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1.  Biophysical significance of the inner mitochondrial membrane structure on the electrochemical potential of mitochondria 
The available literature supports the hypothesis that the morphology of the inner mitochondrial membrane is regulated by different energy states, that the three-dimensional morphology of cristae is dynamic and that both are related to biochemical function. Examination of the correlation between the inner mitochondrial membrane (IMM) structure and mitochondrial energetic function is critical to an understanding of the links between meso-scale morphology and function in progressive mitochondrial dysfunction such as aging, neurodegeneration, and disease. To investigate this relationship, we develop a model to examine the effects of three-dimensional IMM morphology on the electrochemical potential of mitochondria. The 2D axisymmetric finite element method is used to simulate mitochondrial electric potential and proton concentration distribution. This simulation model demonstrates that the proton motive force (PMF) produced on the membranes of cristae can be higher than that on the inner boundary membrane. The model also shows that high proton concentration in cristae can be induced by the morphology-dependent electric potential gradient along the outer side of the IMM. Furthermore, simulation results show that a high PMF is induced by the large surface-to-volume ratio of an individual crista, whereas a high capacity for ATP synthesis can primarily be achieved by increasing the surface area of an individual crista. The mathematical model presented here provides compelling support for the idea that morphology at the meso-scale is a significant driver of mitochondrial function.
PMCID: PMC4315510  PMID: 24483502
2.  Computational fluid dynamics modeling of transport and deposition of pesticides in an aircraft cabin 
Spraying of pesticides in aircraft cabins is required by some countries as part of a disinsection process to kill insects that pose a public health threat. However, public health concerns remain regarding exposures of cabin crew and passengers to pesticides in aircraft cabins. While large scale field measurements of pesticide residues and air concentrations in aircraft cabins scenarios are expensive and time consuming, Computational Fluid Dynamics (CFD) models provide an effective alternative for characterizing concentration distributions and exposures. This study involved CFD modeling of a twin-aisle 11 row cabin mockup with heated manikins, mimicking a part of a fully occupied Boeing 767 cabin. The model was applied to study the flow and deposition of pesticides under representative scenarios with different spraying patterns (sideways and overhead) and cabin air exchange rates (low and high). Corresponding spraying experiments were conducted in the cabin mockup, and pesticide deposition samples were collected at the manikin’s lap and seat top for a limited set of five seats. The CFD model performed well for scenarios corresponding to high air exchange rates, captured the concentration profiles for middle seats under low air exchange rates, and underestimated the concentrations at window seats under low air exchange rates. Additionally, both the CFD and experimental measurements showed no major variation in deposition characteristics between sideways and overhead spraying. The CFD model can estimate concentration fields and deposition profiles at very high resolutions, which can be used for characterizing the overall variability in air concentrations and surface loadings. Additionally, these model results can also provide a realistic range of surface and air concentrations of pesticides in the cabin that can be used to estimate potential exposures of cabin crew and passengers to these pesticides.
PMCID: PMC4310242
CFD; Pesticide; Pyrethroid; Permethrin; Airliner cabin; Disinsection
3.  Enhancement of Mucosal Immunogenicity of Viral Vectored Vaccines by the NKT Cell Agonist Alpha-Galactosylceramide as Adjuvant 
Vaccines  2014;2(4):686-706.
Gene-based vaccination strategies, specifically viral vectors encoding vaccine immunogens are effective at priming strong immune responses. Mucosal routes offer practical advantages for vaccination by ease of needle-free administration, and immunogen delivery at readily accessible oral/nasal sites to efficiently induce immunity at distant gut and genital tissues. However, since mucosal tissues are inherently tolerant for induction of immune responses, incorporation of adjuvants for optimal mucosal vaccination strategies is important. We report here the effectiveness of alpha-galactosylceramide (α-GalCer), a synthetic glycolipid agonist of natural killer T (NKT) cells, as an adjuvant for enhancing immunogenicity of vaccine antigens delivered using viral vectors by mucosal routes in murine and nonhuman primate models. Significant improvement in adaptive immune responses in systemic and mucosal tissues was observed by including α-GalCer adjuvant for intranasal immunization of mice with vesicular stomatitis virus vector encoding the model antigen ovalbumin and adenoviral vectors expressing HIV env and Gag antigens. Activation of NKT cells in systemic and mucosal tissues along with significant increases in adaptive immune responses were observed in rhesus macaques immunized by intranasal and sublingual routes with protein or adenovirus vectored antigens when combined with α-GalCer adjuvant. These results support the utility of α-GalCer adjuvant for enhancing immunogenicity of mucosal vaccines delivered using viral vectors.
