1 receptors in alcohol dependent patients in early and protracted abstinence, and in comparison with control subjects without alcohol use disorders, using positron emission tomography and [(18)F]FMPEP-d2, a radioligand for CB1 receptors. We scanned 18 male in-patients with alcohol dependence twice, within 3-7 days of admission from ongoing drinking, and after 2-4 weeks of supervised abstinence. Imaging data were compared with those from 19 age-matched healthy male control subjects. Data were also analyzed for potential influence of a common functional variation (rs2023239) in the CB1 receptor gene (CNR1) that may moderate CB1 receptor density. On the first scan, CB1 receptor binding was 20-30% lower in patients with alcohol dependence than in control subjects in all brain regions and was negatively correlated with years of alcohol abuse. After 2-4 weeks of abstinence, CB1 receptor binding remained similarly reduced in these patients. Irrespective of the diagnostic status, C allele carriers at rs2023239 had higher CB1 receptor binding compared with non-carriers. Alcohol dependence is associated with a widespread reduction of cannabinoid CB1 receptor binding in the human brain and this reduction persists at least 2-4 weeks into abstinence. The correlation of reduced binding with years of alcohol abuse suggests an involvement of CB1 receptors in alcohol dependence in humans.

Addressing phase errors in fat-water imaging using a mixed magnitude/complex fitting method.

Accurate, noninvasive measurements of liver fat content are needed for the early diagnosis and quantitative staging of nonalcoholic fatty liver disease. Chemical shift-based fat quantification methods acquire images at multiple echo times using a multiecho spoiled gradient echo sequence, and provide fat fraction measurements through postprocessing. However, phase errors, such as those caused by eddy currents, can adversely affect fat quantification. These phase errors are typically most significant at the first echo of the echo train, and introduce bias in complex-based fat quantification techniques. These errors can be overcome using a magnitude-based technique (where the phase of all echoes is discarded), but at the cost of significantly degraded signal-to-noise ratio, particularly for certain choices of echo time combinations. In this work, we develop a reconstruction method that overcomes these phase errors without the signal-to-noise ratio penalty incurred by magnitude fitting. This method discards the phase of the first echo (which is often corrupted) while maintaining the phase of the remaining echoes (where phase is unaltered). We test the proposed method on 104 patient liver datasets (from 52 patients, each scanned twice), where the fat fraction measurements are compared to coregistered spectroscopy measurements. We demonstrate that mixed fitting is able to provide accurate fat fraction measurements with high signal-to-noise ratio and low bias over a wide choice of echo combinations.

Cytochrome P450 polymorphisms and the response of lupus nephritis to cyclophosphamide therapy.

BACKGROUND AND AIMS: The addition of cyclophosphamide to corticosteroids significantly improves the prognosis of severe kidney involvement in systemic lupus erythematosus (SLE). However, not all patients respond to cyclophosphamide. It has been suggested that genetic variations that reduce the metabolism of cyclophosphamide reduce its effectiveness. Cyclophosphamide is metabolized and activated by the cytochrome P450 (CYP) system and in particular CYP enzymes 2B6 and 2C19. Both CYP2B6 and CYP2C19 have variant alleles (CYP2B6*5 and CYP2C19*2) that attenuate or eliminate enzymatic activity. This investigation was done to determine the impact of CYP2B6*5 and CYP2C19*2 on the renal response in cyclophosphamide-treated lupus nephritis (LN) patients. METHODS: Patients with SLE (n = 237), unclassified autoimmune disease (n = 51), and healthy controls (n = 294) were genotyped for CYP2B6*5 and CYP2C19*2. Associations between these alleles and achievement of complete or partial response, development of end-stage renal disease, and time to remission were determined. RESULTS: The frequencies of the variant alleles CYP2B6*5 and CYP2C19*2 were 6.3 % and 15.9%, respectively. CYP2C19*2 genotypes were more frequent among African Americans than European Americans, and CYP2B6*5 genotypes were more frequent among European Americans than African Americans. Among LN patients treated with cyclophosphamide (n = 36), there were no differences between those with or without these genotypes relative to the frequency of complete or partial remissions or time to remission. CONCLUSION: This retrospective analysis failed to show an association between CYP2B6*5 and CYP2C19*2 and treatment outcomes in LN. This suggests that genotyping for these CYP450 variants may not be useful in individualizing treatment for severe LN.

