To estimate recent age- and sex-specific changes in long-term opioid prescription among patients with chronic pain in two large American Health Systems.
Analysis of administrative pharmacy data to calculate changes in prevalence of long-term opioid prescription (90 days or more during a calendar year) from 2000 to 2005, within groups based on sex and age (18–44, 45–64, and 65 years and older). Separate analyses were conducted for patients with and without a diagnosis of a mood disorder or anxiety disorder. Changes in mean dose between 2000 and 2005 were estimated, as were changes in the rate of prescription for different opioid types (short-acting, long-acting, and non-Schedule 2).
Enrollees in HealthCore (N = 2,716,163 in 2000) and Arkansas Medicaid (N = 115,914 in 2000).
Within each of the age and sex groups, less than 10% of patients with a chronic pain diagnosis in HealthCore, and less than 33% in Arkansas Medicaid, received long-term opioid prescriptions. All age, sex, and anxiety/depression groups showed similar and statistically significant increases in long-term opioid prescription between 2000 and 2005 (35–50% increase). Per-patient daily doses did not increase.
No one group showed especially large increases in long-term opioid prescriptions between 2000 and 2005. These results argue against a recent epidemic of opioid prescribing. These trends may result from increased attention to pain in clinical settings, policy or economic changes, or provider and patient openness to opioid therapy. The risks and benefits to patients of these changes are not yet established.
Opioids; Prescriptions; Chronic Pain; Disparities—Gender; Aged; Mood; Anxiety
There has been an increase in over dose deaths and emergency department visits (EDVs) involving use of prescription opioids, but the association between opioid prescribing and adverse outcomes is unclear.
Data were obtained from administrative claim records from Arkansas Medicaid and HealthCore commercially insured enrollees, 18 years and older, who used prescription opioids for at least 90 continuous days within a 6-month period between 2000 and 2005 and had no cancer diagnoses. Regression analysis was used to examine risk factors for EDVs and alcohol- or drug-related encounters (ADEs) in the 12 months following 90 days or more of prescribed opioids.
Headache, back pain, and preexisting substance use disorders were significantly associated with EDVs and ADEs. Mental health disorders were associated with EDVs in HealthCore enrollees and with ADEs in both samples. Opioid dose per day was not consistently associated with EDVs but doubled the risk of ADEs at morphine-equivalent doses over 120 mg/d. Use of short-acting Drug Enforcement Agency Schedule II opioids was associated with EDVs compared with use of non–Schedule II opioids alone (relative risk range, 1.09–1.74). Use of Schedule II long-acting opioids was strongly associated with ADEs (relative risk range, 1.64–4.00).
Use of Schedule II opioids, headache, back pain, and substance use disorders are associated with EDVs and ADEs among adults prescribed opioids for 90 days or more. It may be possible to increase the safety of chronic opioid therapy by minimizing the prescription of Schedule II opioids in these higher-risk recipients.
The aim of this study was to investigate brain structural alterations in adult immigrants who adapted to high altitude (HA). Voxel-based morphometry analysis of gray matter (GM) volumes, surface-based analysis of cortical thickness, and Tract-Based Spatial Statistics analysis of white matter fractional anisotropy (FA) based on MRI images were conducted on 16 adults (20–22 years) who immigrated to the Qinghai-Tibet Plateau (2300–4400 m) for 2 years. They had no chronic mountain sickness. Control group consisted of 16 matched sea level subjects. A battery of neuropsychological tests was also conducted. HA immigrants showed significantly decreased GM volumes in the right postcentral gyrus and right superior frontal gyrus, and increased GM volumes in the right middle frontal gyrus, right parahippocampal gyrus, right inferior and middle temporal gyri, bilateral inferior ventral pons, and right cerebellum crus1. While there was some divergence in the left hemisphere, surface-based patterns of GM changes in the right hemisphere resembled those seen for VBM analysis. FA changes were observed in multiple WM tracts. HA immigrants showed significant impairment in pulmonary function, increase in reaction time, and deficit in mental rotation. Parahippocampal and middle frontal GM volumes correlated with vital capacity. Superior frontal GM volume correlated with mental rotation and postcentral GM correlated with reaction time. Paracentral lobule and frontal FA correlated with mental rotation reaction time. There might be structural modifications occurred in the adult immigrants during adaptation to HA. The changes in GM may be related to impaired respiratory function and psychological deficits.