PMCID: PMC4278383  PMID: 25553254
adenovirus vector; vesicular stomatitis viral vector; intranasal; HIV vaccine; Rhesus macaques; alpha-galactosylceramide; mucosal immunity; NKT cells
4.  Identification and use of the sugarcane bacilliform virus enhancer in transgenic maize 
BMC Plant Biology  2014;14(1):359.
Transcriptional enhancers are able to increase transcription from heterologous promoters when placed upstream, downstream and in either orientation, relative to the promoter. Transcriptional enhancers have been used to enhance expression of specific promoters in transgenic plants and in activation tagging studies to help elucidate gene function.
A transcriptional enhancer from the Sugarcane Bacilliform Virus - Ireng Maleng isolate (SCBV-IM) that can cause increased transcription when integrated into the the genome near maize genes has been identified. In transgenic maize, the SCBV-IM promoter was shown to be comparable in strength to the maize ubiquitin 1 promoter in young leaf and root tissues. The promoter was dissected to identify sequences that confer high activity in transient assays. Enhancer sequences were identified and shown to increase the activity of a heterologous truncated promoter. These enhancer sequences were shown to be more active when arrayed in 4 copy arrays than in 1 or 2 copy arrays. When the enhancer array was transformed into maize plants it caused an increase in accumulation of transcripts of genes near the site of integration in the genome.
The SCBV-IM enhancer can activate transcription upstream or downstream of genes and in either orientation. It may be a useful tool to activate enhance from specific promoters or in activation tagging.
PMCID: PMC4302606  PMID: 25526789
Promoter; Enhancer; Transcription; Transgenic plant; Transient assay
5.  Modeling Flight Attendants’ Exposures to Pesticide in Disinsected Aircraft Cabins 
Environmental science & technology  2013;47(24):14275-14281.
Aircraft cabin disinsection is required by some countries to kill insects that may pose risks to public health and native ecological systems. A probabilistic model has been developed by considering the microenvironmental dynamics of the pesticide in conjunction with the activity patterns of flight attendants, to assess their exposures and risks to pesticide in disinsected aircraft cabins under three scenarios of pesticide application. Main processes considered in the model are microenvironmental transport and deposition, volatilization, and transfer of pesticide when passengers and flight attendants come in contact with the cabin surfaces. The simulated pesticide airborne mass concentration and surface mass loadings captured measured ranges reported in the literature. The medians (means±standard devitions) of daily total exposures intakes were 0.24 (3.8±10.0), 1.4 (4.2±5.7) and 0.15 (2.1±3.2) μg/(day kg BW) for scenarios of Residual Application, Preflight and Top-of-Descent spraying, respectively. Exposure estimates were sensitive to parameters corresponding to pesticide deposition, body surface area and weight, surface-to-body transfer efficiencies, and efficiency of adherence to skin. Preflight spray posed 2.0 and 3.1 times higher pesticide exposure risk levels for flight attendants in disinsected aircraft cabins than Top-of-Descent spray and Residual Application, respectively.
PMCID: PMC3920731  PMID: 24251734
6.  Three synchronous, sporadic and separate periampullary and pancreatic tumors: more than a coincidence? 
Three sporadic, synchronous, and separate lesions in the ampulla of Vater and the head of the pancreas presented in an 81-year-old male. One was symptomatic and two were incidental. One was detected preoperatively (the ampullary lesion) and two by examination of the resected specimen (the neuroendocrine and pancreatic carcinomas). The case is summarized and the literature and the issue of commonality are reviewed.
PMCID: PMC4301858  PMID: 25494951
Pancreas; Synchronous; Pancreatic adenocarcinoma; Neuroendocrine tumor; Adenosquamous
7.  Specificity Rendering ‘Hot-Spots’ for Aurora Kinase Inhibitor Design: The Role of Non-Covalent Interactions and Conformational Transitions 
PLoS ONE  2014;9(12):e113773.
The present study examines the conformational transitions occurring among the major structural motifs of Aurora kinase (AK) concomitant with the DFG-flip and deciphers the role of non-covalent interactions in rendering specificity. Multiple sequence alignment, docking and structural analysis of a repertoire of 56 crystal structures of AK from Protein Data Bank (PDB) has been carried out. The crystal structures were systematically categorized based on the conformational disposition of the DFG-loop [in (DI) 42, out (DO) 5 and out-up (DOU) 9], G-loop [extended (GE) 53 and folded (GF) 3] and αC-helix [in (CI) 42 and out (CO) 14]. The overlapping subsets on categorization show the inter-dependency among structural motifs. Therefore, the four distinct possibilities a) 2W1C (DI, CI, GE) b) 3E5A (DI, CI, GF) c) 3DJ6 (DI, CO, GF) d) 3UNZ (DOU, CO, GF) along with their co-crystals and apo-forms were subjected to molecular dynamics simulations of 40 ns each to evaluate the variations of individual residues and their impact on forming interactions. The non-covalent interactions formed by the 157 AK co-crystals with different regions of the binding site were initially studied with the docked complexes and structure interaction fingerprints. The frequency of the most prominent interactions was gauged in the AK inhibitors from PDB and the four representative conformations during 40 ns. Based on this study, seven major non-covalent interactions and their complementary sites in AK capable of rendering specificity have been prioritized for the design of different classes of inhibitors.