Synthesis and X-ray structure determination of highly active Pd(II), Pd(I), and Pd(0) complexes of di(tert-butyl)neopentylphosphine (DTBNpP) in the arylation of amines and ketones.

The air-stable complex Pd(η(3)-allyl)(DTBNpP)Cl (DTBNpP = di(tert-butyl)neopentylphosphine) serves as a highly efficient precatalyst for the arylation of amines and enolates using aryl bromides and chlorides under mild conditions with yields ranging from 74% to 98%. Amination reactions of aryl bromides were carried out using 1-2 mol % Pd(η(3)-allyl)(DTBNpP)Cl at 23-50 °C without the need to exclude oxygen or moisture. The C-N coupling of the aryl chlorides occurred at relatively lower temperature (80-100 °C) and catalyst loading (1 mol %) using the Pd(η(3)-allyl)(DTBNpP)Cl precatalyst than the catalyst generated in situ from DTBNpP and Pd(2)(dba)(3) (100-140 °C, 2-5 mol % Pd). Other Pd(DTBNpP)(2)-based complexes, (Pd(DTBNpP)(2) and Pd(DTBNpP)(2)Cl(2)) were ineffective precatalysts under identical conditions for the amination reactions. Both Pd(DTBNpP)(2) and Pd(DTBNpP)(2)Cl(2) precatalysts gave nearly quantitative conversions to the product in the α-arylation of propiophenone with p-chlorotoluene and p-bromoanisole at a substrate/catalyst loading of 100/1. At lower substrate/catalyst loading (1000/1), the conversions were lower but comparable to that of Pd(t-Bu(3)P)(2). In many cases, the tri-tert-butylphosphine (TTBP) based Pd(I) dimer, [Pd(µ-Br)(TTBP)](2), stood out to be the most reactive catalyst under identical conditions for the enolate arylation. Interestingly, the air-stable Pd(I) dimer, Pd(2)(DTBNpP)(2)(µ-Cl)(µ-allyl), was less active in comparison to [Pd(µ-Br)(TTBP)](2) and Pd(η(3)-allyl)(DTBNpP)Cl. The X-ray crystal structures of Pd(η(3)-allyl)(DTBNpP)Cl, Pd(DTBNpP)(2)Cl(2), Pd(DTBNpP)(2), and Pd(2)(DTBNpP)(2)(µ-Cl)(µ-allyl) are reported in this paper along with initial studies on the catalyst activation of the Pd(η(3)-allyl)(DTBNpP)Cl precatalyst.

A general design platform for ionic liquid ions based on bridged multi-heterocycles with flexible symmetry and charge.

A conceptual design platform for new ionic liquids with variable heterocycles, bridges, symmetry, and charge was developed using simple alkylation, click, and ionic liquid chemistries and demonstrated with 1-(2-(5-tetrazolidyl)ethyl)-3-(5-1H-tetrazolyl)methylimidazolium and its conversion into room-temperature ionic liquids as cation or as anion.

Influence of exposure route and oral dosage regimen on 1, 1-dichloroethylene toxicokinetics and target organ toxicity.

The objective of this investigation was to elucidate the effects of route of exposure and oral dosage regimen on the toxicokinetics (TK) of 1,1-dichloroethylene (DCE). Fasted male Sprague-Dawley rats that inhaled 100 or 300 ppm for 2 h absorbed total systemic doses of (10 or 30 mg/kg DCE, respectively. Other groups of rats received 10 or 30 mg/kg DCE by intravenous injection, bolus gavage (by mouth), or gastric infusion (g.i.) over a 2-h period. Serial microblood samples were taken from the cannulated, unanesthetized animals and analyzed for DCE content by gas chromatography to obtain concentration versus time profiles. Inhalation resulted in substantially higher peak blood concentrations and area under blood-concentration time curves (AUC(0)(2)) than did gastric infusion of the same dose over the same time frame at each dosage level, although inhalation (AUC(0)(infinity)) values were only modestly higher. Urinary N-acetyl-beta-D-glucosaminidase (NAG) and gamma-glutamyltranspeptidase (GGT) activities were monitored as indices of kidney injury in the high-dose groups. NAG and GGT excretion were much more pronounced after inhalation than gastric infusion. Administration of DCE by gavage also produced much higher Cmax and AUC(0)(2) values than did 2-h g.i., although AUC(0)(infinity) values were not very different. The 30 mg/kg bolus dose produced marked elevation in serum sorbitol dehydrogenase, an index of hepatocellular injury. Administration of this dose by inhalation and gastric infusion was only marginally hepatotoxic. These findings demonstrate the TK and target organ toxicity of DCE vary substantially between different exposure routes, as well as dosage regimens, making direct extrapolations untenable in health risk assessments.

