A case-control study of occupational magnetic field exposure and Alzheimer's disease: results from the California Alzheimer's Disease Diagnosis and Treatment Centers

BACKGROUND: A few studies have investigated a possible relationship between Alzheimer's disease (AD) and occupations with extremely low frequency magnetic field (MF) exposure. The purpose of this study was to further evaluate this possible association in a large patient population with expert diagnoses. METHODS: Subjects came from the 8 of the 9 California Alzheimer's Disease Diagnostic and Treatment Centers not previously used in an earlier study. Cases had probable or definite AD; controls primarily had a dementia-related problem other than vascular dementia (VaD) and some were not demented upon expert examination. Occupations were classified as having low, medium or high MF exposure, based upon previous research, replicating the exposure methodology used in our previous published studies. RESULTS: Occupational information was available for 98.6% of the 1527 cases and 98.5% of the 404 controls with age-at-initial examination known to be at least 65. Among cases, 2.1% and 5.4% had high and medium occupational MF exposure, respectively, while among controls the percentages were 0.8% and 3.0%. In univariate analyses, the odds ratio (OR) for subjects with medium or high MF exposures combined was 2.1 (p < 0.01), while for high exposure alone the OR was 2.9 (p < 0.08). Two models were used in multivariate analyses, with gender, stroke, and either age-at-onset or age-at-initial examination as covariates. The ORs for MF exposure varied little between the two models: 2.2 (p < 0.02) and 1.9 (p < 0.03) for medium or high exposure; 2.7 (p < 0.11) and 3.2 (p < 0.12) for high exposure. OR estimates for females were higher than for males, but not significantly higher. There were no material differences between the ORs resulting from univariate and multivariate analyses. CONCLUSION: Elevated occupational MF exposure was associated with an increased risk of AD. Based on previous published studies, the results likely pertain to the general population

Diagnosis and Conservative Treatment of Skeletal Class III Malocclusion with Anterior Crossbite and Asymmetric Maxillary Crowding

A 28-year-9-month male presented for orthodontic consultation for skeletal Class III malocclusion (ANB -30) with a modest asymmetric Class II/III molar relationship, complicated by an anterior crossbite, deep bite, and 12mm of asymmetric maxillary crowding. Despite the severity of a malocclusion, Discrepancy Index (DI) = 37, the patient desired non-invasive camouflage treatment. Lin’s 3-Ring diagnosis revealed that treatment without extractions or orthognathic surgery was a viable approach. Arch length analysis indicated that differential interproximal enamel reduction (IPR) could resolve the crowding and midline discrepancy, but a miniscrew in the infrazygomatic crest (IZC) was needed to retract the right buccal segment. The patient accepted the complex, staged treatment plan with the understanding that it would require ~3.5 years. Fixed appliance treatment with passive self ligating (PSL) brackets, early light short elastics (ELSE), bite turbos (BTs), IPR, and IZC retraction opened the vertical dimension of occlusion (VDO), improved the ANB 20 and achieved an excellent alignment, as evidenced by a CRE of 26 and a Pink and White (P&W) dental esthetic score of 3. The worksheets for the DI, CRE, and P&W scores are attached within this case report

Probing the Outer Mouth Structure of the hERG Channel with Peptide Toxin Footprinting and Molecular Modeling

Abstract Previous studies have shown that the unusually long S5-P linker lining human ether a-go-go related gene’s (hERG’s) outer vestibule is critical for its channel function: point mutations at high-impact positions here can interfere with the inactivation process and, in many cases, also reduce the pore’s K+ selectivity. Because no data are available on the equivalent region in the available K channel crystal structures to allow for homology modeling, we used alternative approaches to model its three-dimensional structure. The first part of this article describes mutant cycle analysis used to identify residues on hERG’s outer vestibule that interact with specific residues on the interaction surface of BeKm-1, a peptide toxin with known NMR structure and a high binding affinity to hERG. The second part describes molecular modeling of hERG’s pore domain. The transmembrane region was modeled after the crystal structure of KvAP pore domain. The S5-P linker was docked to the transmembrane region based on data from previous NMR and mutagenesis experiments, as well as a set of modeling criteria. The models were further restrained by contact points between hERG’s outer vestibule and the bound BeKm-1 toxin molecule deduced from the mutant cycle analysis. Based on these analyses, we propose a working model for the open conformation of the outer vestibule of the hERG channel, in which the S5-P linkers interact with the pore loops to influence ion flux through the pore