PMCID: PMC4259475  PMID: 25485544
8.  Physiologically-Based Toxicokinetic Modeling of Zearalenone and Its Metabolites: Application to the Jersey Girl Study 
PLoS ONE  2014;9(12):e113632.
Zearalenone (ZEA), a fungal mycotoxin, and its metabolite zeranol (ZAL) are known estrogen agonists in mammals, and are found as contaminants in food. Zeranol, which is more potent than ZEA and comparable in potency to estradiol, is also added as a growth additive in beef in the US and Canada. This article presents the development and application of a Physiologically-Based Toxicokinetic (PBTK) model for ZEA and ZAL and their primary metabolites, zearalenol, zearalanone, and their conjugated glucuronides, for rats and for human subjects. The PBTK modeling study explicitly simulates critical metabolic pathways in the gastrointestinal and hepatic systems. Metabolic events such as dehydrogenation and glucuronidation of the chemicals, which have direct effects on the accumulation and elimination of the toxic compounds, have been quantified. The PBTK model considers urinary and fecal excretion and biliary recirculation and compares the predicted biomarkers of blood, urinary and fecal concentrations with published in vivo measurements in rats and human subjects. Additionally, the toxicokinetic model has been coupled with a novel probabilistic dietary exposure model and applied to the Jersey Girl Study (JGS), which involved measurement of mycoestrogens as urinary biomarkers, in a cohort of young girls in New Jersey, USA. A probabilistic exposure characterization for the study population has been conducted and the predicted urinary concentrations have been compared to measurements considering inter-individual physiological and dietary variability. The in vivo measurements from the JGS fall within the high and low predicted distributions of biomarker values corresponding to dietary exposure estimates calculated by the probabilistic modeling system. The work described here is the first of its kind to present a comprehensive framework developing estimates of potential exposures to mycotoxins and linking them with biologically relevant doses and biomarker measurements, including a systematic characterization of uncertainties in exposure and dose estimation for a vulnerable population.
PMCID: PMC4256163  PMID: 25474635
9.  Nanotechnology in food processing sector-An assessment of emerging trends 
Use of nanoscience based technology in the food industry is fast emerging as new area for research and development. Several research groups including private companies in the industry have initiated research programmes for exploring the wide scope of nanotechnology into the value chain of food processing and manufacturing. This paper discusses the current focus of research in this area and assesses its potential impacts. Using the developed relational database framework with R&D indicators like literature and patent documents for assessment of the potential of nanotechnology in food sector, a model to organize and map nanoresearch areas to the food processing sector was developed. The study indicates that the about five basic categories of nanotechnology applications and functionalities currently in the development of food sector, include food processing, packaging, nutraceuticals delivery, food safety and functional foods.
PMCID: PMC3722391  PMID: 24425990
Nanotechnology; Food processing sector; R&D indicators
10.  Anticancer Active Homoisoflavone from the Underground Bulbs of Ledebouria hyderabadensis 
Pharmacognosy Research  2014;6(4):303-305.
Ledebouria is a genus of deciduous or weakly evergreen bulbs in the Hyacinthaceae family. This is recognized as the first collection made of the new taxon Ledebouria hyderabadensis, exist in the Hyderabad city of Andhra Pradesh, India.
The goal of this work was to investigate the phytochemical constituents present in the new specifies and also to evaluate the cytotoxic properties of the extracts and pure compounds against human cancer cell lines.
Materials and Methods:
The anticancer activity was evaluated in in vitro mode by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test.
Phytochemical investigation of underground bulbs of indigenous, rare, and recently identified herb L. hyderabadensis yielded a bioactive homoisoflavanone, Scillascillin 1. The structure of the compound was established on the basis of various nuclear magnetic resonance and mass spectral data. The compound Scillascillin was isolated for the first time from L. hyderabadensis. In vitro anticancer activity, performed using MTT assay, showed compound 1 as significantly active against human cancer cell lines MCF-7 (breast cancer) and DU-145 (prostate cancer) with inhibitory concentration (IC)50 values 9.59 and 11.32 μg/ml respectively when compared with herb methanol extract (IC50 values 36.21 and 44.86 μg/ml respectively).
