Engineering and public health at CDC

Engineering is the application of scientific and technical knowledge to solve human problems. Using imagination, judgment, and reasoning to apply science, technology, mathematics, and practical experience, engineers develop the design, production, and operation of useful objects or processes. During the 1940s, engineers dominated the ranks of CDC scientists. In fact, the first CDC director, Assistant Surgeon General Mark Hollis, was an engineer. CDC engineers were involved in malaria control through the elimination of standing water. Eventually the CDC mission expanded to include prevention and control of dengue, typhus, and other communicable diseases. The development of chlorination, water filtration, and sewage treatment were crucial to preventing waterborne illness. Beginning in the 1950s, CDC engineers began their work to improve public health while developing the fields of environmental health, industrial hygiene, and control of air pollution. Engineering disciplines represented at CDC today include biomedical, civil, chemical, electrical, industrial, mechanical, mining, and safety engineering. Most CDC engineers are located in the National Institute for Occupational Safety and Health (NIOSH) and the Agency for Toxic Substances and Disease Registry (ATSDR). Engineering research at CDC has a broad stakeholder base. With the cooperation of industry, labor, trade associations, and other stakeholders and partners, current work includes studies of air contaminants, mining, safety, physical agents, ergonomics, and environmental hazards. Engineering solutions remain a cornerstone of the traditional "hierarchy of controls" approach to reducing public health hazards.     

Using healthy community design data to monitor and inform planning and public policy

SettingIn Ontario, Public Health is mandated to work with municipal partners to inform and collaborate on built environment initiatives. For the Healthy Community Design (HCD) Baseline project, Public Health partnered with three communities (approximately 132,000, 29,000 and 22,000 residents, respectively).InterventionThe HCD Baseline Project created a baseline of HCD indicators containing spatial data and self-reported behaviour and perception data. Tailored indicators were determined collaboratively between Public Health and municipal planning staff. Physical HCD indicator data were collected and mapped spatially, while primary data collected from a Neighbourhood Design Survey provided residents’ perceptions of HCD and reported behaviour.OutcomesThe HCD Baseline Project produced a data monitoring system to: track progress of HCD indicators as communities grow; measure current community design to identify municipal and public health priorities, including public policy and supportive environments; and assess the impact of future HCD interventions on the community. By compiling spatial and perception data, areas of strength and opportunity guided the collaborative development of tailored recommendations for each community.ImplicationsFindings from the HCD Baseline Project have created a stronger position for Public Health to support local municipalities. Recommendations are guiding collaborative, evidence-informed initiatives and informing local land use planning and related supportive environment policy. Data collection will be repeated in 5, 10 and 15 years to monitor trends and impact on community design.     

Use of nonexclusionary timeout for the elimination of a stereotyped behavior

The purpose of the present study was to investigate the effectiveness of a nonexclusionary timeout procedure in reducing a high-frequency stereotyped behavior in a 28-year-old profoundly mentally retarded and autistic male. The experimental design consisted of baseline (A), treatment (B), and 1- and 6-month follow-up studies. After 2 weeks of treatment, the target behavior was reduced to a virtually zero rate of occurrence and the low rate of response was maintained throughout follow-up. Findings suggest that nonexclusionary timeout may prove to be a cost-effective intervention for reducing or eliminating disruptive stereotyped behaviors. The need for further research is indicated.     

Neuroprotective efficacy of aminopropyl carbazoles in a mouse model of amyotrophic lateral sclerosis

