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1.  Pharmacodynamic imaging guides dosing of a selective estrogen receptor degrader 
Estrogen receptor (ER) targeting is key in management of receptor-positive breast cancer (BrCa). Currently, there are no methods to optimize anti-ER therapy dosing. This study assesses the utility of 16α-18F-fluoroestradiol (18F-FES) PET for fulvestrant dose optimization in a preclinical ER+ BrCa model.
Experimental Design
In vitro, 18F-FES retention was compared to ERα protein expression (ELISA) and ESR1 mRNA transcription (qPCR) in MCF7 cells (ER+) after treatment with different fulvestrant doses. MCF7 xenografts were grown in ovariectomized nude mice and assigned to vehicle, low- (0.05mg), medium- (0.5mg) or high-dose (5mg) fulvestrant treatment groups (5–7 per group). Two and three days after fulvestrant treatment, PET/CT was performed using 18F-FES and 18F-FDG, respectively. ER expression was assessed by immunohistochemistry, ELISA, and qPCR on xenografts. Tumor proliferation was assessed using Ki-67 immunohistochemistry.
In vitro, we observed a parallel graded reduction in 18F-FES uptake and ER expression with increased fulvestrant doses, despite enhancement of ER mRNA transcription. In xenografts, ER expression significantly decreased with increased fulvestrant dose, despite similar mRNA expression and Ki-67 staining among the treatment groups. We observed a significant dose-dependent reduction of 18F-FES PET mean standardized uptake value (SUVmean) with fulvestrant treatment, but no significant difference among the treatment groups in 18F-FDG PET SUVmean..
We demonstrated that 18F-FES uptake mirrors the dose-dependent changes in functional ER expression with fulvestrant resulting in ER degradation and/or blockade; these precede changes in tumor metabolism and proliferation. Quantitative 18F-FES PET may be useful for tracking early efficacy of ER blockade/degradation and guiding ER-targeted therapy dosing in BrCa patients.
PMCID: PMC4359957  PMID: 25609068
Positron Emission Tomography; 18F-Fluoroestradiol; Breast Cancer; Fulvestrant; Optimal biological dose
2.  Fidelity to and comparative results across behavioral interventions evaluated through the RE-AIM framework: a systematic review 
Systematic Reviews  2015;4:155.
The reach, effectiveness, adoption, implementation, and maintenance (RE-AIM) framework was developed to determine potential public health impact of interventions (i.e., programs, policy, and practice). The purpose of this systematic review was to determine (1) comparative results across accurately reported RE-AIM indicators, (2) relevant information when there remains under-reporting or misclassification of data across each dimension, (3) the degree to which authors intervened to improve outcomes related to each dimension, and (4) the number of articles reporting RE-AIM dimensions for a given study.
In April 2013, a systematic search of the RE-AIM framework was completed in PubMed, PSYCHInfo, EbscoHost, Web of Science, and Scopus. Evidence was analyzed until January 2015.
Eighty-two interventions that included empirical data related to at least one of the RE-AIM dimensions were included in the review. Across these interventions, they reached a median sample size of 320 participants (M = 4894 ± 28,256). Summarizing the effectiveness indicators, we found that: the average participation rate was 45 % (±28 %), 89 % of the interventions reported positive changes in the primary outcome and 11 interventions reported broader outcomes (e.g., quality of life). As for individual-level maintenance, 11 % of studies showed effects ≥6 months post-program. Average setting and staff adoption rates were 75 % (±32 %) and 79 % (±28 %), respectively. Interventions reported being delivered as intended (82 % (±16 %)) and 22 % intervention reported adaptations to delivery. There were insufficient data to determine average maintenance at the organizational level. Data on costs associated with each dimension were infrequent and disparate: four studies reported costs of recruitment, two reported intervention costs per participant, and two reported adoption costs.
The RE-AIM framework has been employed in a variety of populations and settings for the planning, delivery, and evaluation of behavioral interventions. This review highlights inconsistencies in the degree to which authors reported each dimension in its entirety as well as inaccuracies in reporting indicators within each dimension. Further, there are few interventions that aim to improve outcomes related to reach, adoption, implementation, and maintenance.
Electronic supplementary material
The online version of this article (doi:10.1186/s13643-015-0141-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4637141  PMID: 26547687
RE-AIM; Behavior change; Translation
3.  Crown ethers attenuate aggregation of Amyloid beta of Alzheimer’s disease 
The stagnant state of drug development for Alzheimer’s disease demands new approaches for seeking promising candidates. In this report, we reasoned that non-covalent modification of amyloid beta (Aβ) peptide by crown ethers could inhibit its aggregation. To specifically target Aβs, a conjugate of Pittsburgh compound B (PiB) and 12-crown-4 ether (termed PiB-C) was synthesized. Our results indicated that the conjugate could significantly reduce the aggregation of Aβs in vitro. In addition, by two-photon microscopic imaging, we found that PiB-C could readily penetrate the BBB and efficiently label Aβ plaques and CAAs (cerebral amyloid angiophathy) in an APP-PS1 transgenic mouse.