PMCID: PMC4166818  PMID: 25276067
Anticancer activity; Hyacinthaceae; Ledebouria hyderabadensis; Scillascillin
11.  Cine CT without a respiratory surrogate in planning of stereotactic radiotherapy for non-small cell lung cancer 
To determine whether cine computed tomography (CT) can serve as an alternative to four-dimensional (4D)-CT by providing tumor motion information and producing equivalent target volumes when contoured upon for radiation treatment planning without a respiratory surrogate.
Methods and Materials
Cine CT images from a commercial CT scanner were used to form maximum intensity projection (MIP) and respiratory-averaged CT (RACT) image sets. These image sets then were used together to define targets for radiotherapy. Phantoms oscillating under irregular motion were used to assess differences between contouring on cine CT and 4D-CT. We also retrospectively reviewed image sets for 27 patients at our institution who received stereotactic radiotherapy for stage I non-small cell lung cancer. Patients were included if tumor motion was greater than 1 cm. Lesions were first contoured using MIP and RACT image sets processed from cine CT, then with 4D-CT MIP and 10-phase image sets. Mean ratios of volume magnitude were compared with intraobserver variation, mean centroid shifts were calculated, and volume overlap was assessed with the normalized Dice similarity coefficient index.
The phantom studies demonstrated that cine CT captured a greater extent of irregular tumor motion than 4D-CT, producing a larger tumor volume. The patient studies demonstrated that gross tumor defined on cine imaging was similar to or slightly larger than that defined on 4D-CT.
Cine CT is a promising alternative to 4D-CT for stereotactic radiation treatment planning.
PMCID: PMC4160118  PMID: 18644683
4D-CT; cine CT; contouring
12.  Effect of the Electric Field Frequency on Ascorbic Acid Degradation during Thermal Treatment by Ohmic Heating 
In this work, the influence of the electric field frequency and solids content on the degradation kinetics of ascorbic acid during ohmic heating of acerola pulp and acerola serum was investigated. The degradation percentage of ascorbic acid in the pulp after 120 min of heating varied between 12 and 17%. For the serum, the degradation percentage was in the range of 13 and 18%. The results were fitted to the first-order model, and the kinetic rate constants ranged from 1.1 to 1.6 × 10−3 min−1 and from 1.1 to 1.5 × 10−3 min−1 for pulp and serum, respectively. D values ranged between 1480 and 2145 min for the pulp and between 1524 and 1951 min for the serum. A distinct behavior between the kinetic parameters of the pulp and serum in electric field frequencies ranging from 10 to 1000 Hz indicates that the presence of distinct amounts and types of solids might affect the rate of the electron transfer in electrochemical reactions. These variables may also affect the polarization process stimulated by the oscillating electric field. The non-achievement of the equilibrium of the polarization process may have an influence on oxidation reactions, affecting the predisposition to hydrogen donation from the ascorbic acid molecule.
PMCID: PMC4154558  PMID: 24892902
ohmic heating; ascorbic acid; electric field frequency; polarization; solids content
13.  Real world experience with an indigenously manufactured stent Cobal C – A retrospective study 
Indian Heart Journal  2014;66(5):525-529.
Second generation bare metal stents made of cobalt chromium alloy are superior to first generation stain less steel stents. The thin struts are shown to reduce clinical and angiographic adverse outcomes.
To study the long term clinical and angiographic outcomes in patients who underwent coronary angioplasty with an indigenously made cobalt chromium bare metal stents with thin strut Cobal+C™ (Relisys).
A total of 268 consecutive patients who underwent coronary angioplasty with Cobal+C stents were studied retrospectively. Clinical follow up was done after a minimum period of nine months through telephonic interview and angiographic follow up was done in 80 patients chosen randomly. The end points analyzed included major adverse cardiac events (MACE) at nine months and the rate of binary restenosis at follow up angiogram done between 9 and 15 months post angioplasty.
Thirty four percent were diabetic and 33% had acute myocardial infarction. Females constituted 17%. Mean stent diameter was 2.88 ± 0.28 and mean stent length 18.8 ± 4.2. MACE at nine months was 4.5% with TLR 0.3%. The rate of binary restenosis was 21%. Patients with longer stent lengths and non-compliance with medications had significantly higher rates of binary restenosis.
The use of Relisys Cobal+C stents was associated with good long term clinical and angiographic outcomes as evidenced by low incidence of MACE and binary restenosis rates for a bare metal stent.
PMCID: PMC4223194  PMID: 25443606
Bare metal stent; Cobalt chromium stent; Restenosis; Cobalt+C stent
14.  Regression of pulmonary artery hypertension due to development of a pulmonary arteriovenous malformation 
Indian Heart Journal  2014;66(5):535-538.
