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1.  Hyperbaric oxygen therapy for chronic post-concussive syndrome 
In this editorial, the value of hyperbaric oxygen therapy in the management of chronic post-concussive syndrome following mild traumatic brain injury is discussed.
PMCID: PMC3984490  PMID: 24717073
Hyperbaric oxygen; Traumatic brain injury; Outcome
2.  Role of mGluR4 in acquisition of fear learning and memory 
Neuropharmacology  2012;66:365-372.
Group III metabotropic glutamate receptors (mGluRs), which are generally located presynaptically, modulate synaptic transmission by regulating neurotransmitter release. Previously we showed enhanced amygdala-dependent cued fear conditioning in mGluR4−/− mice 24 hr following training involving two tone-shock pairings. In this study, we assessed the effects of modulating mGluR4 signaling on acquisition and extinction of conditioned fear. mGluR4−/− and wild-type female and male mice received 10 tone-shock pairings during training. Compared to wild-type mice, mGluR4−/− mice showed enhanced acquisition and extinction of cued fear. Next, we assessed whether acute pharmacological stimulation of mGluR4 with the specific orthosteric mGluR4 agonist LSP1-2111 also affects acquisition and extinction of cued fear. Consistent with the enhanced acquisition of cued fear in mGluR4−/−, LSP1-2111, at 2.5 and 5mg/kg, inhibited acquisition of cued fear conditioning in wild-type male mice. The drug’s effect on extinction was less clear and only a subtle effect was seen at 5 mg/kg. Finally, analysis of microarray data of amygdala tissues from mGluR4−/− versus wild-type and from wild-type mice treated with a mGluR4 agonist versus saline revealed a significant overlap in pattern of gene expression. Together, these data support a role for mGluR4 signaling in acquisition of fear learning and memory.
PMCID: PMC3508079  PMID: 22884897
mGluR4; fear conditioning; mice; cued
3.  Associations between Body Composition and Bone Density and Structure in Men and Women across the Adult Age Spectrum 
Bone  2012;53(1):34-41.
The objective of this study was identify independent associations between body composition and bone outcomes, including cortical structure and cortical and trabecular volumetric bone mineral density (vBMD) across the adult age spectrum.
This cross-sectional study evaluated over 400 healthy adults (48% male, 44% black race), ages 21–78 years. Multivariable linear regression models evaluated associations between whole-body DXA measures of lean body mass index (LBMI) and fat mass index (FMI) and tibia peripheral quantitative CT (pQCT) measures of cortical section modulus, cortical and trabecular vBMD and muscle density (as a measure of intramuscular fat), adjusted for age, sex, and race. All associations reported below were statistically significant (p < 0.05).
Older age and female sex were associated with lower LBMI and muscle strength. Black race was associated with greater LBMI but lower muscle density. Greater FMI was associated with lower muscle density. Cortical section modulus was positively associated with LBMI and muscle strength and negatively associated with FMI. Adjustment for body composition eliminated the greater section modulus observed in black participants and attenuated the lower section modulus in females. Greater LBMI was associated with lower cortical BMD and greater trabecular BMD. FMI was not associated with either BMD outcome. Greater muscle density was associated with greater trabecular and cortical BMD. Associations between body composition and bone outcomes did not vary by sex (no significant tests for interaction).
These data highlight age, sex- and race-specific differences in body composition, muscle strength and muscle density, and demonstrate discrete associations with bone density and structure. These data also show that age, sex- and race- related patterns of bone density and strength are independent of differences in body composition. Longitudinal studies are needed to examine the temporal relations between changes in bone and body composition.
PMCID: PMC3552077  PMID: 23238122
DXA; lean mass; pQCT; section modulus; bone mineral density; muscle density
4.  A Randomized Controlled Effectiveness Trial of Reciprocal Peer Support in Heart Failure 
Circulation. Heart failure  2013;6(2):246-253.
Disease management programs for patients hospitalized with heart failure (HF) although effective, are often resource intensive, limiting their uptake. Peer support programs have led to improved outcomes among patients with other chronic conditions and may result in similar improvements for HF patients.
