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1.  Does Teriparatide Improve Femoral Neck Fracture Healing: Results From A Randomized Placebo-controlled Trial 
There is a medical need for therapies that improve hip fracture healing. Teriparatide (Forteo®/ Forsteo®, recombinant human parathyroid hormone) is a bone anabolic drug that is approved for treatment of osteoporosis and glucocorticoid-induced osteoporosis in men and postmenopausal women at high fracture risk. Preclinical and preliminary clinical data also suggest that teriparatide may enhance bone healing.
We wished to test the hypotheses that treatment with teriparatide versus placebo would improve femoral neck fracture healing after internal fixation as measured by (1) frequency of revision surgery, (2) radiographic fracture healing, and (3) other outcomes including pain control, gait speed, and safety.
We initiated two separate, but identically designed, clinical trials to meet FDA requirements to provide substantial evidence to support approval of a new indication. The two prospective, randomized double-blind, placebo-controlled Phase III studies were designed to evaluate the effect of subcutaneous teriparatide (20 μg/day) for 6 months versus placebo on fracture healing at 24 months. The trials were conducted concurrently with a planned enrollment of 1220 patients per trial. However, enrollment was stopped owing to very slow patient accrual, and an a priori decision was made to pool the results of those studies for statistical analyses before study completion; pooling was specified in both protocols. Randomization was stratified by fixation (sliding hip screw or multiple cancellous screws) and fracture type (displaced or nondisplaced). An independent Central Adjudication Committee reviewed revision surgical procedures and radiographs. A total of 159 patients were randomized in the two trials (81 placebo, 78 teriparatide). The combined program had very low power to detect the originally expected treatment effect but had approximately 80% power to detect a larger difference of 12% between treatment groups for risk of revision surgery.
The proportion of patients undergoing revision surgery at 12 months was 14% (11 of 81) in the placebo group versus 17% (13 of 78) in the teriparatide group. Central Adjudication Committee review excluded two of these patients treated with placebo from the primary analysis. After exclusions, the proportion of patients who did not undergo revision surgery at 12 months (primary endpoint) was not different between the study and placebo groups, at 88% in the placebo group (90% CI, 0.79–0.93) versus 84% in the teriparatide group (90% CI, 0.75–0.90; p = 0.743). There also were no differences between groups in the proportion of patients achieving radiographic fracture healing at 12 months (75% [61 of 81] placebo versus 73% [57 of 78] teriparatide; odds ratio, 0.89; 90% CI, 0.46–1.72; p = 0.692) or in measures of pain control (such as pain during ambulation, 92% [55 of 62] placebo versus 91% [52 of 57] teriparatide; odds ratio, 0.91; 90% CI, 0.25–3.37; p = 0.681). The frequency of patients reporting adverse events was 49% [40 of 81] in the placebo group versus 45% [35 of 78] in the teriparatide group (p = 0.634) during the 6-month treatment period.
The small sample size limited this study’s power to detect potential differences, and the results are exploratory. With the patients available, teriparatide did not decrease the risk of revision surgery, improve radiographic signs of fracture healing, or decrease pain compared with the placebo. The adverse event data observed were consistent with the teriparatide safety profile. Functional and health outcome data from the studies may help improve our understanding of patients recovering from femoral neck fractures. Further large controlled studies are required to determine the effect of teriparatide on fracture healing.
Level of Evidence
Level II, prospective study.
PMCID: PMC4814417  PMID: 26932738
2.  Liver X receptor β: new player in the regulatory network of thyroid hormone and ‘browning’ of white fat 
Adipocyte  2016;5(2):238-242.