PMCID: PMC4617529  PMID: 25372154
4.  Tiered Approaches to Chromatographic Bioanalytical Method Performance Evaluation: Recommendation for Best Practices and Harmonization from the Global Bioanalysis Consortium Harmonization Team 
The AAPS Journal  2014;17(1):17-23.
The A2 harmonization team, a part of the Global Bioanalysis Consortium (GBC), focused on defining possible tiers of chromatographic-based bioanalytical method performance. The need for developing bioanalytical methods suitable for the intended use is not a new proposal and is already referenced in regulatory guidance language. However, the practical implementation of approaches that differ from the well-established full validation requirements has proven challenging. Advances in technologies, the need to progress drug development more efficiently, and emerging new drug compound classes support the use of categorized tiers of bioanalytical methods. This paper incorporated the input from an international team of experienced bioanalysts to surmise the advantages and the challenges of tiered approaches and to provide recommendations on paths forward.
PMCID: PMC4287281  PMID: 25338740
bioanalysis; chromatographic; regulated; tiered approaches
5.  PET Imaging of Fatty Acid Amide Hydrolase with [18F]DOPP in Nonhuman Primates 
Molecular Pharmaceutics  2014;11(11):3832-3838.
Fatty acid amide hydrolase (FAAH) regulates endocannabinoid signaling. [11C]CURB, an irreversibly binding FAAH inhibitor, has been developed for clinical research imaging with PET. However, no fluorine-18 labeled radiotracer for FAAH has yet advanced to human studies. [18F]DOPP ([18F]3-(4,5-dihydrooxazol-2-yl)phenyl (5-fluoropentyl)carbamate) has been identified as a promising 18F-labeled analogue based on rodent studies. The goal of this work is to evaluate [18F]DOPP in nonhuman primates to support its clinical translation. High specific activity [18F]DOPP (5–6 Ci·μmol–1) was administered intravenously (iv) to three baboons (2M/1F, 3–4 years old). The distribution and pharmacokinetics were quantified following a 2 h dynamic imaging session using a simultaneous PET/MR scanner. Pretreatment with the FAAH-selective inhibitor, URB597, was carried out at 200 or 300 μg/kg iv, 10 min prior to [18F]DOPP administration. Rapid arterial blood sampling for the first 3 min was followed by interval sampling with metabolite analysis to provide a parent radiotracer plasma input function that indicated ∼95% baseline metabolism at 60 min and a reduced rate of metabolism after pretreatment with URB597. Regional distribution data were analyzed with 1-, 2-, and 3-tissue compartment models (TCMs), with and without irreversible trapping since [18F]DOPP covalently links to the active site of FAAH. Consistent with previous findings for [11C]CURB, the 2TCM with irreversible binding was found to provide the best fit for modeling the data in all regions. The composite parameter λk3 was therefore used to evaluate whole brain (WB) and regional binding of [18F]DOPP. Pretreatment studies showed inhibition of λk3 across all brain regions (WB baseline: 0.112 mL/cm3/min; 300 μg/kg URB597: 0.058 mL/cm3/min), suggesting that [18F]DOPP binding is specific for FAAH, consistent with previous rodent data.
PMCID: PMC4224570  PMID: 25004399
[18F]DOPP; fatty acid amide hydrolase; FAAH; positron emission tomography; PET; kinetic modeling
6.  Maternal Plane of Nutrition during Late Gestation and Weaning Age Alter Angus × Simmental Offspring Longissimus Muscle Transcriptome and Intramuscular Fat 
PLoS ONE  2015;10(7):e0131478.