Methods and Results
In this randomized controlled trial, Reciprocal Peer Support (RSP) arm patients participated in a HF nurse practitioner (NP)-led goal setting group session, received brief training in peer communication skills, and were paired with another participant in their cohort with whom they were encouraged to talk weekly using a telephone platform. Participants were also encouraged to attend three NP-facilitated peer support group sessions. Patients in the Nurse Care Management (NCM) arm attended a NP-led session to address their HF care questions and receive HF educational materials and information on how to access care management services. The median age of the patients was 69 years, 51% were female, and 26% were racial/ethnic minorities. Only 55% of RPS patients participated in peer calls or group sessions. In intention-to-treat analyses, the RPS and NCM groups did not differ in time to first all-cause rehospitalization or death or in mean numbers of rehospitalizations or deaths. There were no differences in improvements in 6-month measures of HF-specific quality of life or social support.
Among patients recently hospitalized for HF, over half of RPS participants had no or minimal engagement with the reciprocal peer support program, and the program did not improve outcomes compared to usual HF-nurse care management.
PMCID: PMC3782294  PMID: 23388114
heart failure; peer support; randomized controlled trial; self-management; nurse case management
5.  Did You Hear the One About the Doctor? An Examination of Doctor Jokes Posted on Facebook 
Social networking sites such as Facebook have become immensely popular in recent years and present a unique opportunity for researchers to eavesdrop on the collective conversation of current societal issues.
We sought to explore doctor-related humor by examining doctor jokes posted on Facebook.
We performed a cross-sectional study of 33,326 monitored Facebook users, 263 (0.79%) of whom posted a joke that referenced doctors on their Facebook wall during a 6-month observation period (December 15, 2010 to June 16, 2011). We compared characteristics of so-called jokers to nonjokers and identified the characteristics of jokes that predicted joke success measured by having elicited at least one electronic laugh (eg, an LOL or “laughing out loud”) as well as the total number of Facebook “likes” the joke received.
Jokers told 156 unique doctor jokes and were the same age as nonjokers but had larger social networks (median Facebook friends 227 vs 132, P<.001) and were more likely to be divorced, separated, or widowed (P<.01). In 39.7% (62/156) of unique jokes, the joke was at the expense of doctors. Jokes at the expense of doctors compared to jokes not at the expense of doctors tended to be more successful in eliciting an electronic laugh (46.5% vs 37.3%), although the association was statistically insignificant. In our adjusted models, jokes that were based on current events received considerably more Facebook likes (rate ratio [RR] 2.36, 95% CI 0.97-5.74).
This study provides insight into the use of social networking sites for research pertaining to health and medicine, including the world of doctor-related humor.
PMCID: PMC3936271  PMID: 24550095
physicians; physician-patient relations; social networking; humor
6.  Building a Bridge to Somewhere Better: Linking Health Care Research and Health Policy 
Health Services Research  2012;47(1 Pt 2):329-336.
PMCID: PMC3393014  PMID: 22239661
7.  The Covert World of Fish Biofluorescence: A Phylogenetically Widespread and Phenotypically Variable Phenomenon 
PLoS ONE  2014;9(1):e83259.
The discovery of fluorescent proteins has revolutionized experimental biology. Whereas the majority of fluorescent proteins have been identified from cnidarians, recently several fluorescent proteins have been isolated across the animal tree of life. Here we show that biofluorescence is not only phylogenetically widespread, but is also phenotypically variable across both cartilaginous and bony fishes, highlighting its evolutionary history and the possibility for discovery of numerous novel fluorescent proteins. Fish biofluorescence is especially common and morphologically variable in cryptically patterned coral-reef lineages. We identified 16 orders, 50 families, 105 genera, and more than 180 species of biofluorescent fishes. We have also reconstructed our current understanding of the phylogenetic distribution of biofluorescence for ray-finned fishes. The presence of yellow long-pass intraocular filters in many biofluorescent fish lineages and the substantive color vision capabilities of coral-reef fishes suggest that they are capable of detecting fluoresced light. We present species-specific emission patterns among closely related species, indicating that biofluorescence potentially functions in intraspecific communication and evidence that fluorescence can be used for camouflage. This research provides insight into the distribution, evolution, and phenotypic variability of biofluorescence in marine lineages and examines the role this variation may play.
PMCID: PMC3885428  PMID: 24421880
8.  Reduction of VLDL Secretion Decreases Cholesterol Excretion in Niemann-Pick C1-Like 1 Hepatic Transgenic Mice 
PLoS ONE  2014;9(1):e84418.