Inferring stabilizing mutations from protein phylogenies : application to influenza hemagglutinin

One selection pressure shaping sequence evolution is the requirement that a protein fold with sufficient stability to perform its biological functions. We present a conceptual framework that explains how this requirement causes the probability that a particular amino acid mutation is fixed during evolution to depend on its effect on protein stability. We mathematically formalize this framework to develop a Bayesian approach for inferring the stability effects of individual mutations from homologous protein sequences of known phylogeny. This approach is able to predict published experimentally measured mutational stability effects (ΔΔG values) with an accuracy that exceeds both a state-of-the-art physicochemical modeling program and the sequence-based consensus approach. As a further test, we use our phylogenetic inference approach to predict stabilizing mutations to influenza hemagglutinin. We introduce these mutations into a temperature-sensitive influenza virus with a defect in its hemagglutinin gene and experimentally demonstrate that some of the mutations allow the virus to grow at higher temperatures. Our work therefore describes a powerful new approach for predicting stabilizing mutations that can be successfully applied even to large, complex proteins such as hemagglutinin. This approach also makes a mathematical link between phylogenetics and experimentally measurable protein properties, potentially paving the way for more accurate analyses of molecular evolution

Case report: novel PCDH15 variant causes usher syndrome type 1F with congenital hearing loss and syndromic retinitis pigmentosa

Background Usher syndrome (USH) is an autosomal recessive disorder primarily responsible for deaf-blindness. Patients with subtype Usher syndrome type 1 (USH1) typically experience congenital sensorineural hearing loss, abnormal vestibular function, and retinitis pigmentosa (RP). Here we present a case of Usher syndrome type 1F (USH1F) with a novel homozygous variant in the calcium-dependent cell-cell adhesion protocadherin-15 (PCDH15) gene. Case presentation Ophthalmic examinations were evaluated over a course of 10 years and the disease-causing variant was identified by whole exome sequencing (WES). Initial and follow-up examination of color fundus photos after 10 years revealed an increase in bone spicule pigment deposits in both eyes. A parafoveal hyper-AF ring in both eyes was shown in fundus autofluorescence (FAF) with a progressive diameter-wise constriction observed over 8 years. Outer nuclear layer (ONL) loss was observed in parafoveal and perifoveal regions of both eyes on spectral domain–optical coherence tomography (SD-OCT). Full-field electroretinography (ffERG) showed extinguished global retinal function. WES identified a novel two-base-pair deletion, c.60_61del (p.Phe21Ter), in the PCDH15 gene, confirming the diagnosis of USH1F. Conclusions We report a novel homozygous PCDH15 pathogenic variant expected to lead to nonsense-mediated decay (NMD) of PCDH15 mRNA. The patient exhibits a loss of function with USH1F, experiencing congenital hearing loss and syndromic RP

Observations of turbulence in the ocean surface boundary layer : energetics and transport

Author Posting. © American Meteorological Society, 2009. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 39 (2009): 1077–1096, doi:10.1175/2008JPO4044.1.Observations of turbulent kinetic energy (TKE) dynamics in the ocean surface boundary layer are presented here and compared with results from previous observational, numerical, and analytic studies. As in previous studies, the dissipation rate of TKE is found to be higher in the wavy ocean surface boundary layer than it would be in a flow past a rigid boundary with similar stress and buoyancy forcing. Estimates of the terms in the turbulent kinetic energy equation indicate that, unlike in a flow past a rigid boundary, the dissipation rates cannot be balanced by local production terms, suggesting that the transport of TKE is important in the ocean surface boundary layer. A simple analytic model containing parameterizations of production, dissipation, and transport reproduces key features of the vertical profile of TKE, including enhancement near the surface. The effective turbulent diffusion coefficient for heat is larger than would be expected in a rigid-boundary boundary layer. This diffusion coefficient is predicted reasonably well by a model that contains the effects of shear production, buoyancy forcing, and transport of TKE (thought to be related to wave breaking). Neglect of buoyancy forcing or wave breaking in the parameterization results in poor predictions of turbulent diffusivity. Langmuir turbulence was detected concurrently with a fraction of the turbulence quantities reported here, but these times did not stand out as having significant differences from observations when Langmuir turbulence was not detected.The Office of Naval Research funded this work as a part of CBLAST-Low