In model organisms both the nutrition of the mother and the young offspring could induce long-lasting transcriptional changes in tissues. In livestock, such changes could have important roles in determining nutrient use and meat quality. The main objective was to evaluate if plane of maternal nutrition during late-gestation and weaning age alter the offspring’s Longissimus muscle (LM) transcriptome, animal performance, and metabolic hormones. Whole-transcriptome microarray analysis was performed on LM samples of early (EW) and normal weaned (NW) Angus × Simmental calves born to grazing cows receiving no supplement [low plane of nutrition (LPN)] or 2.3 kg high-grain mix/day [medium plane of nutrition (MPN)] during the last 105 days of gestation. Biopsies of LM were harvested at 78 (EW), 187 (NW) and 354 (before slaughter) days of age. Despite greater feed intake in MPN offspring, blood insulin was greater in LPN offspring. Carcass intramuscular fat content was greater in EW offspring. Bioinformatics analysis of the transcriptome highlighted a modest overall response to maternal plane of nutrition, resulting in only 35 differentially expressed genes (DEG). However, weaning age and a high-grain diet (EW) strongly impacted the transcriptome (DEG = 167), especially causing a lipogenic program activation. In addition, between 78 and 187 days of age, EW steers had an activation of the innate immune system due presumably to macrophage infiltration of intramuscular fat. Between 187 and 354 days of age (the “finishing” phase), NW steers had an activation of the lipogenic transcriptome machinery, while EW steers had a clear inhibition through the epigenetic control of histone acetylases. Results underscored the need to conduct further studies to understand better the functional outcome of transcriptome changes induced in the offspring by pre- and post-natal nutrition. Additional knowledge on molecular and functional outcomes would help produce more efficient beef cattle.
PMCID: PMC4496061  PMID: 26153887
7.  On-command drug release from nanochains inhibits growth of breast tumors 
Pharmaceutical research  2013;31(6):1460-1468.
To evaluate the ability of radiofrequency (RF)-triggered drug release from a multicomponent chain-shaped nanoparticle to inhibit the growth of an aggressive breast tumor.
A two-step solid phase chemistry was employed to synthesize doxorubicin-loaded nanochains, which were composed of three iron oxide nanospheres and one doxorubicin-loaded liposome assembled in a 100-nm-long linear nanochain. The nanochains were tested in the Luc-GFP-4T1 orthotopic mouse model, which is a highly aggressive breast cancer model. The Luc-GFP-4T1 cell line stably expresses firefly luciferase, which allowed the non-invasive in vivo imaging of tumor response to the treatment using bioluminescence imaging (BLI).
Longitudinal BLI imaging showed that a single nanochain treatment followed by application of RF resulted in an at least 100-fold lower BLI signal compared to the groups treated with nanochains (without RF) or free doxorubicin followed by RF. A statistically significant increase in survival time of the nanochain-treated animals followed by RF (64.3 days) was observed when compared to the nanochain-treated group without RF (35.7 days), free doxorubicin-treated group followed by RF (38.5 days), and the untreated group (30.5 days; n=5 animals per group).
These studies showed that the combination of RF and nanochains has the potential to effectively treat highly aggressive cancers and prolong survival.
PMCID: PMC3875625  PMID: 23934254
Nanochain; multicomponent nanoparticle; triple-negative breast cancer; radiofrequency-triggered release; doxorubicin; chemotherapy; 4T1 cells; bioluminescence imaging
8.  Network analysis of RE-AIM framework: chronology of the field and the connectivity of its contributors 
The reach, effectiveness, adoption, implementation, and maintenance (RE-AIM) framework has been widely used for translational research. We used social network analysis (SNA) to explore how innovative research frameworks, such as RE-AIM, have diffused over time in academic literature. A structured literature review was conducted on RE-AIM between 1999 and 2012. SNA indices of degree score, betweenness, centrality, and authorship ties were used to examine use of RE-AIM. Use of RE-AIM has grown since its inception and spread from a few research centers to use internationally. Investigation of co-authorship revealed many have published on RE-AIM, but a much smaller core of RE-AIM researchers have published together two or more times. SNA revealed how the RE-AIM framework has been used over time and identified areas to further expand use of the framework. SNA can be useful to understand how research frameworks diffuse over time.
PMCID: PMC4444708  PMID: 26029284
RE-AIM; Evaluation; Social network analyses; Co-authorship analyses
9.  Membrane Potential-dependent Uptake of 18F-triphenylphosphonium - A New Voltage Sensor as an Imaging Agent for Detecting Burn-induced Apoptosis 
The Journal of surgical research  2014;188(2):473-479.
Mitochondrial dysfunction has been closely related to many pathological processes, such as cellular apoptosis. Alterations in organelle membrane potential are associated with mitochondrial dysfunction. A fluorine -18 labeled phosphonium compound: 18F-triphenylphosphonium (18F-TPP) was prepared to determine its potential use as a mitochondria-targeting radiopharmaceutical to evaluate cellular apoptosis.
Studies were conducted in both ex vivo cell lines and in vivo using a burned animal model. Uptake of 18F-TPP was assessed in PC-3 cells by gamma counting under the following conditions: graded levels of extra-cellular potassium concentrations, incubation with carbonyl cyanide m-chlorophenylhydrazone (CCCP) and staurosporine. Apoptosis was studied in a burn animal model using TUNEL staining and simultaneous assessment of 18F-TPP uptake by biodistribution.