Idiopathic Pulmonary Hypertension (IPAH) is characterized by elevated pulmonary arterial pressure in the absence of an identifiable underlying cause. The condition is usually relentlessly progressive with a short survival in the absence of treatment.1 We describe a patient of IPAH in whom the pulmonary artery pressures significantly abated with complete disappearance of symptoms, following spontaneous development of a pulmonary arterio-venous malformation (PAVM).
PMCID: PMC4223210  PMID: 25443608
Pulmonary arterial hypertension; Arterio-venous malformation; Hemoptysis; Pregnancy; Regression
15.  Comparison of modeling approaches to prioritize chemicals based on estimates of exposure and exposure potential 
While only limited data are available to characterize the potential toxicity of over 8 million commercially available chemical substances, there is even less information available on the exposure and use-scenarios that are required to link potential toxicity to human and ecological health outcomes. Recent improvements and advances such as high throughput data gathering, high performance computational capabilities, and predictive chemical inherency methodology make this an opportune time to develop an exposure-based prioritization approach that can systematically utilize and link the asymmetrical bodies of knowledge for hazard and exposure. In response to the US EPA’s need to develop novel approaches and tools for rapidly prioritizing chemicals, a “Challenge” was issued to several exposure model developers to aid the understanding of current systems in a broader sense and to assist the US EPA’s effort to develop an approach comparable to other international efforts. A common set of chemicals were prioritized under each current approach. The results are presented herein along with a comparative analysis of the rankings of the chemicals based on metrics of exposure potential or actual exposure estimates. The analysis illustrates the similarities and differences across the domains of information incorporated in each modeling approach. The overall findings indicate a need to reconcile exposures from diffuse, indirect sources (far-field) with exposures from directly, applied chemicals in consumer products or resulting from the presence of a chemical in a microenvironment like a home or vehicle. Additionally, the exposure scenario, including the mode of entry into the environment (i.e. through air, water or sediment) appears to be an important determinant of the level of agreement between modeling approaches.
PMCID: PMC3983788  PMID: 23707726
Exposure; Modeling; Prioritization; Chemicals; Expocast
16.  Identification of sVSG117 as an Immunodiagnostic Antigen and Evaluation of a Dual-Antigen Lateral Flow Test for the Diagnosis of Human African Trypanosomiasis 
The diagnosis of human African trypanosomiasis (HAT) caused by Trypanosoma brucei gambiense relies mainly on the Card Agglutination Test for Trypanosomiasis (CATT). There is no immunodiagnostic for HAT caused by T. b. rhodesiense. Our principle aim was to develop a prototype lateral flow test that might be an improvement on CATT.
Methodology/Principle Findings
Pools of infection and control sera were screened against four different soluble form variant surface glycoproteins (sVSGs) by ELISA and one, sVSG117, showed particularly strong immunoreactivity to pooled infection sera. Using individual sera, sVSG117 was shown to be able to discriminate between T. b. gambiense infection and control sera by both ELISA and lateral flow test. The sVSG117 antigen was subsequently used with a previously described recombinant diagnostic antigen, rISG65, to create a dual-antigen lateral flow test prototype. The latter was used blind in a virtual field trial of 431 randomized infection and control sera from the WHO HAT Specimen Biobank.
In the virtual field trial, using two positive antigen bands as the criterion for infection, the sVSG117 and rISG65 dual-antigen lateral flow test prototype showed a sensitivity of 97.3% (95% CI: 93.3 to 99.2) and a specificity of 83.3% (95% CI: 76.4 to 88.9) for the detection of T. b. gambiense infections. The device was not as good for detecting T. b. rhodesiense infections using two positive antigen bands as the criterion for infection, with a sensitivity of 58.9% (95% CI: 44.9 to 71.9) and specificity of 97.3% (95% CI: 90.7 to 99.7). However, using one or both positive antigen band(s) as the criterion for T. b. rhodesiense infection improved the sensitivity to 83.9% (95% CI: 71.7 to 92.4) with a specificity of 85.3% (95% CI: 75.3 to 92.4). These results encourage further development of the dual-antigen device for clinical use.
Author Summary
Human African Trypanosomiasis (HAT) is caused by infection with Trypanosoma brucei gambiense or T. b. rhodesiense. The diagnosis of T. b. gambiense infections currently relies primarily on a Card Agglutination Test for Trypanosomiasis (CATT), which has acknowledged limitations, and there is no simple test for T. b. rhodesiense infection. Our overall aim is to produce a simple lateral flow test device with a similar or better sensitivity and specificity than CATT but with better stability and ease of use at point of care. In this study, we identified a particular variant surface glycoprotein, sVSG117, with good diagnostic potential and combined it with a previously identified recombinant diagnostic antigen, rISG65, to produce a prototype dual-antigen lateral flow test. We performed a virtual field trial by testing the device blind with 431 randomized serum samples provided by the WHO HAT Specimen Biobank. The results show that, although the prototype lateral flow test is un-optimized, it was able to diagnose T. b. gambiense HAT with a sensitivity and specificity of 97.3% and 83.3% and T. b. rhodesiense HAT with a sensitivity and specificity of 83.9% and 85.3%.