A method for the isolation of human gastric mucous epithelial cells for primary cell culture: A comparison of biopsy vs surgical tissue

We have developed a method for the isolation and growth of normal human gastric mucous epithelial cells using biopsies or surgically resected tissues as the source of the cells. The attachment and growth of cells were dependent upon: (1) cell planting density, ∼50,000 cells/cm 2 ; (2) extracellular matrix (fibronectin); and (3) and the use of a porous filter. In all experiments we found better cells attachment and growth of human gastric mucous cells isolated from surgical specimens compared with those gastric mucous cells isolated from gastric biopsies. The initial cell viability (as measured by Trypan-blue) was the same in both populations of gastric mucous epithelial cells isolated from either gastric biopsies or surgical specimens. After 4–5 days in culture one could detect various amounts of mucin in all the cells using either periodic acid Schiff (PAS) staining or a specific anti-mucin antibody. A similar pattern of much straining was also found in primary cultures of guinea pig gastric mucous epithelial cells. Immunohistochemical staining for chief cells (anti-pepsinogen) or parietal cells (anti-H + /K + ATPasc) in the gastric mucous cuboidal-like epithelial cells with tight junctions, desmosomes,short microvilli, a filamentous terminal web, mucous granules, and basal lamina-like structure. We could not detect the presence of fibroblasts during the 7–9 days that the primary cells were in culture. This cell culture method will prove useful in the isolation of normal human gastric mucous epithelial cells for in vitro studies of gastric mucosal injury and repair.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43235/1/11022_2004_Article_BF00127904.pd

A molecular mechanism for bacterial susceptibility to zinc

Transition row metal ions are both essential and toxic to microorganisms. Zinc in excess has significant toxicity to bacteria, and host release of Zn(II) at mucosal surfaces is an important innate defence mechanism. However, the molecular mechanisms by which Zn(II) affords protection have not been defined. We show that in Streptococcus pneumonia extracellular Zn(II) inhibits the acquisition of the essential metal Mn(II) by competing for binding to the solute binding protein PsaA. We show that, although Mn(II) is the high-affinity substrate for PsaA, Zn(II) can still bind, albeit with a difference in affinity of nearly two orders of magnitude. Despite the difference in metal ion affinities, high-resolution structures of PsaA in complex with Mn(II) or Zn(II) showed almost no difference. However, Zn(II)-PsaA is significantly more thermally stable than Mn(II)-PsaA, suggesting that Zn(II) binding may be irreversible. In vitro growth analyses show that extracellular Zn(II) is able to inhibit Mn(II) intracellular accumulation with little effect on intracellular Zn(II). The phenotype of S. pneumoniae grown at high Zn(II):Mn(II) ratios, i.e. induced Mn(II) starvation, closely mimicked a DpsaA mutant, which is unable to accumulate Mn(II). S. pneumoniae infection in vivo elicits massive elevation of the Zn(II):Mn(II) ratio and, in vitro, these Zn(II):Mn(II) ratios inhibited growth due to Mn(II) starvation, resulting in heightened sensitivity to oxidative stress and polymorphonuclear leucocyte killing. These results demonstrate that microbial susceptibility to Zn(II) toxicity is mediated by extracellular cation competition and that this can be harnessed by the innate immune response.Christopher A. McDevitt, Abiodun D. Ogunniyi, Eugene Valkov, Michael C. Lawrence, Bostjan Kobe, Alastair G. McEwan and James C. Pato

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