An effective way to reduce LDL cholesterol, the primary risk factor of atherosclerotic cardiovascular disease, is to increase cholesterol excretion from the body. Our group and others have recently found that cholesterol excretion can be facilitated by both hepatobiliary and transintestinal pathways. However, the lipoprotein that moves cholesterol through the plasma to the small intestine for transintestinal cholesterol efflux (TICE) is unknown. To test the hypothesis that hepatic very low-density lipoproteins (VLDL) support TICE, antisense oligonucleotides (ASO) were used to knockdown hepatic expression of microsomal triglyceride transfer protein (MTP), which is necessary for VLDL assembly. While maintained on a high cholesterol diet, Niemann-Pick C1-like 1 hepatic transgenic (L1Tg) mice, which predominantly excrete cholesterol via TICE, and wild type (WT) littermates were treated with control ASO or MTP ASO. In both WT and L1Tg mice, MTP ASO decreased VLDL triglyceride (TG) and cholesterol secretion. Regardless of treatment, L1Tg mice had reduced biliary cholesterol compared to WT mice. However, only L1Tg mice treated with MTP ASO had reduced fecal cholesterol excretion. Based upon these findings, we conclude that VLDL or a byproduct such as LDL can move cholesterol from the liver to the small intestine for TICE.
PMCID: PMC3880293  PMID: 24404162
9.  ACAT inhibition reduces the progression of pre-existing, advanced atherosclerotic mouse lesions without plaque or systemic toxicity 
Acyl-CoA:cholesterol acyltransferase (ACAT) converts cholesterol to cholesteryl esters in plaque foam cells. Complete deficiency of macrophage ACAT has been shown to increase atherosclerosis in hypercholesterolemic mice due to cytotoxicity from free cholesterol accumulation, while we previously showed that partial ACAT inhibition by Fujirebio compound F1394 decreased early atherosclerosis development. In this report, we tested F1394 effects on pre-established, advanced lesions of apoE-/- mice.
Methods & Results
ApoE-/- mice on Western diet for 14 weeks developed advanced plaques, and were either sacrificed (“Baseline”), or continued on Western diet without or with F1394 and sacrificed after 14 more weeks. F1394 was not associated with systemic toxicity. Compared to the baseline group, lesion size progressed in both groups; however, F1394 significantly retarded plaque progression, and reduced plaque macrophage, free and esterified cholesterol, and tissue factor contents compared to the untreated group. Apoptosis of plaque cells was not increased, consistent with the decrease in lesional free cholesterol, plaque necrosis was not increased, and efferocytosis (phagocytic clearance of apoptotic cells) was not impaired. The effects of F1394 were independent of changes in plasma cholesterol levels.
Partial ACAT inhibition by F1394 lowered plaque cholesterol content and had other antiatherogenic effects in advanced lesions in apoE-/- mice without overt systemic or plaque toxicity, suggesting the continued potential of ACAT inhibition for the clinical treatment of atherosclerosis in spite of recent trial data.
PMCID: PMC3617493  PMID: 23139293
10.  US Spending On Complementary And Alternative Medicine During 2002–08 Plateaued, Suggesting Role In Reformed Health System 
Health affairs (Project Hope)  2013;32(1):45-52.
Complementary and alternative medicine services in the United States are an approximately $9 billion market each year, equal to 3 percent of national ambulatory health care expenditures. Unlike conventional allopathic health care, complementary and alternative medicine is primarily paid for out of pocket, although some services are covered by most health insurance. Examining trends in demand for complementary and alternative medicine services in the United States reported in the Medical Expenditure Panel Survey during 2002–08, we found that use of and spending on these services, previously on the rise, have largely plateaued. The higher proportion of out-of-pocket responsibility for payment for services may explain the lack of growth. Our findings suggest that any attempt to reduce national health care spending by eliminating coverage for complementary and alternative medicine would have little impact at best. Should some forms of complementary and alternative medicine—for example, chiropractic care for back pain—be proven more efficient than allopathic and specialty medicine, the inclusion of complementary and alternative medicine providers in new delivery systems such as accountable care organizations could help slow growth in national health care spending.
PMCID: PMC3644505  PMID: 23297270
11.  The Serine Hydrolase ABHD6 is a Critical Regulator of the Metabolic Syndrome 
Cell reports  2013;5(2):10.1016/j.celrep.2013.08.047.