We found that stepwise membrane depolarization by potassium (K) resulted in a linear decrease in 18F-TPP uptake, with a slope of 0.62+/−0.08 and a correlation coefficient of 0.936+/−0.11. Gradually increased concentrations of CCCP lead to decreased uptakes of 18F-TPP. Staurosporine significantly decreased the uptake of 18F-TPP in PC-3 cells from 14.2+/−3.8% to 5.6+/−1.3% (P<0.001). Burn induced significant apoptosis (sham: 4.4 +/−1.8% vs. burn: 24.6+/− 6.7 %; p<0.005) and a reduced uptake of tracer in the spleens of burn injured animals as compared to sham burn controls (burn: 1.13+/−0.24% vs. sham: 3.28+/−0.67%; p<0.005). Biodistribution studies demonstrated that burn induced significant reduction in 18F-TPP uptake in spleen, heart, lung, and liver, which were associated with significantly increased apoptosis.
18F-TPP is a promising new voltage sensor for detecting mitochondrial dysfunction and apoptosis in various tissues.
PMCID: PMC3988254  PMID: 24582214
18F-TPP; Mitochondrion; Membrane Potential; Apoptosis
10.  Single Particle Fluorescence Burst Analysis of Epsin Induced Membrane Fission 
PLoS ONE  2015;10(3):e0119563.
Vital cellular processes, from cell growth to synaptic transmission, rely on membrane-bounded carriers and vesicles to transport molecular cargo to and from specific intracellular compartments throughout the cell. Compartment-specific proteins are required for the final step, membrane fission, which releases the transport carrier from the intracellular compartment. The role of fission proteins, especially at intracellular locations and in non-neuronal cells, while informed by the dynamin-1 paradigm, remains to be resolved. In this study, we introduce a highly sensitive approach for the identification and analysis of membrane fission machinery, called burst analysis spectroscopy (BAS). BAS is a single particle, free-solution approach, well suited for quantitative measurements of membrane dynamics. Here, we use BAS to analyze membrane fission induced by the potent, fission-active ENTH domain of epsin. Using this method, we obtained temperature-dependent, time-resolved measurements of liposome size and concentration changes, even at sub-micromolar concentration of the epsin ENTH domain. We also uncovered, at 37°C, fission activity for the full-length epsin protein, supporting the argument that the membrane-fission activity observed with the ENTH domain represents a native function of the full-length epsin protein.
PMCID: PMC4370887  PMID: 25799353
11.  A Mixed Methods Study of Parental Vaccine Decision Making and Parent-Provider Trust 
Academic pediatrics  2013;13(5):481-488.
To describe parental vaccine decision making behaviors and characterize trust in physician advice among parents with varying childhood vaccination behaviors.
Between 2008 and 2011, a mixed methods study was conducted with parents of children aged <4 years who were members of Kaiser Permanente Colorado health plan. Seven focus groups were conducted with vaccine hesitant parents. Based on findings from the focus groups, a survey was developed, pilot tested and mailed to a stratified sample of 854 parents who accepted (n=500), delayed (n=227), or refused (n=127) vaccinations for one of their children. Survey results were analyzed using chi-square tests and multivariable logistic regression.
Several themes emerged from the focus groups, including: 1) the vaccine decision making process begins prenatally, 2) vaccine decision making is an evolving process, and 3) there is overall trust in the pediatrician, but a lack of trust in the information they provided about vaccines. The survey response rate was 52% (n=443). Parents who refused or delayed vaccines were 2-times more likely to report that they began thinking about vaccines before their child was born, and 8-times more likely to report that they constantly re-evaluate their vaccine decisions than parents who accepted all vaccines. While parents tended to report trusting their pediatrician’s advice on nutrition, behavior and the physical examination, they did not believe their pediatrician provided balanced information on both the benefits and risks of vaccination.
These results have implications for future interventions to address parental vaccination concerns. Such interventions may be more effective if they are applied early (during pregnancy), often (pregnancy through infancy), and cover both the risks and benefits of vaccination.