We previously reported the discovery of P7C3, an aminopropyl carbazole having proneurogenic and neuroprotective properties in newborn neural precursor cells of the hippocampal dentate gyrus. We have further found that chemicals having efficacy in this in vivo screening assay also protect dopaminergic neurons of the substantia nigra following exposure to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a mouse model of Parkinson disease. Here, we provide evidence that an active analog of P7C3, known as P7C3A20, protects ventral horn spinal cord motor neurons from cell death in the G93A-SOD1 mutant mouse model of amyotrophic lateral sclerosis (ALS). P7C3A20 is efficacious in this model when administered at disease onset, and protection from cell death correlates with preservation of motor function in assays of walking gait and in the accelerating rotarod test. The prototypical member of this series, P7C3, delays disease progression in G93A-SOD1 mice when administration is initiated substantially earlier than the expected time of symptom onset. Dimebon, an antihistaminergic drug with significantly weaker proneurogenic and neuroprotective efficacy than P7C3, confers no protection in this ALS model. We propose that the chemical scaffold represented by P7C3 and P7C3A20 may provide a basis for the discovery and optimization of pharmacologic agents for the treatment of ALS.Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a relatively rare, adult-onset, rapidly progressive and fatal disease that involves degeneration of spinal cord motor neurons (1). This disorder causes muscle weakness and atrophy throughout the body, and patients with ALS ultimately lose all voluntary movement. The earliest parts of the body affected in ALS reflect those motor neurons that are damaged first. Regardless of the region of onset, however, muscle weakness and atrophy invariably spread to other parts of the body as the disease progresses. Although disease progression varies between individuals, most patients are eventually unable to stand or walk, get in or out of bed on their own, or use their hands and arms. Difficulty with chewing, swallowing, and breathing leads to progressive weight loss and increased risk of choking and aspiration pneumonia. Toward the end stages of disease, as the diaphragm and intercostal muscles weaken, most patients require ventilator support. Individuals with ALS most commonly die of respiratory failure or pneumonia within 2–5 y of diagnosis. There are no current treatments for ALS.Approximately 20% of inherited cases of ALS, and 3% of sporadic cases, are associated with autosomal dominant mutations in the SOD1 gene on chromosome 21 (2–4), and about 150 different mutations dispersed throughout the gene have been identified thus far (5). SOD1 encodes cytosolic Cu/Zn superoxide dismutase, an antioxidant enzyme that protects cells by converting superoxide (a toxic free radical generated through normal metabolic activity of mitochondria) to hydrogen peroxide. Unchecked, free radicals damage both mitochondrial and nuclear DNA, as well as proteins within cells. In ALS linked to mutations in SOD1, cytotoxicity of motor neurons appears to result from a gain of toxic SOD1 function, rather than from loss of dismutase activity. Although the exact molecular mechanisms underlying toxicity are unclear, mutation-induced conformational changes in SOD1 lead to misfolding and subsequent aggregation of mutant SOD1 in cell bodies and axons (6–10). Aggregate accumulation of mutant SOD1 is thought to disrupt cellular functions and precipitate neuron death by damaging mitochondria, proteasomes, protein-folding chaperones, or other proteins (10).Transgenic animal models of mutant SOD1, such as G93A-SOD1 mutant mice, are currently used for research into the pathogenic mechanisms thought to broadly underlie ALS. Mice hemizygous for the G93A-SOD1 transgene express 18 ± 2.6 copies of a form of SOD1 found in some patients with inherited ALS (a substitution of glycine to alanine at codon 93). This was the first mutant form of SOD1 to be expressed in mice and is the most widely used and well-characterized mouse model of ALS. Superoxide dismutase activity in these mice is intact, and the pathogenic effect of the mutant transgene appears to be gain of function, as is thought to occur in human patients (11). Death of motor neurons in these mice occurs in the ventral horn of the spinal cord and is associated with paralysis and muscle atrophy (12). Around 100 d of age, G93A-SOD1 mice characteristically experience the onset of paralysis in one or more limbs, due to loss of spinal cord motor neurons. Paralysis spreads rapidly throughout the body, culminating in death of 50% of the mice within 7 wk of disease onset.We have previously reported the identification of a proneurogenic, neuroprotective aminopropyl carbazole (P7C3) discovered through a target-agnostic in vivo screen of postnatal hippocampal neurogenesis (13). Prolonged administration of P7C3 to mice suffering from pathologically high levels of neuronal apoptosis in the dentate gyrus (14) safely restored hippocampal structure and function with no observable physiologic side effects (13). Furthermore, extended administration of P7C3 to aged rats impeded hippocampal cell death and preserved cognitive ability as a function of terminal aging (13).We have synthesized and characterized a variant of P7C3, known as P7C3A20, which has greater potency and proneurogenic efficacy than the parent compound. P7C3A20 differs structurally by replacement of the hydroxyl group at the chiral center of the linker with a fluorine and the addition of a methoxy group to the aniline ring. P7C3A20 also displays a more favorable toxicity profile than P7C3, with no hERG channel binding, histamine receptor binding, or toxicity to HeLa cells (13, 15, 16). We have also found that Dimebon, an antihistaminergic drug that is reported to have anti-apoptotic and mitochondrial protective properties (17, 18), displays modest efficacy in the same biologic assays used to discover and characterize P7C3 and P7C3A20. However, it does so with substantially less potency and ceiling of efficacy (CoE) (13).Armed with three related chemicals, one having very high proneurogenic activity (P7C3A20), one having intermediate activity (P7C3), and one having only modest activity (Dimebon), we initiated efficacy studies in two animal models of neurodegenerative disease. In our companion article (19), we report evidence of significant neuroprotective activity of P7C3A20 in a rodent model of Parkinson disease (PD). P7C3 exhibited intermediate activity in the PD animal model, and Dimebon showed no evidence of efficacy. The correlative activities of chemicals tested in the neurogenesis and PD assays were extended to eight additional analogs of P7C3. In every case, derivatives of P7C3 that were active in the neurogenesis assay were also active in the animal model of PD, and inactive variants were inactive in both assays (19).Here, we have used the same approach to score the activities of P7C3A20, P7C3, and Dimebon in a model of neuron death outside of the brain. To address this question, we used G93A-SOD1 mutant mice, a model of ALS characterized by spinal motor neuron death associated with decreased motor functioning. As was observed for the rodent model of PD, we hereby report robust activity of P7C3A20 in the G93A-SOD1 mouse model of ALS, intermediate activity for P7C3, and no activity for Dimebon.     