The recent discovery of browning of white adipose tissue (WAT) has raised great research interest because of its significant potential in counteracting obesity and type II diabetes. However, the mechanisms underlying browning are still poorly understood. Liver X receptors (LXRs) are one class of nuclear receptors, which play a vital role in regulating cholesterol, triglyceride and glucose metabolism. Following our previous finding that LXRs serve as repressors of UCP1 in classic brown adipose tissue in female mice, we found that LXRs, especially LXRβ, also repress the browning process of subcutaneous adipose tissue (SAT) in male rodents fed a normal diet. Depletion of LXRs activated thyrotropin releasing hormone positive neurons in the paraventricular area of the hypothalamus, and thus stimulated secretion of thyroid-stimulating hormone from the pituitary. Consequently production of thyroid hormones in the thyroid gland and circulating thyroid hormone level were increased. Moreover, the activity of thyroid signaling in SAT was markedly increased. One unexpected finding of our study is that LXRs are indispensable in the thyroid hormone negative feedback loop at the level of the hypothalamus. LXRs maintain expression of thyroid receptors in the brain and when they are inactivated there is no negative feedback of thyroid hormone in the hypothalamus. Together, our findings have uncovered the basis of increased energy expenditure in male LXR knock-out mice and provided support for targeting LXRs in treatment of obesity.
PMCID: PMC4916863  PMID: 27386163
beige cells; browning of adipose tissue; HPT axis; liver X receptors; negative feedback loop; thyroid hormones; UCP1
3.  Defective cholesterol metabolism in amyotrophic lateral sclerosis[S] 
Journal of Lipid Research  2016;58(1):267-278.
As neurons die, cholesterol is released in the central nervous system (CNS); hence, this sterol and its metabolites may represent a biomarker of neurodegeneration, including in amyotrophic lateral sclerosis (ALS), in which altered cholesterol levels have been linked to prognosis. More than 40 different sterols were quantified in serum and cerebrospinal fluid (CSF) from ALS patients and healthy controls. In CSF, the concentration of cholesterol was found to be elevated in ALS samples. When CSF metabolite levels were normalized to cholesterol, the cholesterol metabolite 3β,7α-dihydroxycholest-5-en-26-oic acid, along with its precursor 3β-hydroxycholest-5-en-26-oic acid and product 7α-hydroxy-3-oxocholest-4-en-26-oic acid, were reduced in concentration, whereas metabolites known to be imported from the circulation into the CNS were not found to differ in concentration between groups. Analysis of serum revealed that (25R)26-hydroxycholesterol, the immediate precursor of 3β-hydroxycholest-5-en-26-oic acid, was reduced in concentration in ALS patients compared with controls. We conclude that the acidic branch of bile acid biosynthesis, known to be operative in-part in the brain, is defective in ALS, leading to a failure of the CNS to remove excess cholesterol, which may be toxic to neuronal cells, compounded by a reduction in neuroprotective 3β,7α-dihydroxycholest-5-en-26-oic acid.
PMCID: PMC5234729  PMID: 27811233
oxysterols; mass spectrometry; cytochrome P450; nuclear receptors/LXR; brain lipids; bile acids and salts/biosynthesis; cholestenoic acids; neurodeneneration.
4.  An ERβ agonist induces browning of subcutaneous abdominal fat pad in obese female mice 
Scientific Reports  2016;6:38579.
Estrogen, via estrogen receptor alpha (ERα), exerts several beneficial effects on metabolism and energy homeostasis by controlling size, enzymatic activity and hormonal content of adipose tissue. The actions of estrogen on sympathetic ganglia, which are key players in the browning process, are less well known. In the present study we show that ERβ influences browning of subcutaneous adipose tissue (SAT) via its actions both on sympathetic ganglia and on the SAT itself. A 3-day-treatment with a selective ERβ agonist, LY3201, induced browning of SAT in 1-year-old obese WT and ERα−/− female mice. Browning was associated with increased expression of ERβ in the nuclei of neurons in the sympathetic ganglia, increase in tyrosine hydroxylase in both nerve terminals in the SAT and sympathetic ganglia neurons and an increase of β3-adrenoceptor in the SAT. LY3201 had no effect on browning in young female or male mice. In the case of young females browning was already maximal while in males there was very little expression of ERβ in the SAT and very little expression of the β3-adrenoceptor. The increase in both sympathetic tone and responsiveness of adipocytes to catecholamines reveals a novel role for ERβ in controlling browning of adipose tissue.