PMCID: PMC4102454  PMID: 25033401
17.  Saudi Guidelines on the Diagnosis and Treatment of Pulmonary Hypertension: Challenges in managing pulmonary hypertension in the developing countries 
Annals of Thoracic Medicine  2014;9(Suppl 1):S127-S130.
There is scant published data about pulmonary hypertension (PH) from the developing countries. True prevalence of the disease, its biology, etiology and response to treatment are not well known, and they are likely to be somewhat different from that of the developed countries.
In this review, we will discuss the main challenges for managing PH in developing countries and propose real-life recommendations to deal with such difficulties.
PMCID: PMC4114281  PMID: 25076991
Developing world; pulmonary hypertension; Saudi association for pulmonary hypertension guidelines
18.  Saudi guidelines on the diagnosis and treatment of pulmonary hypertension: 2014 updates 
Annals of Thoracic Medicine  2014;9(Suppl 1):S1-S15.
The Saudi Association for Pulmonary Hypertension (previously called Saudi Advisory Group for Pulmonary Hypertension) has published the first Saudi Guidelines on Diagnosis and Treatment of Pulmonary Arterial Hypertension back in 2008.[1] That guideline was very detailed and extensive and reviewed most aspects of pulmonary hypertension (PH). One of the disadvantages of such detailed guidelines is the difficulty that some of the readers who just want to get a quick guidance or looking for a specific piece of information might face.
All efforts were made to develop this guideline in an easy-to-read form, making it very handy and helpful to clinicians dealing with PH patients to select the best management strategies for the typical patient suffering from a specific condition. This Guideline was designed to provide recommendations for problems frequently encountered by practicing clinicians involved in management of PH. This publication targets mainly adult and pediatric PH-treating physicians, but can also be used by other physicians interested in PH.
PMCID: PMC4114283  PMID: 25076987
Pulmonary hypertension; pulmonary vascular resistance; modified functional class; target therapy; SAPH guidelines
19.  Studying permethrin exposure in flight attendants using a physiologically based pharmacokinetic model 
Assessment of potential health risks to flight attendants from exposure to pyrethroid insecticides, used for aircraft disinsection, is limited because of (a) lack of information on exposures to these insecticides, and (b) lack of tools for linking these exposures to biomarker data. We developed and evaluated a physiologically based pharmacokinetic (PBPK) model to assess the exposure of flight attendants to the pyrethroid insecticide permethrin attributable to aircraft disinsection. The permethrin PBPK model was developed by adapting previous models for pyrethroids, and was parameterized using currently available metabolic parameters for permethrin. The human permethrin model was first evaluated with data from published human studies. Then, it was used to estimate urinary metabolite concentrations of permethrin in flight attendants who worked in aircrafts, which underwent residual and pre-flight spray treatments. The human model was also applied to analyze the toxicokinetics following permethrin exposures attributable to other aircraft disinsection scenarios. Predicted levels of urinary 3-phenoxybenzoic acid (3-PBA), a metabolite of permethrin, following residual disinsection treatment were comparable to the measurements made for flight attendants. Simulations showed that the median contributions of the dermal, oral and inhalation routes to permethrin exposure in flight attendants were 83.5%, 16.1% and 0.4% under residual treatment scenario, respectively, and were 5.3%, 5.0% and 89.7% under pre-flight spray scenario, respectively. The PBPK model provides the capability to simulate the toxicokinetic profiles of permethrin, and can be used in the studies on human exposure to permethrin.
PMCID: PMC4063416  PMID: 23462847
aircraft disinsection; flight attendants; PBPK modeling; permethrin; pesticides; pyrethroids; toxicokinetics
20.  Proteomic Selection of Immunodiagnostic Antigens for Trypanosoma congolense 
Animal African Trypanosomosis (AAT) presents a severe problem for agricultural development in sub-Saharan Africa. It is caused by several trypanosome species and current means of diagnosis are expensive and impractical for field use. Our aim was to discover antigens for the detection of antibodies to Trypanosoma congolense, one of the main causative agents of AAT. We took a proteomic approach to identify potential immunodiagnostic parasite protein antigens. One hundred and thirteen proteins were identified which were selectively recognized by infected cattle sera. These were assessed for likelihood of recombinant protein expression in E. coli and fifteen were successfully expressed and assessed for their immunodiagnostic potential by ELISA using pooled pre- and post-infection cattle sera. Three proteins, members of the invariant surface glycoprotein (ISG) family, performed favorably and were then assessed using individual cattle sera. One antigen, Tc38630, evaluated blind with 77 randomized cattle sera in an ELISA assay gave sensitivity and specificity performances of 87.2% and 97.4%, respectively. Cattle immunoreactivity to this antigen diminished significantly following drug-cure, a feature helpful for monitoring the efficacy of drug treatment.