PMCID: PMC3767928  PMID: 24011751
immunization; vaccine refusal; vaccine decision making; mixed methods
12.  A Concise Radiosynthesis of the Tau Radiopharmaceutical, [18F]T807 
Fluorine-18 labelled 7-(6-fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole ([18F]T807) is a potent and selective agent for imaging paired helical filaments of tau (PHF-tau) and is among the most promising PET radiopharmaceuticals for this target in early clinical trials. The present study reports a simplified one-step method for the synthesis of [18F]T807 that is broadly applicable for routine clinical production using a GE Tracerlab™ FXFN radiosynthesis module. Key facets of our optimized radiosynthesis include development and use of a more soluble protected precursor, tert-butyl 7-(6-nitropyridin-3-yl)-5H-pyrido[4,3-b]indole-5-carboxylate, as well as new HPLC separation conditions that enable a facile one-step synthesis. During the nucleophilic fluorinating reaction with potassium cryptand [18F]fluoride (K[18F]/K222) in DMSO at 130 °C over 10 min, the precursor is concurrently deprotected. Formulated [18F]T807 was prepared in an uncorrected radiochemical yield of 14 ± 3%, with a specific activity of 216 ± 60 GBq/μmol (5837 ± 1621 mCi/μmol) at the end of synthesis (60 min; n = 3) and validated for human use. This methodology offers the advantage of faster synthesis in fewer steps, with simpler automation which we anticipate will facilitate widespread clinical use of [18F]T807.
PMCID: PMC4114396  PMID: 24339014
T807; Tau; PET; fluorine-18
13.  Diffusion-controlled reaction rates for two active sites on a sphere 
BMC Biophysics  2014;7:3.
The diffusion-limited reaction rate of a uniform spherical reactant is generalized to anisotropic reactivity. Previous work has shown that the protein model of a uniform sphere is unsatisfactory in many cases. Competition of ligands binding to two active sites, on a spherical enzyme or cell is studied analytically.
The reaction rate constant is given for two sites at opposite ends of the species of interest. This is compared with twice the reaction rate for a single site. It is found that the competition between sites lowers the reaction rate over what is expected for two sites individually. Competition between sites does not show up, until the site half angle is greater than 30 degrees.
Competition between sites is negligible until the site size becomes large. The competitive effect grows as theta becomes large. The maximum effect is given for theta = pi/2.
PMCID: PMC4058695  PMID: 24982756
14.  Effect of Particle Size, Density and Shape on Margination of Nanoparticles in Microcirculation 
Nanotechnology  2011;22(11):115101.
In the recent past, remarkable advances in nanotechnology have generated nanoparticles of different shapes and sizes, which have been shown to exhibit unique properties suitable for biomedical applications such as cancer therapy and imaging. Obviously, all nanoparticles are not made equal. This becomes evident when we consider their transport behavior under blood flow in microcirculation. In this work, we evaluated the effect of critical physical characteristics such as the particle shape, size and density on a nanoparticle’s tendency to marginate towards the vessel walls in microcirculation using an in vitro model. The wall-deposition of nanoparticles was tested in a fibronectin-coated microfluidic channel at a physiologically relevant flow rate. Different classes of nanoparticles (liposome, metal particles) of different sizes (60–130 nm), densities (1–19 g/mL) and shapes (sphere, rod) displayed significantly different deposition as a result of different margination rates. The smaller-sized and the oblate-shaped particles displayed a favorable behavior as indicated by their higher margination rates. Notably, the particle density showed an even more essential role, as it was observed that the lighter particles marginated significantly more. Since nanoparticles must escape the flow in order to approach the vascular bed and subsequently extravascular components for meaningful interactions, the design of nanoparticles strongly affects their margination, a key factor for their ultimate in vivo effectiveness.
PMCID: PMC3530262  PMID: 21387846
Margination; drifting; nanoparticles; microfluidic channel; tumor microcirculation; nanoparticle shape; nanoparticle size; nanoparticle density
15.  Mannose-Binding Lectin Binds to Amyloid β Protein and Modulates Inflammation 
Mannose-binding lectin (MBL), a soluble factor of the innate immune system, is a pattern recognition molecule with a number of known ligands, including viruses, bacteria, and molecules from abnormal self tissues. In addition to its role in immunity, MBL also functions in the maintenance of tissue homeostasis. We present evidence here that MBL binds to amyloid β peptides. MBL binding to other known carbohydrate ligands is calcium-dependent and has been attributed to the carbohydrate-recognition domain, a common feature of other C-type lectins. In contrast, we find that the features of MBL binding to Aβ are more similar to the reported binding characteristics of the cysteine-rich domain of the unrelated mannose receptor and therefore may involve the MBL cysteine-rich domain. Differences in MBL ligand binding may contribute to modulation of inflammatory response and may correlate with the function of MBL in processes such as coagulation and tissue homeostasis.