Ionic liquids based on azolate anions.

Compartmentalized molecular level design of new energetic materials based on energetic azolate anions allows for the examination of the effects of both cation and anion on the physiochemical properties of ionic liquids. Thirty one novel salts were synthesized by pairing diverse cations (tetraphenylphosphonium, ethyltriphenylphosphonium, N-phenyl pyridinium, 1-butyl-3-methylimidazolium, tetramethyl-, tetraethyl-, and tetrabutylammonium) with azolate anions (5-nitrobenzimidazolate, 5-nitrobenzotriazolate, 3,5-dinitro-1,2,4-triazolate, 2,4-dinitroimidazolate, 4-nitro-1,2,3-triazolate, 4,5-dinitroimidazolate, 4,5-dicyanoimidazolate, 4-nitroimidazolate, and tetrazolate). These salts have been characterized by DSC, TGA, and single crystal X-ray crystallography. The azolates in general are surprisingly stable in the systems explored. Ionic liquids were obtained with all combinations of the 1-butyl-3-methylimidazolium cation and the heterocyclic azolate anions studied, and with several combinations of tetraethyl- or tetrabutylammonium cations and the azolate anions. Favorable structure-property relationships were most often achieved when changing from 4- and 4,5-disubstituted anions to 3,5- and 2,4-disubstituted anions. The most promising anion for use in energetic ionic liquids of those studied here, was 3,5-dinitro-1,2,4-triazolate, based on its contributions to the entire set of target properties.

Ionic liquid-based routes to conversion or reuse of recycled ammonium perchlorate.

New, potentially green, and efficient synthetic routes for the remediation and/or re-use of perchlorate-based energetic materials have been developed. Four simple organic imidazolium- and phosphonium-based perchlorate salts/ionic liquids have been synthesized by simple, inexpensive, and nonhazardous methods, using ammonium perchlorate as the perchlorate source. By appropriate choice of the cation, perchlorate can be incorporated into an ionic liquid which serves as its own electrolyte for the electrochemical reduction of the perchlorate anion, allowing for the regeneration of the chloride-based parent ionic liquid. The electrochemical degradation of the hazardous perchlorate ion and its conversion to harmless chloride during electrolysis was studied using IR and (35)Cl NMR spectroscopies.

Using ionic liquids to trap unique coordination environments: polymorphic solvates of ErCl3(OH2)(4).2([C2mim]Cl).

Two polymorphs of ErCl(3)(OH(2))(4).2([C(2)mim]Cl) solvates were isolated from the same solution of 1-ethyl-3-methylimidazolium chloride when HCl(aq) was added, while [C(2)mim](3)[ErCl(6)] was isolated without HCl addition, illustrating how ionic liquids can be used to trap unusual coordination environments in the solid state.

Fungicide application practices and personal protective equipment use among orchard farmers in the agricultural health study.