Separate critical periods exist for testosterone-induced differentiation of the brain and genitals in sheep

Sheep exposed to testosterone during a critical period from gestational day (GD) 30 to GD 90 develop masculine genitals and an enlarged male-typical ovine sexually dimorphic nucleus of the preoptic area (oSDN). The present study tested the hypothesis that separate critical periods exist for masculinization of these two anatomical end points. Pregnant ewes were treated with testosterone propionate (TP) either from GD 30 to GD 60 (early TP) or GD 60 to GD 90 (late TP). Control (C) pregnant ewes were treated with corn oil. Fetuses were delivered at GD 135 and the volume of the oSDN was measured. Early TP females possessed a penis and a scrotum devoid of testes, whereas late TP and C females had normal female genitals. Neither period of TP exposure grossly affected the genitals of male fetuses. Despite masculinized genitals, the mean volume of the oSDN in early TP females (0.32 ± 0.06 mm3) was not different from C females (0.24 ± 0.02 mm3) but was significantly enlarged in late TP females (0.49 ± 0.04 mm3; P < 0.05 vs. C) when the genitals appeared normal. In contrast, the volume of the oSDN in late TP males (0.51 ± 0.02 mm3) was not different from C males (0.51 ± 0.04 mm3) but was significantly smaller in the early TP males (0.35 ± 0.04 mm3; P < 0.05 vs. C). These results demonstrate that the prenatal critical period for androgen-dependent differentiation of the oSDN occurs later than, and can be separated temporally from, the period for development of masculine genitals.     

Comparison of air sampling methods for aerosolized spores of B. anthracis Sterne

Bacillus anthracis Sterne spores were aerosolized within a chamber at concentrations ranging from 1 x 103 to 1.7 x 10? spores per cubic meter of air (particles (p)/m3) to compare three different sampling methods: Andersen samplers, gelatin filters, and polytetrafluoroethylene (PTFE) membrane filters. Three samples of each type were collected during each of 19 chamber runs. Chamber concentration was determined by an aerodynamic particle sizer (APS) for the size range of 1.114-1.596 μm. Runs were categorized (low, medium, and high) based on tertiles of the APS estimated air concentrations. Measured air concentrations and recovery efficiency [ratio of the measured (colony forming units (CFU)/m3) to the APS estimated (particles/m3) air concentrations] for the sampling methods were compared using mixed-effects regression models. Limits of detection for each method were estimated based on estimated recovery efficiencies. Mean APS estimated air concentrations were 1600 particles/m3, 4100 particles/m3, and 9100 particles/m3 at the low, medium, and high tertiles, respectively; coefficient of variation (CV) ranged from 25 to 40%. Statistically significant differences were not observed among the three sampling methods. At the high and medium tertiles, estimated correlations of measured air concentration (CFU/m3) among samples collected from the same run of the same type were high (0.73 to 0.93). Among samples collected from the same run but of different types, correlations were moderate to high (0.45 to 0.85); however, correlations were somewhat lower at the low tertile (-0.31 to 0.75). Estimated mean recovery efficiencies ranged from 0.22 to 0.25 CFU/particle with total CVs of approximately 84 to 97%. Estimated detection limits ranged from 35 to 39 particles/m3. These results will enable investigators to conduct environmental sampling, quantify contamination levels, and conduct risk assessments of B. anthracis.     