The serine hydrolase α/β hydrolase domain 6 (ABHD6) has recently been implicated as a key lipase for the endocannabinoid 2-arachidonylglycerol (2-AG) in the brain. However, the biochemical and physiological function for ABHD6 outside of the central nervous system has not been established. To address this we utilized targeted antisense oligonucleotides (ASOs) to selectively knock down ABHD6 in peripheral tissues to identify in vivo substrates and to understand ABHD6's role in energy metabolism. Here we show that selective knockdown of ABHD6 in metabolic tissues protects mice from high fat diet-induced obesity, hepatic steatosis, and systemic insulin resistance. Using combined in vivo lipidomic identification and in vitro enzymology approaches we show that ABHD6 can hydrolyze several lipid substrates, positioning ABHD6 at the interface of glycerophospholipid metabolism and lipid signal transduction. Collectively, these data suggest that ABHD6 inhibitors may serve as novel therapeutics for obesity, nonalcoholic fatty liver disease, and type II diabetes.
PMCID: PMC3833083  PMID: 24095738
12.  Apolipoprotein E Genotype-Dependent Paradoxical Short-Term Effects of 56Fe Irradiation on the Brain 
In humans, apolipoprotein E (apoE) is encoded by three major alleles (ε2, ε3, and ε4) and, compared to apoE3, apoE4 increases the risk of developing Alzheimer disease and cognitive impairments following various environmental challenges. Exposure to irradiation, including that of 56Fe, during space missions poses a significant risk to the central nervous system, and apoE isoform might modulate this risk.
Methods and Materials
We investigated whether apoE isoform modulates hippocampus-dependent cognitive performance starting 2 weeks after 56Fe irradiation. Changes in reactive oxygen species (ROS) can affect cognition and are induced by irradiation. Therefore, after cognitive testing, we assessed hippocampal ROS levels in ex vivo brain slices, using the ROS-sensitive fluorescent probe, dihydroethidium (DHE). Brain levels of 3-nitrotyrosine (3-NT), CuZn superoxide dismutase (CuZnSOD), extracellular SOD, and apoE were assessed using Western blotting analysis.
In the water maze, spatial memory retention was impaired by irradiation in apoE2 and apoE4 mice but enhanced by irradiation in apoE3 mice. Irradiation reduced DHE-oxidation levels in the enclosed blade of the dentate gyrus and levels of 3-NT and CuZnSOD in apoE2 but not apoE3 or apoE4 mice. Finally, irradiation increased apoE levels in apoE3 but not apoE2 or apoE4 mice.
The short-term effects of 56Fe irradiation on hippocampal ROS levels and hippocampus-dependent spatial memory retention are apoE isoform-dependent.
PMCID: PMC3742074  PMID: 22401921
ApoE; Irradiation; ROS
13.  Health Behaviors and Utilization among Users of Complementary and Alternative Medicine for Treatment versus Health Promotion 
Health Services Research  2011;46(5):1402-1416.
To compare the characteristics, health behaviors, and health services utilization of U.S. adults who use complementary and alternative medicine (CAM) to treat illness to those who use CAM for health promotion.
Data Source
The 2007 National Health Interview Survey (NHIS).
Study Design
We compared adult (age ≥18 years) NHIS respondents based on whether they used CAM in the prior year to treat an illness (n = 973), for health promotion (n = 3,281), or for both purposes (n = 3,031). We used complex survey design methods to make national estimates and examine respondents' self-reported health status, health behaviors, and conventional health services utilization.
Principal Findings
Adults who used CAM for health promotion reported significantly better health status and healthier behaviors overall (higher rates of physical activity and lower rates of obesity) than those who used CAM as treatment. While CAM Users in general had higher rates of conventional health services utilization than those who did not use CAM; adults who used CAM as treatment consumed considerably more conventional health services than those who used it for health promotion.
This study suggests that there are two distinct types of CAM User that must be considered in future health services research and policy decisions.
PMCID: PMC3207184  PMID: 21554272
Complementary and alternative medicine; health services; preventive health services
14.  ApoE Isoform-Dependent Deficits in Extinction of Contextual Fear Conditioning 
Genes, brain, and behavior  2012;11(7):806-812.