PMCID: PMC5138613  PMID: 27922125
5.  Improving National Data Systems for Surveillance of Suicide-related Events 
American journal of preventive medicine  2014;47(3 Suppl 2):S122-S129.
Describing the characteristics and patterns of suicidal behavior is an essential component in developing successful prevention efforts. The Data and Surveillance Task Force (DSTF) of the National Action Alliance for Suicide Prevention was charged with making recommendations for improving national data systems for public health surveillance of suicide-related problems, including suicidal thoughts, suicide attempts and deaths due to suicide. Data from the national systems can be used to draw attention to the magnitude of the problem and are useful for establishing national health priorities. National data can also be used to examine differences in rates across groups (e.g., sex, racial/ethnic, and age groups) and geographic regions, and are useful in identifying patterns in the mechanism of suicide, including those that rarely occur.
Using evaluation criteria from the Centers for Disease Control and Prevention, the World Health Organization, and the U.S.-based Safe States Alliance, the DSTF reviewed 28 national data systems for feasibility of use in the surveillance of suicidal behavior, including deaths, non-fatal attempts and suicidal thoughts. The review criteria included such attributes as the aspects of the suicide-related spectrum (e.g., thoughts, attempts, deaths) covered by the system, how the data are collected (e.g., census, sample, survey, administrative data files, self-report, reporting by care providers), and the strengths and limitations of the survey or data system.
The DSTF identified common strengths and challenges among the data systems based on the underlying data source (e.g., death records, health care provider records, population-based surveys, health insurance claims). From these findings, the DSTF proposed several recommendations for improving existing data systems, such as using standard language and definitions, adding new variables to existing surveys, expanding the geographic scope of surveys to include areas where data are not currently collected, oversampling of underrepresented groups, and improving the completeness and quality of information on death certificates.
Some of the DSTF recommendations are potentially achievable in the short term (<1–3 years) within existing data systems, while others involve more extensive changes and will require longer term efforts (4–10 years). Implementing these recommendations would assist in the development of a national coordinated program of fatal and nonfatal suicide surveillance to facilitate evidence-based action to reduce the incidence of suicide and suicidal behavior in all populations.
PMCID: PMC4959537  PMID: 25145729
6.  Hot spots in mortality from drug poisoning in the United States, 2007–2009 
Health & place  2013;26:14-20.
Over the past several years, the death rate associated with drug poisoning has increased by over 300% in the U.S. Drug poisoning mortality varies widely by state, but geographic variation at the substate level has largely not been explored. National mortality data (2007–2009) and small area estimation methods were used to predict age-adjusted death rates due to drug poisoning at the county level, which were then mapped in order to explore: whether drug poisoning mortality clusters by county, and where hot and cold spots occur (i.e., groups of counties that evidence extremely high or low age-adjusted death rates due to drug poisoning). Results highlight several regions of the U.S. where the burden of drug poisoning mortality is especially high. Findings may help inform efforts to address the growing problem of drug poisoning mortality by indicating where the epidemic is concentrated geographically.
PMCID: PMC4659494  PMID: 24333939
Empirical Bayes prediction; Spatial variation; Overdose; Cold spots
7.  Trends and Geographic Patterns in Drug-Poisoning Death Rates in the U.S., 1999–2009 
Drug poisoning mortality has increased substantially in the U.S. over the past 3 decades. Previous studies have described state-level variation and urban–rural differences in drug-poisoning deaths, but variation at the county level has largely not been explored in part because crude county-level death rates are often highly unstable.
The goal of the study was to use small-area estimation techniques to produce stable county-level estimates of age-adjusted death rates (AADR) associated with drug poisoning for the U.S., 1999–2009, in order to examine geographic and temporal variation.
Population-based observational study using data on 304,087 drug-poisoning deaths in the U.S. from the 1999–2009 National Vital Statistics Multiple Cause of Death Files (analyzed in 2012). Because of the zero-inflated and right-skewed distribution of drug-poisoning death rates, a two-stage modeling procedure was used in which the first stage modeled the probability of observing a death for a given county and year, and the second stage modeled the log-transformed drug-poisoning death rate given that a death occurred. Empirical Bayes estimates of county-level drug-poisoning death rates were mapped to explore temporal and geographic variation.