Role of the soft palate in laryngeal functions and selected voice qualities. Simultaneous velolaryngeal videoendoscopy

The role of the soft palate in normal laryngeal functions and in the production of selected voice qualities was studied by a simultaneous velolaryngeal videoendoscopy technique. For this technique, the Olympus ENF-P flexible nasopharyngolaryngoscope was passed via one nostril to study the function of the larynx, while the Hopkins 70 degrees rhinoscopic telescope was passed via the other nostril to study the function of the soft palate and velopharyngeal closure. A Kay Elemetrics DSP Sona-Graph, model 5500, was used to analyze a complex vocal figure of five consecutive voice qualities, three of which were nasal, and two, oral. Simultaneous velolaryngeal videoendoscopy proved to be of great value for the understanding of the interaction of velar and laryngeal functions and for clarifying the mechanisms of nasal and twang qualities.     

Supraglottic contributions to pitch raising. Videoendoscopic study with spectroanalysis

Several questions pertaining to pitch raising recur frequently. Does the larynx rise with the production of higher frequencies? What happens to the pharyngeal walls between the soft palate and the larynx when the fundamental frequency is raised? How does the soft palate participate in pitch raising? To answer these questions, the present study was undertaken with the recently described simultaneous velolaryngeal endoscopy technique. Nine professional singers were asked to find the limits of their vocal range in any of six voice qualities: speech, falsetto, cry/sob, twang, belting, and opera. Simultaneous activities of the larynx, the pharyngeal walls, and the soft palate were submitted to videoendoscopy with synchronous voice recording and studied with spectroanalysis of discrete segments of the total phonation range. Our dual endoscopic study showed that 1) the larynx rose in all subjects with the production of higher frequencies, 2) with the highest fundamental frequency, the lateral pharyngeal walls significantly contracted toward the midline in an "upside-down V shape," creating a very narrow pharyngeal tube, and 3) the soft palate lifted and the velopharyngeal port narrowed considerably with higher frequencies.     

An SNP resource for rice genetics and breeding based on subspecies indica and japonica genome alignments

Dense coverage of the rice genome with polymorphic DNA markers is an invaluable tool for DNA marker-assisted breeding, positional cloning, and a wide range of evolutionary studies. We have aligned drafts of two rice subspecies, indica and japonica, and analyzed levels and patterns of genetic diversity. After filtering multiple copy and low quality sequence, 408,898 candidate DNA polymorphisms (SNPs/INDELs) were discerned between the two subspecies. These filters have the consequence that our data set includes only a subset of the available SNPs (in particular excluding large numbers of SNPs that may occur between repetitive DNA alleles) but increase the likelihood that this subset is useful: Direct sequencing suggests that 79.8% +/- 7.5% of the in silico SNPs are real. The SNP sample in our database is not randomly distributed across the genome. In fact, 566 rice genomic regions had unusually high (328 contigs/48.6 Mb/13.6% of genome) or low (237 contigs/64.7 Mb/18.1% of genome) polymorphism rates. Many SNP-poor regions were substantially longer than most SNP-rich regions, covering up to 4 Mb, and possibly reflecting introgression between the respective gene pools that may have occurred hundreds of years ago. Although 46.2% +/- 8.3% of the SNPs differentiate other pairs of japonica and indica genotypes, SNP rates in rice were not predictive of evolutionary rates for corresponding genes in another grass species, sorghum. The data set is freely available at http://www.plantgenome.uga.edu/snp.