The three major human apoE isoforms (apoE2, apoE3, and apoE4) are encoded by distinct alleles (ε2, ε3, and ε4). Compared to ε3, ε4 is associated with increased risk to develop Alzheimer’s disease (AD), cognitive impairments in Parkinson’s disease (PD), and other conditions. In contrast, a recent study indicated an increased susceptibility to the recurring and re-experiencing symptom cluster of Post Traumatic Stress Disorder (PTSD), as well as related memory impairments, in patients carrying at least one ε2 allele. Contextual fear conditioning and extinction are used in human and animal models to study this symptom cluster. In this study, acquisition (day 1, training), consolidation (day 2, first day of re- exposure) and extinction (days 2–5) of conditioned contextual fear in human apo 2, apo 3, and apo 4 targeted replacement (TR) and C57BL/6J wild-type (WT) mice was investigated. Male and female apo 2 mice showed acquisition and retrieval of conditioned fear, but failed to exhibit extinction. In contrast, WT, apoE3 and apoE4 mice showed extinction. While apoE2 mice exhibited lower freezing in response to the context on day 2 than apoE3 and apoE4 mice, this cannot explain their extinction deficit as WT mice exhibited similar freezing levels as apoE2 mice on day 2 but still exhibited extinction. Elevating freezing through extended training preserved extinction in controls, but failed to ameliorate extinction deficits in apoE2 animals. These data along with clinical data showing an association of apoE2 with susceptibility to specific symptom clusters in PTSD supports an important role for apoE isoform in the extinction of conditioned fear.
PMCID: PMC3642038  PMID: 22883220
apoE; PTSD; extinction; acquisition
15.  Use of Chiropractic Spinal Manipulation in Older Adults is Strongly Correlated with Supply 
Spine  2012;37(20):1771-1777.
Study Design
Retrospective cross-sectional analysis of administrative data.
To examine the relationship between regional chiropractic supply and both use and utilization intensity of chiropractic services among Medicare beneficiaries.
Summary of Background Data
Numerous studies have documented trends and patterns in the utilization of chiropractic services in the United States, but little is known about geographic variation in the relationship between chiropractic supply and utilization.
We analyzed Medicare claims data for services provided by chiropractic physicians in 2008. We aggregated the data to the hospital referral region level and employed small area analysis techniques to generate descriptive statistics. We mapped geographic variations in chiropractic supply, use and utilization intensity (treatments per user) and quantified the variation by coefficient of variation and extremal ratio. We employed Spearman’s rank correlation coefficient to correlate use with supply. We employed a logistic regression model for chiropractic use and a multiple linear regression model for chiropractic utilization intensity.
The average regional supply of chiropractic physicians was 21.5 per 100,000 adult capita. The average percentage of beneficiaries who used chiropractic was approximately 7.6 (SD 3.9). The average utilization intensity was 10.6 (SD 1.8). Regional chiropractic supply varied more than 14 fold, and chiropractic use varied more than 17 fold. Chiropractic supply and use were positively correlated (Spearman’s rho 0.68; p<.001). A low back or cervical spine problem was strongly associated with chiropractic use (OR 21.6 and 14.3, respectively). Increased chiropractic supply was associated with increased chiropractic use (OR 1.04), but not with increased chiropractic utilization intensity.
Both the supply of chiropractors and the utilization of chiropractic by older US adults varied widely by region. Increased chiropractic supply was associated with increased chiropractic use, but not with increased chiropractic utilization intensity. Utilization of chiropractic care is likely sensitive to both supply and patient preference.
PMCID: PMC3414681  PMID: 22487711
Chiropractic; Spinal Manipulation; Medicare
16.  Where the United States Spends its Spine Dollars: Expenditures on different ambulatory services for the management of back and neck conditions 
Spine  2012;37(19):1693-1701.
Study Design
Serial, cross-sectional, nationally representative surveys of non-institutionalized adults.
To examine expenditures on common ambulatory health services for the management of back and neck conditions.
Summary of Background Data
Although it is well recognized that national costs associated with back and neck conditions have grown considerably in recent years, little is known about the costs of care for specific ambulatory health services that are used to manage this population.
We used the Medical Expenditure Panel Survey (MEPS) to examine adult (age ≥ 18 years) respondents from 1999 to 2008 who sought ambulatory health services for the management of back and neck conditions. We used complex survey design methods to make national estimates of mean inflation-adjusted annual expenditures on medical care, chiropractic care, and physical therapy per user for back and neck conditions.
Approximately 6% of US adults reported an ambulatory visit for a primary diagnosis of a back or neck condition (13.6 million in 2008). Between 1999 and 2008, the mean inflation-adjusted annual expenditures on medical care for these patients increased by 95% (from $487 to $950); most of the increase was accounted for by increased costs for medical specialists, as opposed to primary care physicians. Over the study period, the mean inflation-adjusted annual expenditures on chiropractic care were relatively stable; while physical therapy was the most costly service overall, in recent years those costs have contracted.