Only 3% of counties had drug-poisoning AADRs greater than ten per 100,000 per year in 1999–2000, compared to 54% in 2008–2009. Drug-poisoning AADRs grew by 394% in rural areas compared to 279% for large central metropolitan counties, but the highest drug-poisoning AADRs were observed in central metropolitan areas from 1999 to 2009.
There was substantial geographic variation in drug-poisoning mortality across the U.S.
PMCID: PMC4659504  PMID: 24237925
8.  Structural Basis for Receptor Activity-Modifying Protein-Dependent Selective Peptide Recognition by a G Protein-Coupled Receptor 
Molecular cell  2015;58(6):1040-1052.
Association of receptor activity-modifying proteins (RAMP1–3) with the G protein-coupled receptor (GPCR) calcitonin receptor-like receptor (CLR) enables selective recognition of the peptides calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) that have diverse functions in the cardiovascular and lymphatic systems. How peptides selectively bind GPCR:RAMP complexes is unknown. We report crystal structures of CGRP analog-bound CLR: RAMP1 and AM-bound CLR:RAMP2 extracellular domain heterodimers at 2.5 and 1.8 Å resolutions, respectively. The peptides similarly occupy a shared binding site on CLR with conformations characterized by a β-turn structure near their C termini rather than the α-helical structure common to peptides that bind related GPCRs. The RAMPs augment the binding site with distinct contacts to the variable C-terminal peptide residues and elicit subtly different CLR conformations. The structures and accompanying pharmacology data reveal how a class of accessory membrane proteins modulate ligand binding of a GPCR and may inform drug development targeting CLR:RAMP complexes.
Graphical abstract
PMCID: PMC4504005  PMID: 25982113
9.  Structural Basis for Receptor Activity-Modifying Protein-Dependent Selective Peptide Recognition by a G Protein-Coupled Receptor 
Molecular Cell  2015;58(6):1040-1052.
Association of receptor activity-modifying proteins (RAMP1-3) with the G protein-coupled receptor (GPCR) calcitonin receptor-like receptor (CLR) enables selective recognition of the peptides calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) that have diverse functions in the cardiovascular and lymphatic systems. How peptides selectively bind GPCR:RAMP complexes is unknown. We report crystal structures of CGRP analog-bound CLR:RAMP1 and AM-bound CLR:RAMP2 extracellular domain heterodimers at 2.5 and 1.8 Å resolutions, respectively. The peptides similarly occupy a shared binding site on CLR with conformations characterized by a β-turn structure near their C termini rather than the α-helical structure common to peptides that bind related GPCRs. The RAMPs augment the binding site with distinct contacts to the variable C-terminal peptide residues and elicit subtly different CLR conformations. The structures and accompanying pharmacology data reveal how a class of accessory membrane proteins modulate ligand binding of a GPCR and may inform drug development targeting CLR:RAMP complexes.
Graphical Abstract
•Crystal structures reveal how CGRP and AM peptides bind their heterodimeric receptors•CGRP and AM occupy a shared binding site on CLR with minimal contact to the RAMPs•Peptide binding modes were confirmed for intact receptors in cells by mutagenesis•Peptide selectivity arises from RAMP-specific contacts and subtle alteration of CLR
Booe et al. report two crystal structures that reveal how selectivity of the GPCR CLR for CGRP and AM peptides is modulated by RAMP proteins. The peptides similarly occupy a shared binding site on CLR. RAMPs augment the binding site with distinct contacts to the peptides and subtly alter CLR.