Author Summary
Animal African Trypanosomosis (AAT) is a set of diseases whereby animals are infected with single-cell parasites that replicate in their bloodstream. The disease in cattle results in weight-loss and death, and AAT is a significant veterinary problem for sub-Saharan Africa. One of the principal trypanosome species responsible for AAT in cattle is Trypanosoma congolense and, although there are drug-treatments for these infections, current diagnostic methods are impractical for field use. Our aim was to discover protein molecules from the parasite to which infected animals make antibodies, to then make these proteins in bacteria and to subsequently demonstrate that they can be used to detect antibodies in cattle serum, thus diagnosing AAT. To discover the diagnostic proteins, we dissolved parasites in a detergent solution and applied them to beads coated with antibodies from infected cattle and to beads coated with antibodies from un-infected cattle. We then compared the proteins bound to each and selected those proteins that were at least 100-fold enriched by the infected cattle antibodies. We refined this list, according to practical and performance considerations, and settled on one protein, called Tc38630. Testing Tc38630 with cattle sera showed that it can detect about nine out of ten AAT infections.
PMCID: PMC4055490  PMID: 24922510
21.  ARID1B, a member of the human SWI/SNF chromatin remodeling complex, exhibits tumour-suppressor activities in pancreatic cancer cell lines 
British Journal of Cancer  2013;108(10):2056-2062.
The human ATP-dependent SWItch/sucrose nonfermentable (SWI/SNF) complex functions as a primary chromatin remodeler during ontogeny, as well as in adult life. Several components of the complex have been suggested to function as important regulators of tumorigenesis in various cancers. In the current study, we have characterised a possible tumour suppressor role for the largest subunit of the complex, namely the AT-rich interaction domain 1B (ARID1B).
We performed Azacytidine and Trichostatin A treatments, followed by bisulphite sequencing to determine the possible DNA methylation-induced transcription repression of the gene in pancreatic cancer (PaCa) cell lines. Functional characterisation of effect of ARID1B ectopic expression in MiaPaCa2 PaCa cell line, which harboured ARID1B homozygous deletion, was carried out. Finally, we evaluated ARID1B protein expression in pancreatic tumour samples using immunohistochemistry on a tissue microarray.
ARID1B was transcriptionally repressed due to promoter hypermethylation, and ectopic expression severely compromised the ability of MiaPaCa2 cells to form colonies in liquid culture and soft agar. In addition, ARID1B exhibited significantly reduced/loss of expression in PaCa tissue, especially in samples from advanced-stage tumours, when compared with normal pancreas.
The results therefore suggest a possible tumour-suppressor function for ARID1B in PaCa, thus adding to the growing list of SWI/SNF components with a similar function. Given the urgent need to design efficient targeted therapies for PaCa, our study assumes significance.
PMCID: PMC3670478  PMID: 23660946
ARID1B; SWI/SNF; tumour-suppressor gene; pancreatic cancer
22.  Aldehyde dehydrogenase 1 defines and protects a nigrostriatal dopaminergic neuron subpopulation 
The Journal of Clinical Investigation  2014;124(7):3032-3046.
Subpopulations of dopaminergic (DA) neurons within the substantia nigra pars compacta (SNpc) display a differential vulnerability to loss in Parkinson’s disease (PD); however, it is not clear why these subsets are preferentially selected in PD-associated neurodegeneration. In rodent SNpc, DA neurons can be divided into two subpopulations based on the expression of aldehyde dehydrogenase 1 (ALDH1A1). Here, we have shown that, in α-synuclein transgenic mice, a murine model of PD-related disease, DA neurodegeneration occurs mainly in a dorsomedial ALDH1A1-negative subpopulation that is also prone to cytotoxic aggregation of α-synuclein. Notably, the topographic ALDH1A1 pattern observed in α-synuclein transgenic mice was conserved in human SNpc. Postmortem evaluation of brains of patients with PD revealed a severe reduction of ALDH1A1 expression and neurodegeneration in the ventral ALDH1A1-positive DA subpopulations. ALDH1A1 expression was also suppressed in α-synuclein transgenic mice. Deletion of Aldh1a1 exacerbated α-synuclein–mediated DA neurodegeneration and α-synuclein aggregation, whereas Aldh1a1-null and control DA neurons were comparably susceptible to 1-methyl-4-phenylpyridinium–, glutamate-, or camptothecin-induced cell death. ALDH1A1 overexpression appeared to preferentially protect against α-synuclein–mediated DA neurodegeneration but did not rescue α-synuclein–induced loss of cortical neurons. Together, our findings suggest that ALDH1A1 protects subpopulations of SNpc DA neurons by preventing the accumulation of dopamine aldehyde intermediates and formation of cytotoxic α-synuclein oligomers.