Although this study did not explore the relative effectiveness of different ambulatory services, recent increasing costs associated with providing medical care for back and neck conditions (particularly subspecialty care) are contributing to the growing economic burden of managing these conditions.
PMCID: PMC3423501  PMID: 22433497
Medical Expenditure Panel Survey (MEPS); Spine Expenditures; Back Pain; Neck Pain
17.  The VALUE Framework: Training Residents to Provide Value-Based Care for their Patients 
Journal of General Internal Medicine  2012;27(9):1210-1214.
National efforts to improve the value of health care must include graduate medical education (GME) if they are to succeed. Proposals to teach residents to provide value-based care have come from the Medicare Payment Advisory Commission (MedPAC), the Accreditation Council for Graduate Medical Education (ACGME) and the American College of Physicians (ACP). Such proposals skip a key step: residency programs currently lack a clear strategy to prepare residents to assess and deliver value-based care. In this article, we present the VALUE Framework for programs to utilize to teach residents to assess and deliver value-based care for their patients. We then present more than 20 opportunities for residency programs to incorporate training in value-based care.
PMCID: PMC3514984  PMID: 22573146
medical education; residency training; graduate medical education; value; health care value; value-based care
18.  Lexical Influences on Auditory Streaming 
Current Biology  2013;23(16):1585-1589.
Biologically salient sounds, including speech, are rarely heard in isolation. Our brains must therefore organize the input arising from multiple sources into separate “streams” and, in the case of speech, map the acoustic components of the target signal onto meaning. These auditory and linguistic processes have traditionally been considered to occur sequentially and are typically studied independently [1, 2]. However, evidence that streaming is modified or reset by attention [3], and that lexical knowledge can affect reports of speech sound identity [4, 5], suggests that higher-level factors may influence perceptual organization. In two experiments, listeners heard sequences of repeated words or acoustically matched nonwords. After several presentations, they reported that the initial /s/ sound in each syllable formed a separate stream; the percept then fluctuated between the streamed and fused states in a bistable manner. In addition to measuring these verbal transformations, we assessed streaming objectively by requiring listeners to detect occasional targets—syllables containing a gap after the initial /s/. Performance was better when streaming caused the syllables preceding the target to transform from words into nonwords, rather than from nonwords into words. Our results show that auditory stream formation is influenced not only by the acoustic properties of speech sounds, but also by higher-level processes involved in recognizing familiar words.
•Linguistic processing affects perceptual organization•The acoustic elements of words fuse more readily than those of nonwords•Bistable speech sounds share dynamics with other ambiguous perceptual objects
PMCID: PMC3748342  PMID: 23891107
19.  Temporal Patterns of Diversification across Global Cichlid Biodiversity (Acanthomorpha: Cichlidae) 
PLoS ONE  2013;8(8):e71162.
The contrasting distribution of species diversity across the major lineages of cichlids makes them an ideal group for investigating macroevolutionary processes. In this study, we investigate whether different rates of diversification may explain the disparity in species richness across cichlid lineages globally. We present the most taxonomically robust time-calibrated hypothesis of cichlid evolutionary relationships to date. We then utilize this temporal framework to investigate whether both species-rich and depauperate lineages are associated with rapid shifts in diversification rates and if exceptional species richness can be explained by clade age alone. A single significant rapid rate shift increase is detected within the evolutionary history of the African subfamily Pseudocrenilabrinae, which includes the haplochromins of the East African Great Lakes. Several lineages from the subfamilies Pseudocrenilabrinae (Australotilapiini, Oreochromini) and Cichlinae (Heroini) exhibit exceptional species richness given their clade age, a net rate of diversification, and relative rates of extinction, indicating that clade age alone is not a sufficient explanation for their increased diversity. Our results indicate that the Neotropical Cichlinae includes lineages that have not experienced a significant rapid burst in diversification when compared to certain African lineages (rift lake). Neotropical cichlids have remained comparatively understudied with regard to macroevolutionary patterns relative to African lineages, and our results indicate that of Neotropical lineages, the tribe Heroini may have an elevated rate of diversification in contrast to other Neotropical cichlids. These findings provide insight into our understanding of the diversification patterns across taxonomically disparate lineages in this diverse clade of freshwater fishes and one of the most species-rich families of vertebrates.