PMCID: PMC3322523  PMID: 22536027
16.  Changes in Physiology before, during, and after Yawning 
The ultimate function of yawning continues to be debated. Here, we examine physiological measurements taken before, during, and after yawns in humans, in an attempt to identify key proximate mechanisms associated with this behavior. In two separate studies we measured changes in heart rate, lung volume, eye closure, skin conductance, ear pulse, respiratory sinus arrhythmia, and respiratory rate. Data were depicted from 75 s before and after yawns, and analyzed at baseline, during, and immediately following yawns. Increases in heart rate, lung volume, and eye muscle tension were observed during or immediately following yawning. Patterns of physiological changes during yawning were then compared to data from non-yawning deep inhalations. In one study, respiration period increased following the execution of a yawn. Much of the variance in physiology surrounding yawning was specific to the yawning event. This was not the case for deep inhalation. We consider our findings in light of various hypotheses about the function of yawning and conclude that they are most consistent with the brain cooling hypothesis.
PMCID: PMC3251816  PMID: 22319494
yawning; thermoregulation; temperature; brain cooling; heart rate; respiration; physiology
17.  Synthesis and characterization of complexes of the {ReO}3+ core with SNS and S donor ligands 
Inorganica chimica acta  2000;306(1):30-37.
The reaction of [ReOCl3(PPh3)2] with N,N-bis(2-mercaptoethyl)benzylamine and 4-bromobenzenethiol allowed for the isolation of [ReO{η3-(SCH2CH2)2N(CH2C6H5)}-(η1-C6H4Br-4-S)] (1). The reaction of [ReOCl3(PPh3)2] with [(HSCH2CH2)2N(CH2C5H4N)] and the appropriate thiol in chloroform treated with triethylamine has led to the isolation of a series of neutral rhenium complexes of the type [ReO{η3-(SCH2CH2)2N(CH2C5H4N)}(η1-C6H4X-4-S)] (X = Br (2), Cl (3), F (4), and OCH3 (5)) and [ReO{η3-(SCH2CH2)2N(CH2C5H4N)}(η1-C6H4OCH3-4-CH2S)] (6). Likewise, under similar reaction conditions, the use of the related tridentate ligand, [(HSCH2CH2)2N(CH2CH2C5H4N)], has led to the isolation of a series of rhenium complexes of the type [ReO{η3-(SCH2CH2)2N(CH2CH2C5H4N)}(η1-C6H4X-4-S)] (X=Br (7), Cl (8), OCH3 (9)), as well as [ReO{η3-(SCH2CH2)2N(CH2CH2C5H4N)}(η1-C6H4Cl-4-CH2S)]·0.5CH3(CH2)4CH3 (10). These compounds are extensions of the ‘3+1’ approach to the synthesis of materials with the {MO}3+ core (M=Tc and Re), which have applications in nuclear medicine. The ligands chosen allow systematic exploration of the consequences of para-substitution on the monodentate thiolate ligand [S] and of derivatization of the substituent R on the tridentate aminodithiol ligand [SNS] of the type (HSCH2CH2)2NR. Such modifications can influence lipophilicity, charge, size and molecular weight of the complex and consequently the biodistribution.
PMCID: PMC2901872  PMID: 20628539
Crystal structure; Rhenium complexes; Oxo complexes; SNS-donor ligand complexes; S-donor ligand complexes
18.  Yawning and Stretching Predict Brain Temperature Changes in Rats: Support for the Thermoregulatory Hypothesis 
Recent research suggests that yawning is an adaptive behavior that functions to promote brain thermoregulation among homeotherms. To explore the relationship between brain temperature and yawning we implanted thermocoupled probes in the frontal cortex of rats to measure brain temperature before, during and after yawning. Temperature recordings indicate that yawns and stretches occurred during increases in brain temperature, with brain temperatures being restored to baseline following the execution of each of these behaviors. The circulatory changes that accompany yawning and stretching may explain some of the thermal similarities surrounding these events. These results suggest that yawning and stretching may serve to maintain brain thermal homeostasis.
PMCID: PMC2965053  PMID: 21031034
yawning; stretching; thermoregulation; brain cooling; brain temperature
19.  Unfavourable prognosis associated with K‐ras gene mutation in pancreatic cancer surgical margins 
Gut  2006;55(11):1598-1605.
Despite intent to cure surgery with negative resection margins, locoregional recurrence is common in pancreatic cancer.
To determine whether detection of K‐ras gene mutation in the histologically negative surgical margins of pancreatic cancer reflects unrecognised disease.
Seventy patients who underwent curative resection for pancreatic ductal adenocarcinoma were evaluated.
All patients had surgical resection margins (pancreatic transection and retroperitoneal) that were histologically free of invasive cancer. DNA was extracted from these paraffin embedded surgical margins and assessed by quantitative real time polymerase chain reaction to detect the K‐ras gene mutation at codon 12. Detection of K‐ras mutation was correlated with standard clinicopathological factors.