PMCID: PMC4071380  PMID: 24865427
23.  Passenger Rail Security, Planning, and Resilience: Application of Network, Plume, and Economic Simulation Models as Decision Support Tools 
We built three simulation models that can assist rail transit planners and operators to evaluate high and low probability rail-centered hazard events that could lead to serious consequences for rail-centered networks and their surrounding regions. Our key objective is to provide these models to users who, through planning with these models, can prevent events or more effectively react to them. The first of the three models is an industrial systems simulation tool that closely replicates rail passenger traffic flows between New York Penn Station and Trenton, New Jersey. Second, we built and used a line source plume model to trace chemical plumes released by a slow-moving freight train that could impact rail passengers, as well as people in surrounding areas. Third, we crafted an economic simulation model that estimates the regional economic consequences of a variety of rail-related hazard events through the year 2020. Each model can work independently of the others. However, used together they help provide a coherent story about what could happen and set the stage for planning that should make rail-centered transport systems more resistant and resilient to hazard events. We highlight the limitations and opportunities presented by using these models individually or in sequence.
PMCID: PMC4029054  PMID: 23718133
Passenger rail risk; resilience; simulation
24.  A personal exposure study employing scripted activities and paths in conjunction with atmospheric releases of perfluorocarbon tracers in Manhattan, New York 
A personal exposure study was conducted in New York City as part of the Urban Dispersion Program (UDP). It examined the contact of individuals with four harmless perflourocarbon tracers (PFT) released in Midtown Manhattan with approval by city agencies at separate locations, during two types of experiments, completed during each release period. Two continuous 1 h release periods separated by a 1.5 h ventilation time were completed on 3 October 2005. Stationary site and personal exposure measurements were taken during each period, and the first half hour after the release ended. Two types of scripted exposure activities are reported: Outdoor Source Scale, and Outdoor Neighborhood Scale; requiring 1- and 10-min duration samples, respectively. The results showed that exposures were influenced by the surface winds, the urban terrain, and the movements of people and vehicles typical in urban centers. The source scale exposure data indicated that local conditions significantly affected the distribution of each tracer, and consequently the exposures. The highest PFT exposures resulted from interaction of the scripted activities with local surface conditions. The range measured for 1- min exposures were large with measured values exceeding 5000 ppqv (parts per quadrillion by volume). The neighborhood scale measurements quantified exposures at distances up to seven blocks away from the release points. Generally, but not always, the PFT levels returned quickly to zero indicating that after cessation of the emissions the concentrations decrease rapidly, and reduce the intensity of local exposures. The near source and neighborhood personal exposure route results provided information to establish a baseline for determining how a release could affect both the general public and emergency responders, and evaluate the adequacy of re-entry or exit strategies from a local area. Finally, the data also show that local characteristics can produce “hot spots”.
PMCID: PMC4023470  PMID: 17505505
personal exposure; perfluorocarbon tracers; emission sources and urban populations; neighborhood activities; emergency responders
25.  Prevalence of Invasive Aspergillosis Among (PTB) Patients in Kanchipuram, India 
Background: Tuberculosis (TB) remains a major health problem worldwide. (PTB) is commonly associated with secondary aspergilloma. Repeated exposure of Aspergillus spores can aggravate the bronchial pathology and can manifest as asthmatic episodes.
Aim and Objective: Pulmonary invasive aspergillosis is difficult to evaluate. Culture based diagnosis is time consuming. Hence (PCR) was done to evaluate the invasive fungal aspergillosis in (PTB) patients.
Materials and Methods: Eighty sputum samples collected from TB patients were processed as per standard protocol. Species level identification was done using PCR.
Results: Among 80 patients, 26 isolates were obtained, only 8 were Aspergillus species. All Aspergillus were taken up for PCR evaluation.
Conclusion: Fungal infection should be suspected in all sputum positive patients. PCR is an effective tool to diagnose invasive aspergillosis.
PMCID: PMC4003648  PMID: 24783070
Aspergillus; PulmonaryTuberculosis; Polymerase chain reaction

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