The present study aimed to investigate structural modulation of brain by high level of oxygen during its peak period of development. Voxel-based morphometry analysis of gray matter (GM) and white matter (WM) volumes and Tract-Based Spatial Statistics analysis of WM fractional anisotropy (FA) and mean diffusion (MD) based on MRI images were carried out on 21 Tibetan adolencents (15–18 years), who were born and raised in Qinghai-Tibetan Plateau (2900–4700 m) and have lived at sea level (SL) in the last 4 years. The control group consisted of matched Tibetan adolescents born and raised at high altitude all the time. SL immigrants had increased GM volume in the left insula, left inferior parietal gyrus, and right superior parietal gyrus and decreased GM in the left precentral cortex and multiple sites in cerebellar cortex (left lobule 8, bilateral lobule 6 and crus 1/2). Decreased WM volume was found in the right superior frontal gyrus in SL immigrants. SL immigrants had higher FA and lower MD at multiple sites of WM tracts. Moreover, we detected changes in ventilation and circulation. GM volume in cerebellum lobule 8 positively correlated with diastolic pressure, while GM volume in insula positively correlated vital capacity and hypoxic ventilatory response. Our finding indicate that the structural modulations of GM by high level of oxygen during its peak period of development are related to respiratory and circulatory regulations, while the modulation in WM mainly exhibits an enhancement in myelin maturation.
Motivation: Systematic and scalable parameter estimation is a key to construct complex gene regulatory models and to ultimately facilitate an integrative systems biology approach to quantitatively understand the molecular mechanisms underpinning gene regulation.
Results: Here, we report a novel framework for efficient and scalable parameter estimation that focuses specifically on modeling of gene circuits. Exploiting the structure commonly found in gene circuit models, this framework decomposes a system of coupled rate equations into individual ones and efficiently integrates them separately to reconstruct the mean time evolution of the gene products. The accuracy of the parameter estimates is refined by iteratively increasing the accuracy of numerical integration using the model structure. As a case study, we applied our framework to four gene circuit models with complex dynamics based on three synthetic datasets and one time series microarray data set. We compared our framework to three state-of-the-art parameter estimation methods and found that our approach consistently generated higher quality parameter solutions efficiently. Although many general-purpose parameter estimation methods have been applied for modeling of gene circuits, our results suggest that the use of more tailored approaches to use domain-specific information may be a key to reverse engineering of complex biological systems.
Supplementary data are available at Bioinformatics online.
Growing evidences indicate microRNAs play important roles in cancer development, progression, metastasis and may constitute robust biomarkers for cancer prognosis. The aim of this study was to identify the clinical and functional association of microRNA-20a (miR-20a) in hepatocellular carcinoma (HCC).
MiR-20a was detected using Taqman real-time polymerase chain reaction. Kaplan-Meier and Cox proportional regression analyses were utilized to determine the association of miR-20a with survival of patients. The potential functions of miR-20a on proliferation were evaluated by proliferation and flow cytometry analysis. The direct target gene of miR-20a was also identified by luciferase reporter assays.
MiR-20a was lower in primary HCC than normal liver, and were further decreased in those with post-liver transplantation (LT) HCC recurrence compared with those with non-recurrence (p = 0.001). Patients with lower miR-20a expression had significantly poorer recurrence-free survival (RFS, Log rank p < 0.001) and overall survival (OS, Log rank p < 0.001). Multivariate analysis revealed that lower miR-20a was an independent predictor of poor prognosis. MiR-20a restoration could suppress HepG2 and SMMC-7721 cells proliferation and induce cell cycle G1 arrest and apoptosis. Subsequent investigations revealed that miR-20a directly targeted myeloid cell leukemia sequence 1 (Mcl-1) and reduced the endogenous protein level of Mcl-1 in HCC cells.
MiR-20a is decreased in HCCs and correlates with HCC recurrence and prognosis. Down-regulation of miR-20a increases the proliferation abilities of HCC cells. Our findings suggest miR-20a may represent a novel potential therapeutic target and biomarker for survival of HCC patients.
MicroRNA-20a; Hepatocellular Carcinoma; Recurrence; Prognosis; Liver transplantation
To explore the sociodemographic patterning of risk factors for cardiovascular disease (CVD) in three isolated-based subgroups of the Uyghur population in Xinjiang, China.
A cross-sectional study. Between 2005 and 2008, a non-probability sampling design method was used to select three specific groups of the Uyghur rural populations based on their potential socioeconomic status (ie, isolated, semi-isolated and open-environment status).
Three communities (named Desert, Turpan and Yuli Rob) in Southern Xinjiang autonomous region, China.
1656 people were included in this study. The inclusion criteria were that all participants were 18 years or older, they were descendants of at least three generations living in the same region, and there was no history of intermarriage.