K‐ras mutation was detected in histologically negative surgical margins of 37 of 70 (53%) patients. A significant difference in overall survival was demonstrated between patients with margins that were K‐ras mutation positive compared with negative (median 15 v 55 months, respectively; p = 0.0008). By univariate and multivariate analyses, detection of K‐ras mutation in the margins was a significant prognostic factor for poor survival (hazard ratio (HR) 2.8 (95% confidence interval (CI) 1.5–5.3), p = 0.0009; and HR 2.8 (95% CI 1.4–5.5), p = 0.004, respectively).
Detection of cells harbouring K‐ras mutation in histologically negative surgical margins of pancreatic cancer may represent unrecognised disease and correlates with poor disease outcome. The study demonstrates that molecular‐genetic evaluation of surgical resection margins can improve pathological staging and prognostic evaluation of patients with pancreatic ductal adenocarcinoma.
PMCID: PMC1860104  PMID: 16682430
K‐ras; pancreatic cancer; surgical margin; quantitative polymerase chain reaction
20.  Imaging amyloid deposition in Lewy body diseases 
Neurology  2008;71(12):903-910.
Extrapyramidal motor symptoms precede dementia in Parkinson disease (PDD) by many years, whereas dementia occurs early in dementia with Lewy bodies (DLB). Despite this clinical distinction, the neuropsychological and neuropathologic features of these conditions overlap. In addition to widespread distribution of Lewy bodies, both diseases have variable burdens of neuritic plaques and neurofibrillary tangles characteristic of Alzheimer disease (AD).
To determine whether amyloid deposition, as assessed by PET imaging with the β-amyloid–binding compound Pittsburgh Compound B (PiB), can distinguish DLB from PDD, and to assess whether regional patterns of amyloid deposition correlate with specific motor or cognitive features.
Eight DLB, 7 PDD, 11 Parkinson disease (PD), 15 AD, and 37 normal control (NC) subjects underwent PiB-PET imaging and neuropsychological assessment. Amyloid burden was quantified using the PiB distribution volume ratio.
Cortical amyloid burden was higher in the DLB group than in the PDD group, comparable to the AD group. Amyloid deposition in the PDD group was low, comparable to the PD and NC groups. Relative to global cortical retention, occipital PiB retention was lower in the AD group than in the other groups. For the DLB, PDD, and PD groups, amyloid deposition in the parietal (lateral and precuneus)/posterior cingulate region was related to visuospatial impairment. Striatal PiB retention in the DLB and PDD groups was associated with less impaired motor function.
Global cortical amyloid burden is high in dementia with Lewy bodies (DLB) but low in Parkinson disease dementia. These data suggest that β-amyloid may contribute selectively to the cognitive impairment of DLB and may contribute to the timing of dementia relative to the motor signs of parkinsonism.
= Automated Anatomic Labeling;
= Alzheimer disease;
= Alzheimer’s Disease Research Center;
= American version of the National Adult Reading Test;
= analysis of covariance;
= Blessed Dementia Scale;
= cerebral amyloid angiopathy;
= Clinical Dementia Rating;
= Clinical Dementia Rating Sum of Boxes;
= dementia with Lewy bodies;
= distribution volume ratio;
= Cued Selective Reminding Test;
= Free Selective Reminding Test;
= Hoehn and Yahr;
= Massachusetts General Hospital;
= Mini-Mental State Examination;
= normal control;
= neurofibrillary tangle;
= Neuropsychiatric Inventory Questionnaire;
= not significant;
= Parkinson disease;
= Parkinson disease dementia;
= Pittsburgh Compound B;
= region of interest;
= Statistical Parametric Mapping;
= UK Parkinson’s Disease Society Brain Bank Research Center;
= United Parkinson’s Disease Rating Scale;
= Wechsler Adult Intelligence Scale–Revised.
PMCID: PMC2637553  PMID: 18794492
21.  Imaging amyloid deposition in Lewy body diseases 
Neurology  2008;71(12):903-910.
Extrapyramidal motor symptoms precede dementia in Parkinson disease (PDD) by many years, whereas dementia occurs early in dementia with Lewy bodies (DLB). Despite this clinical distinction, the neuropsychological and neuropathologic features of these conditions overlap. In addition to widespread distribution of Lewy bodies, both diseases have variable burdens of neuritic plaques and neurofibrillary tangles characteristic of Alzheimer disease (AD).
To determine whether amyloid deposition, as assessed by PET imaging with the β-amyloid–binding compound Pittsburgh Compound B (PiB), can distinguish DLB from PDD, and to assess whether regional patterns of amyloid deposition correlate with specific motor or cognitive features.