Fungicides are routinely applied to deciduous tree fruits for disease management. Seventy-four private orchard applicators enrolled in the Agricultural Health Study participated in the Orchard Fungicide Exposure Study in 2002-2003. During 144 days of observation, information was obtained on chemicals applied and applicator mixing, application, personal protective, and hygiene practices. At least half of the applicators had orchards with <100 trees. Air blast was the most frequent application method used (55%), followed by hand spray (44%). Rubber gloves were the most frequently worn protective equipment (68% mix; 59% apply), followed by respirators (45% mix; 49% apply), protective outerwear (36% mix; 37% apply), and rubber boots (35% mix; 36% apply). Eye protection was worn while mixing and applying on only 35% and 41% of the days, respectively. Bivariate analyses were performed using repeated logistic or repeated linear regression. Mean duration of mixing, pounds of captan applied, total acres sprayed, and number of tank mixes sprayed were greater for air blast than for hand spray (p < 0.05). Spraying from a tractor/vehicle without an enclosed cab was associated with wearing some type of coverall (p < 0.05). Applicators often did not wash their hands after mixing (77%), a finding not explained by glove use. Glove use during mixing was associated with younger age, while wearing long-sleeve shirts was associated with older age (p < 0.05 each). Self-reported unusually high fungicide exposures were more likely on days applicators performed repairs (p < 0.05). These data will be useful for evaluating fungicide exposure determinants among orchard applicators.

An intermediate for the clean synthesis of ionic liquids: isolation and crystal structure of 1,3-dimethylimidazolium hydrogen carbonate monohydrate.

1,3-Dimethylimidazolium-2-carboxylate and carbonic acid have been used to prepare a 1,3-dimethylimidazolium hydrogen carbonate salt by means of a Krapcho reaction. The ability to form hydrogen carbonate azolium salts allows for them to be used as precursors for fast, efficient, environmentally benign, and halide-free syntheses of many ionic liquids by a simple, acid-base reaction of virtually any acid (inorganic, organic, and organic noncarboxylic) with a pK(a) less than that of HCO(3) (-). Additionally, the kinetics of this reaction can be accelerated by employing catalytic amounts of DMSO (a traditional Krapcho solvent used in decarboxylation reactions) to catalyze the decarboxylation. The crystal structure of 1,3-dimethylimidazolium hydrogen carbonate monohydrate is the first example of an imidazolium-based hydrogen carbonate salt. There is a strong 2D hydrogen-bonded network with facially pi-stacked imidazolium cations located in the cavities created by this framework.

Characterization of endotoxin and 3-hydroxy fatty acid levels in air and settled dust from commercial aircraft cabins.

Endotoxin was measured in air and dust samples collected during four commercial aircraft flights. Samples were analyzed for endotoxin biological activity using the Limulus assay. 3-hydroxy fatty acids (3-OH FA) of carbon chain lengths C10:0-C18:0 were determined in dust by gas chromatography-ion trap tandem mass spectrometry. The geometric mean (geometric standard deviation) endotoxin air level was 1.5 EU/m3 (1.9, n = 28); however, significant differences were found by flight within aircraft type. Mean endotoxin levels were significantly higher in carpet dust than in seat dust (140 +/- 81 vs. 51 +/- 25 EU/mg dust, n = 32 each, P < 0.001). Airborne endotoxin levels were not significantly related to either carpet or seat dust endotoxin levels. Mean 3-OH FA levels were significantly higher in carpet dust than in seat dust for C10:2, C12:0, and C14:0 (P < 0.001 for each), while the mean level of C16:0 was significantly higher in seat dust than in carpet dust (P < 0.01). Carpet dust endotoxin was significantly, but moderately, correlated with 3-OH-C12:0 and 3-OH-C14:0 (Pearson r = 0.52 and 0.48, respectively), while correlation of seat dust endotoxin with individual 3-OH FAs depended on the test statistic used. Mean endotoxin potency was significantly higher for carpet dust than for seat dust (6.3 +/- 3.0 vs. 3.0 +/- 1.4 EU/pmol LPS, P < 0.0001). Mean endotoxin levels in the air and dust of commercial aircraft cabins were generally higher than mean levels reported in homes and office buildings. These results suggest that exposure route and dust source are important considerations when relating endotoxin exposure to specific health outcomes.

Distribution of 2,4-D in air and on surfaces inside residences after lawn applications: comparing exposure estimates from various media for young children.