PMCID: PMC4504005  PMID: 25982113
10.  Research Using Emergency Department–related Data Sets: Current Status and Future Directions 
The 2009 Academic Emergency Medicine consensus conference focused on “Public Health in the ED: Surveillance, Screening and Intervention.” One conference breakout session discussed the significant research value of health-related data sets. This article represents the proceedings from that session, primarily focusing on emergency department (ED)-related data sets and includes examples of the use of a data set based on ED visits for research purposes. It discusses types of ED-related data sets available, highlights barriers to research use of ED-related data sets, and notes limitations of these data sets. The paper highlights future directions and challenges to using these important sources of data for research, including identification of five main needs related to enhancing the use of ED-related data sets. These are 1) electronic linkage of initial and follow-up ED visits and linkage of information about ED visits to other outcomes, including costs of care, while maintaining deidentification of the data; 2) timely data access with minimal barriers; 3) complete data collection for clinically relevant and/or historical data elements, such as the external cause-of-injury code; 4) easy access to data that can be parsed into smaller jurisdictions (such as states) for policy and/or research purposes, while maintaining confidentiality; and 5) linkages between health survey data and health claims data. ED-related data sets contain much data collected directly from health care facilities, individual patient records, and multiple other sources that have significant potential impact for studying and improving the health of individuals and the population.
PMCID: PMC3744773  PMID: 20053229
emergency departments; research; data sets; health services
13.  Mapping and Application of Enhancer-trap Flippase Expression in Larval and Adult Drosophila CNS 
The Gal4/ UAS binary method is powerful for gene and neural circuitry manipulation in Drosophila. For most neurobiological studies, however, Gal4 expression is rarely tissue-specific enough to allow for precise correlation of the circuit with behavioral readouts. To overcome this major hurdle, we recently developed the FINGR method to achieve a more restrictive Gal4 expression in the tissue of interest. The FINGR method has three components: 1) the traditional Gal4/UAS system; 2) a set of FLP/FRT-mediated Gal80 converting tools; and 3) enhancer-trap FLP (ET-FLP). Gal4 is used to define the primary neural circuitry of interest. Paring the Gal4 with a UAS-effector, such as UAS-MJD78Q or UAS-Shits, regulates the neuronal activity, which is in turn manifested by alterations in the fly behavior. With an additional UAS-reporter such as UAS-GFP, the neural circuit involved in the specific behavior can be simultaneously mapped for morphological analysis. For Gal4 lines with broad expression, Gal4 expression can be restricted by using two complementary Gal80-converting tools: tubP>Gal80> ('flip out') and tubP>stop>Gal80 ('flip in'). Finally, investigators can turn Gal80 on or off, respectively, with the help of tissue-specific ET-FLP. In the flip-in mode, Gal80 will repress Gal4 expression wherever Gal4 and ET-FLP intersect. In the flip-out mode, Gal80 will relieve Gal4 repression in cells in which Gal4 and FLP overlap. Both approaches enable the restriction of the number of cells in the Gal4-defined circuitry, but in an inverse pattern. The FINGR method is compatible with the vast collection of Gal4 lines in the fly community and highly versatile for traditional clonal analysis and for neural circuit mapping. In this protocol, we demonstrate the mapping of FLP expression patterns in select ET-FLPx2 lines and the effectiveness of the FINGR method in photoreceptor cells. The principle of the FINGR method should also be applicable to other genetic model organisms in which Gal4/UAS, Gal80, and FLP/FRT are used.
PMCID: PMC3155963  PMID: 21673643
14.  Epidemiology of Anesthesia-related Mortality in the United States, 1999–2005 
Anesthesiology  2009;110(4):759-765.
Previous research on anesthesia-related mortality in the United States was limited to data from individual hospitals. The purpose of this study was to examine the epidemiologic patterns of anesthesia-related deaths at the national level.
We searched the International Classification of Diseases, 10th Revision, manuals for codes specifically related to anesthesia/anesthetics. These codes were used to identify anesthesia-related deaths from the US multiple-cause-of-death data files for the years 1999–2005. Rates from anesthesia-related deaths were calculated based on population and hospital surgical discharge data.