PMCID: PMC3747193  PMID: 23990936
Plastic and reconstructive surgery  2012;130(2):369-378.
We aimed to characterize patterns in the timing of initial emergency procedures for patients with open tibia fracture and examine the relationship between initial procedure timing and in-hospital amputation.
Study Design
Data were analyzed from the Nationwide Inpatient Sample, 2003–2009. Adult patients were included if they had a primary diagnosis code of open tibia fracture. Patients were excluded for the following: transferred from or to another hospital, an immediate amputation was performed, more than one amputation was performed, no emergency procedure was documented, or treated at a facility that did not perform any amputations. We evaluated the association between timing of the first procedure and the outcome of amputation using multiple logistic regression, controlled for patient risk factors and hospital characteristics.
Of 7,560 patients included in the analysis, 1.3% (n=99 patients) underwent amputation on hospital day 2 or later. The majority of patients (52.6%) underwent first operative procedure on day 0 or 1. In adjusted analyses, timing of first operative procedure beyond the day of admission is associated with more than three times greater odds of amputation (day 1 OR 3.81, 95% CI 1.80–8.07).
Delay of first operative procedure beyond the day of admission appears to be associated with a significantly increased probability of amputation in patients with open tibia fracture. All practitioners involved in the management of patients with open tibia fracture should seek a solution for any barrier, other than medical stability of the patient, of achieving early operative intervention.
PMCID: PMC3432295  PMID: 22842411
amputation; debridement; emergent procedures; lower extremity reconstruction; lower extremity trauma; open tibial fracture
21.  Measures of anxiety, sensorimotor function, and memory in male and female mGluR4-/- mice 
Behavioural Brain Research  2012;229(1):21-28.
Metabotropic glutamate receptors (mGluRs) are coupled to second messenger pathways via G proteins and modulate synaptic transmission. Of the eight different types of mGluRs (mGluR1-mGluR8), mGluR4, mGluR6, mGluR7, and mGluR8 are members of group III. Group III receptors are generally located presynaptically, where they regulate neurotransmitter release. Because of their role in modulating neurotransmission, mGluRs are attractive targets for therapies aimed at treating anxiety disorders. Previously we showed that the mGluR4-selective allosteric agonist VU 0155041 reduces anxiety-like behavior in wild-type male mice. Here, we explore the role of mGluR4 in adult (6-month-old) and middle-aged (12-month-old) male and female mice lacking this receptor. Compared to age- and sex-matched wild-type mice, middle-aged mGluR4-/- male mice showed increased measures of anxiety in the open field and elevated zero maze and impaired sensorimotor function on the rotarod. These changes were not seen in adult 6-month old male mice. In contrast to the male mice, mGluR4-/- female mice showed reduced measures of anxiety in the open field and elevated zero maze and enhanced rotarod performance. During the hidden platform training sessions of the water maze, mGluR4-/-mice swam father away from the platform than wild-type mice at 6, but not at 12, months of age. mGluR4-/- mice also showed enhanced amygdala-dependent cued fear conditioning. No genotype differences were seen in hippocampus-dependent contextual fear conditioning. These data indicate that effects of mGluR4 on sensorimotor function and measures of anxiety, but not cued fear conditioning, are critically modulated by sex and age.
PMCID: PMC3294097  PMID: 22227508
mGluR4; anxiety; Group-III mGluR; learning; memory
22.  Hospitalizations for Intussusception Before and After the Reintroduction of Rotavirus Vaccine in the United States 
To determine whether hospital discharges for intussusception in children younger than 1 year have changed since the reintroduction of rotavirus vaccine in the United States.
Serial cross-sectional analysis.
US hospitals.
Children younger than 1 year with a discharge diagnosis of intussusception identified in the Kids’ Inpatient Database, a series of nationally representative data sets of pediatric hospital discharges in the United States with 4 available years prior to vaccine reintroduction (1997, 2000, 2003, and 2006) and 1 year after (2009).
Main Exposures
Hospital discharge before vs after rotavirus vaccine reintroduction.
Outcome Measures
Total number and rate of hospital discharges for infants younger than 1 year with a diagnosis of intussusception (International Classification of Diseases, Ninth Revision, Clinical Modification code 560.0).