Eight DLB, 7 PDD, 11 Parkinson disease (PD), 15 AD, and 37 normal control (NC) subjects underwent PiB-PET imaging and neuropsychological assessment. Amyloid burden was quantified using the PiB distribution volume ratio.
Cortical amyloid burden was higher in the DLB group than in the PDD group, comparable to the AD group. Amyloid deposition in the PDD group was low, comparable to the PD and NC groups. Relative to global cortical retention, occipital PiB retention was lower in the AD group than in the other groups. For the DLB, PDD, and PD groups, amyloid deposition in the parietal (lateral and precuneus)/posterior cingulate region was related to visuospatial impairment. Striatal PiB retention in the DLB and PDD groups was associated with less impaired motor function.
Global cortical amyloid burden is high in dementia with Lewy bodies (DLB) but low in Parkinson disease dementia. These data suggest that β-amyloid may contribute selectively to the cognitive impairment of DLB and may contribute to the timing of dementia relative to the motor signs of parkinsonism.
PMCID: PMC2637553  PMID: 18794492
22.  Validation of a survey instrument to assess home environments for physical activity and healthy eating in overweight children 
Few measures exist to measure the overall home environment for its ability to support physical activity (PA) and healthy eating in overweight children. The purpose of this study was to develop and test the reliability and validity of such a measure.
The Home Environment Survey (HES) was developed to reflect availability, accessibility, parental role modelling, and parental policies related to PA resources, fruits and vegetables (F&V), and sugar sweetened drinks and snacks (SS). Parents of overweight children (n = 219) completed the HES and concurrent behavioural assessments. Children completed the Block Kids survey and wore an accelerometer for one week. A subset of parents (n = 156) completed the HES a second time to determine test-retest reliability. Finally, 41 parent dyads living in the same home (n = 41) completed the survey to determine inter-rater reliability. Initial psychometric analyses were completed to trim items from the measure based on lack of variability in responses, moderate or higher item to scale correlation, or contribution to strong internal consistency. Inter-rater and test-retest reliability were completed using intraclass correlation coefficients. Validity was assessed using Pearson correlations between the HES scores and child and parent nutrition and PA.
Eight items were removed and acceptable internal consistency was documented for all scales (α = .66–84) with the exception of the F&V accessibility. The F&V accessibility was reduced to a single item because the other two items did not meet reliability standards. Test-retest reliability was high (r > .75) for all scales. Inter-rater reliability varied across scales (r = .22–.89). PA accessibility, parent role modelling, and parental policies were all related significantly to child (r = .14–.21) and parent (r = .15–.31) PA. Similarly, availability of F&V and SS, parental role modelling, and parental policies were related to child (r = .14–36) and parent (r = .15–26) eating habits.
The HES shows promise as a potentially valid and reliable assessment of the physical and social home environment related to a child's physical activity and eating habits.
PMCID: PMC2253552  PMID: 18190709
23.  Heterotopic bone formation within a missile track. 
A case is presented which is thought to be the first described example of heterotopic ossification occurring within the path of a bullet. Although the information was not available from prior medical records, the bullet presumably passed though bone or periosteum, thereby seeding the permanent cavity and facilitating ossification within the surrounding muscle and soft tissue.
PMCID: PMC1342706  PMID: 8733674
24.  Implementation of a Public Health Client Data Base — Lessons Learned 
A Health Department client data base was developed in 1983 in conjunction with City-owned Brackenridge Hospital. From systems analyses through implementation phases, the Health Department's Information Management team worked closely with Hospital Data Processing to insure mutual accessibility of information between the Hospital Admission/Registration system and the Health Department client data base. Shared information facilitates continuity of health care, effective discharge planning, networking/referral, and program evaluation/monitoring. Of particular concern are the numerous problems encountered during the process: Factors ranging from under-estimates of time required to program and actual implementation to functional impact on clinic operations. These underscore the need to realistically and adequately plan the development of a mainframe client data base in a local Health Department.
PMCID: PMC2578579
25.  Austin-Travis County Health Department's Information System 
In response to increased organizational complexity, reduced financial resources and an expanding client population, an Information Management Division was created within the Austin-Travis County Health Department in March 1982.
An important component of this Division is the Information Systems Plan which insures the systematic collection, storage and analysis of data and information used by managers to facilitate decision making and to meet reporting requirements. In addition to providing Public Health Services to the community, the Health Department is responsible for indigent health care. After three years of managing the Medical Assistance Program for indigent care, it became apparent that a shared data base with city-owned Brackenridge Hospital was appropriate to insure continuity of health care, program monitoring/evaluation and effective discharge planning.
PMCID: PMC2578332

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