We identified 46 anesthesia/anesthetic codes, including complications of anesthesia during pregnancy, labor, and puerperium (O29.0–O29.9, O74.0–74.9, O89.0–O89.9), overdose of anesthetics (T41.0–T41.4), adverse effects of anesthetics in therapeutic use (Y45.0, Y47.1, Y48.0–Y48.4, Y55.1), and other complications of anesthesia (T88.2–T88.5, Y65.3). Of the 2,211 recorded anesthesia-related deaths in the United States during 1999–2005, 46.6% were attributable to overdose of anesthetics, 42.5% to adverse effects of anesthetics in therapeutic use, 3.6% to complications of anesthesia during pregnancy, labor, and puerperium, and 7.3% to other complications of anesthesia. The estimated rates from anesthesia-related deaths were 1.1 per million population per year (1.45 for males and 0.77 for females) and 8.2 per million hospital surgical discharges (11.7 for men and 6.5 for women). The highest death rates were found in persons aged 85 years and older.
Each year in the United States, anesthesia/anesthetics are reported as the underlying cause in approximately 34 deaths and contributing factors in another 281 deaths, with excess mortality risk in the elderly and men.
PMCID: PMC2697561  PMID: 19322941
15.  The effect of tadalafil on the time to exercise-induced myocardial ischaemia in subjects with coronary artery disease 
To investigate the effect of tadalafil on the time to exercise-induced myocardial ischaemia in subjects with coronary artery disease (CAD).
CAD and erectile dysfunction (ED) share similar risk factors. It is important to know the cardiovascular effects of tadalafil in patients with CAD during physical exertion that is comparable with sexual activity.
A randomized, placebo-controlled, double-blind, two-period, crossover study comparing the effects of tadalafil 10 mg and placebo on the time to exercise treadmill test (ETT)-induced myocardial ischaemia in subjects with stable CAD (n = 23; age range: 53–75 years, all exhibited ST-segment depression >1.5 mm at screening ETT at >5METS). Haemodynamic responses to sublingual nitroglycerin (NTG) were assessed before and after ETT.
Compared with placebo, tadalafil did not significantly affect the time to ETT-induced ischaemia (13 min/31 s vs. 13 min/36 s, respectively). Before exercise, NTG evoked decreases in sitting systolic blood pressure (SBP) that were significantly greater when subjects received tadalafil compared with placebo, and after exercise, more subjects experienced a decrease in SBP <85 mmHg in response to NTG after taking tadalafil vs. placebo. When subjects received tadalafil compared with placebo, SBP was lower at rest (−7 mmHg; −12,-2), during ETT (−10 mmHg; −16, −3), and after ETT (−13 mmHg; −19, −7).
Tadalafil did not significantly alter the time to ETT-induced ischaemia compared with placebo in subjects with CAD. Tadalafil reduced resting and exercise SBP. Due to the potential for hypotension, the concomitant use of nitrates and tadalafil is contraindicated.
PMCID: PMC1884941  PMID: 16236035
phosphodiesterase 5 inhibitors; nitrate; exercise induced ischaemia; tadalafil
16.  Regulation of Postnatal Lung Development and Homeostasis by Estrogen Receptor β 
Molecular and Cellular Biology  2003;23(23):8542-8552.
Estrogens have well-documented effects on lung development and physiology. However, the classical estrogen receptor α (ERα) is undetectable in the lung, and this has left many unanswered questions about the mechanism of estrogen action in this organ. Here we show, both in vivo and in vitro, that ERβ is abundantly expressed and biologically active in the lung. Comparisons of lungs from wild-type mice and mice with an inactivated ERβ gene (ERβ−/−) revealed decreased numbers of alveoli in adult female ERβ−/− mice and findings suggesting deficient alveolar formation as well as evidence of surfactant accumulation. Platelet-derived growth factor A (PDGF-A) and granulocyte-macrophage colony-stimulating factor (GM-CSF), key regulators of alveolar formation and surfactant homeostasis, respectively, were decreased in lungs of adult female ERβ−/− mice, and direct transcriptional regulation of these genes by ERβ was demonstrated. This suggests that estrogens act via ERβ in the lung to modify PDGF-A and GM-CSF expression. These results provide a potential molecular mechanism for the gender differences in alveolar structure observed in the adult lung and establish ERβ as a previously unknown regulator of postnatal lung development and homeostasis.
PMCID: PMC262653  PMID: 14612399

Results 1-17 (17)