From 1997 to 2006, there was no change in the total number of hospital discharges for intussusception, with a small decrease in the rate of intussusception discharges (41.6 [95% CI, 36.7–46.5] to 36.5 [95% CI, 31.7–41.2] per 100 000 infants). Based on the trend, the predicted rate of discharges for intussusception in 2009 was 36.0 (95% CI, 30.2–41.8) per 100 000 infants. The measured rate of hospital discharges for intussusception in 2009 was 33.3 (95% CI, 29.0–37.6) per 100 000 infants.
The reintroduction of rotavirus vaccine since 2006 has not resulted in a detectable increase in the number of hospital discharges for intussusception among US infants.
PMCID: PMC3442774  PMID: 22213609
23.  Medical Home Disparities for Children by Insurance Type and State of Residence 
Maternal and child health journal  2012;16(Suppl 1):S178-S187.
The objectives of this study are (1) to compare the prevalence of a medical home between children with public and private insurance across states, (2) to investigate the association between a medical home and state health care characteristics for children with public and private insurance. We performed a cross-sectional analysis of the 2007 National Survey of Children’s Health, estimating the prevalence of parents’ report of a medical home and its components for publicly- and privately-insured children in all 50 states and the District of Columbia. We then performed a series of random-effects multilevel logistic regression models to assess the associations between a medical home and insurance type, individual sociodemographic characteristics, and state level characteristics/policies. The prevalence of a medical home varied significantly across states for both publicly- and privately-insured children (ranges: 33–63 % and 57–76 %, respectively). Compared to privately-insured children, publicly-insured children had a lower prevalence of a medical home in all states (public–private difference: 5–34 %). Low prevalence of a medical home was driven primarily by less family-centered care. Variation across states and differences by insurance type were largely attributable to lower reports of a medical home among traditionally vulnerable groups of children, including racial/ethnic minorities and non-English primary language speakers. The prevalence of a medical home was not associated with state level characteristics/policies. There are significant disparities between states in parents’ report of a medical home for their children, especially for publicly-insured children. Interventions seeking to address these disparities will need to target family-centered care for traditionally vulnerable populations of children.
PMCID: PMC3444255  PMID: 22453328
Medical home; Public insurance; Disparities; Health policy; National Survey of Children’s Health
24.  The genesis of Zelboraf: Targeting mutant B-Raf in melanoma 
The Journal of Cell Biology  2012;199(1):15-19.
The protein kinase B-Raf is a critical component of the Ras/MAPK signaling pathway. An oncogenic B-Raf mutation that constitutively activates the kinase was identified in z50% of melanoma patients and in other cancers. A structure-guided drug discovery approach enabled the development of Zelboraf, a targeted inhibitor of oncogenic B-Raf. This drug has been used successfully in the clinic to treat metastatic melanoma patients harboring B-Raf mutations.
PMCID: PMC3461519  PMID: 23027900
25.  Aging Baby Boomers and the Rising Cost of Chronic Back Pain: Secular Trend Analysis of Longitudinal Medical Expenditures Panel Survey Data for Years 2000 to 2007 
The purposes of this study were to analyze data from the longitudinal Medical Expenditures Panel Survey (MEPS) to evaluate the impact of an aging population on secular trends in back pain and chronicity and to provide estimates of treatment costs for patients who used only ambulatory services.
Using the MEPS 2-year longitudinal data for years 2000 to 2007, we analyzed data from all adult respondents. Of the total number of MEPS respondent records analyzed (N = 71 838), we identified 12 104 respondents with back pain and further categorized 3842 as chronic cases and 8262 as nonchronic cases.
Secular trends from the MEPS data indicate that the prevalence of back pain has increased by 29%, whereas chronic back pain increased by 64%. The average age among all adults with back pain increased from 45.9 to 48.2 years; the average age among adults with chronic back pain increased from 48.5 to 52.2 years. Inflation-adjusted (to 2010 dollars) biennial expenditures on ambulatory services for chronic back pain increased by 129% over the same period, from $15.6 billion in 2000 to 2001 to $35.7 billion in 2006 to 2007.
The prevalence of back pain, especially chronic back pain, is increasing. To the extent that the growth in chronic back pain is caused, in part, by an aging population, the growth will likely continue or accelerate. With relatively high cost per adult with chronic back pain, total expenditures associated with back pain will correspondingly accelerate under existing treatment patterns. This carries implications for prioritizing health policy, clinical practice, and research efforts to improve care outcomes, costs, and cost-effectiveness and for health workforce planning.
PMCID: PMC3596008  PMID: 23380209
Back pain; Costs and cost analysis; Aging; Spine; Economics; Chronic disease

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