We collected indoor air, surface wipes (floors, table tops, and window sills), and floor dust samples at multiple locations within 11 occupied and two unoccupied homes both before and after lawn application of the herbicide 2,4-D. We measured residues 1 week before and after application. We used collected samples to determine transport routes of 2,4-D from the lawn into the homes, its subsequent distribution between the indoor surfaces, and air concentration as a function of airborne particle size. We used residue measurements to estimate potential exposures within these homes. After lawn application, 2,4-D was detected in indoor air and on all surfaces throughout all homes. Track-in by an active dog and by the homeowner applicator were the most significant factors for intrusion. Resuspension of floor dust was the major source of 2,4-D in indoor air, with highest levels of 2,4-D found in the particle size range of 2.5-10 microm. Resuspended floor dust was also a major source of 2,4-D on tables and window sills. Estimated postapplication indoor exposure levels for young children from nondietary ingestion may be 1-10 microg/day from contact with floors, and 0.2-30 microg/day from contact with table tops. These are estimated to be about 10 times higher than the preapplication exposures. By comparison, dietary ingestion of 2,4-D is approximately 1.3 microg/day.

Evaluation of acute sensory--motor effects and test sensitivity using termiticide workers exposed to chlorpyrifos.

Sensory and motor testing was performed on a group of termiticide workers primarily using chlorpyrifos-containing products to evaluate both the acute effects from current exposure and sensitivity of the measures to detect effects. The study group comprised 106 applicators and 52 nonexposed participants. Current exposure was measured by urinary concentrations of 3,5,6-trichloro-2-pyridinol (TCP) collected the morning of testing. The mean TCP value for the 106 applicators was 200 microg/g creatinine. Participants received 4--5 h of testing and were evaluated using a sensory--motor test battery recommended by a National Institute for Occupational Safety and Health (NIOSH)-sponsored advisory panel to be appropriate for testing effects from pesticide exposures. Measurements testing olfactory dysfunction, visual acuity, contrast sensitivity, color vision, vibrotactile sensitivity, tremor, manual dexterity, eye--hand coordination, and postural stability were analyzed. Study results indicated limited acute effects from exposure to chlorpyrifos using urinary TCP as a measure of current exposure. The effects occurred primarily on measures of postural sway in the eyes closed and soft-surface conditions, which suggests a possible subclinical effect involving the proprioceptive and vestibular systems. Several other tests of motor and sensory functions did not show any evidence of acute exposure effects, although statistically significant effects of urinary TCP on the Lanthony color vision test scores and one contrast sensitivity test score were found. The visual measures, however, were not significant when a step-down Bonferroni correction was applied. Information also is presented on the sensitivity of the measures to detect effects in an occupationally exposed population using standard error of the parameter estimates.

Development of sampling and analytical methods for concerted determination of commonly used chloroacetanilide, chlorotriazine, and 2,4-D herbicides in hand-wash, dermal-patch, and air samples.

Sampling and analytical methods were developed for commonly used chloroacetanilide, chlorotriazine, and 2,4-D herbicides in hand washes, on dermal patches, and in air. Eight herbicides selected for study were alachlor, atrazine, cyanazine, 2,4-dichlorophenoxyacetic acid (2,4-D), metolachlor, simazine, and two esters of 2,4-D, the 2-butoxyethyl ester (2,4-D, BE) and the 2-ethylhexyl ester (2,4-D, EH). The hand-wash method consisted of shaking the worker's hand in 150 mL of isopropanol in a polyethylene bag for 30 seconds. The dermal-patch method entailed attaching a 10-cm x 10-cm x 0.6-cm polyurethane foam (PUF) patch to the worker for exposure; recovery of the herbicides was achieved by extraction with 40 mL of isopropanol. The air method involved sampling with an OVS-2 tube (which contained an 11-mm quartz fiber filter and two beds of XAD-2 resin) and recovery with 2 mL of 10:90 methanol:methyl t-butyl ether. Analysis of each of the three sample types was performed by gas chromatography with an electron-capture detector. Diazomethane in solution was employed to convert 2,4-D as the free acid to the methyl ester in each of the three methods for ease of gas chromatography. Silicic acid was added to sample solutions to quench excess diazomethane. Limits of detection for all eight herbicides were matrix-dependent and, generally, less than 1 microgram per sample for each matrix. Sampling and analytical methods met NIOSH evaluation criteria for all herbicides in hand-wash samples, for seven herbicides in air samples (all herbicides except cyanazine), and for six herbicides in dermal-patch samples (all herbicides except cyanazine and 2,4-D). Speciation of 2,4-D esters and simultaneous determination of 2,4-D acid were possible without losses of the esters or of other herbicides (acetanilides and triazines) being determined.