Main outcome measures
The prevalence of CVD risk factors (ie, tobacco use, alcohol use, obesity, dyslipidemia, hypertension, diabetes, etc) was assessed.
Compared with the Desert and Turpan communities, Yuli Rob had the highest levels of obesity, dyslipidemia and hypertension, and the Desert had the lowest levels of CVD risk factors. Age standardisation slightly altered the estimates, though the patterns remained unchanged. Some unique characteristics were also found. For example, the Desert group displayed significantly lower high-density lipoprotein cholesterol (HDLC) level compared with Yuli Rob and Turpan groups. The mean values were 0.63, 1.06 and 1.45 mmol/l for men and 0.64, 1.22 and 1.51 mmol/l for women (p<0.0001). The HDLC levels in the Desert group increased with increase in body mass index and fasting glucose levels, which was inconsistent with previous studies.
Identifying the unique CVD risk factors of the ethnic-specific populations is very important in development of tailored strategies for the prevention of CVD.
HEALTH PROMOTION; HEALTH STATUS; ENVIRONMENTAL HEALTH
Mesenchymal stem cells (MSCs) are multipotent cells capable of differentiating into dopaminergic (DAergic) neurons, which is one of the major cell types damaged in Parkinson’s disease (PD). For this reason, MSCs are considered a potential cell source for PD therapy. It has been proved that hypoxia is involved in the proliferation and differentiation of stem cells. In this study, we investigated the effect of hypoxia on MSC proliferation and DAergic neuronal differentiation. Our results demonstrate that 3% O2 treatment can enhance rat MSC proliferation by upregulation of phosphorylated p38 MAPK and subsequent nuclear translocation of hypoxia inducible factor (HIF)-1α. During neural differentiation, 3% O2 treatment increases the expression of HIF-1α, phosphorylated ERK and p38 MAPK. These changes are followed by promotion of neurosphere formation and further DAergic neuronal differentiation. Furthermore, we explored the physiological function of hypoxia-induced DAergic neurons from human fetal MSCs by transplanting them into parkinsonian rats. Grafts induced with hypoxia display more survival of DAergic neurons and greater amelioration of behavioral impairments. Altogether, these results suggest that hypoxia can promote MSC proliferation and DAergic neuronal differentiation, and benefit for intrastriatal transplantation. Therefore, this study may provide new perspectives in application of MSCs to clinical PD therapy.
To report chronic opioid therapy discontinuation rates after five years and identify factors associated with discontinuation.
Medical and pharmacy claims records from January 2000 through December 2005 from a national private health network (HealthCore), and Arkansas (AR) Medicaid were used to identify ambulatory adult enrollees who had 90 days of opioids supplied. Recipients were followed until they discontinued opioid prescription fills or disenrolled. Kaplan Meier survival models and Cox proportional hazards models were estimated to identify factors associated with time until opioid discontinuation.
There were 23,419 and 6,848 chronic opioid recipients followed for a mean of 1.9 and 2.3 years in the HealthCore and AR Medicaid samples. Over a maximum follow up of 4.8 years, 67.0% of HealthCore and 64.9% AR Medicaid recipients remained on opioids. Recipients on high daily opioid dose (greater than 120 milligrams morphine equivalent (MED)) were less likely to discontinue than recipients taking lower doses: HealthCore hazard ratio (HR) = 0.66 (95%CI: 0.57–0.76), AR Medicaid HR = 0.66 (95%CI: 0.50–0.82). Recipients with possible opioid misuse were also less likely to discontinue: HealthCore HR = 0.83 (95%CI: 0.78–0.89), AR Medicaid HR = 0.78 (95%CI: 0.67–0.90).
Over half of persons receiving 90 days of continuous opioid therapy remain on opioids years later. Factors most strongly associated with continuation were intermittent prior opioid exposure, daily opioid dose ≥ 120 mg MED, and possible opioid misuse. Since high dose and opioid misuse have been shown to increase the risk of adverse outcomes special caution is warranted when prescribing more than 90 days of opioid therapy in these patients.
opioids; opioid misuse; persistence; discontinuation
Opioids are among the most commonly abused drugs among adolescents and the prescription of these drugs has increased over the last decade. The goal of the current study is to examine trends and factors associated with prescription opioid use among adolescents with common non-cancer pain (NCP) conditions, sampled from two contrasting populations.
We conducted a secondary data analysis examining time trends from 2001 to 2005 in opioid use in two dissimilar populations: a national, commercially-insured population and a state Medicaid plan. We examined trends in mean dose prescribed, mean number of prescriptions, and types of medications given, as well as clinical and demographic features of adolescents receiving opioids.
In 2005, 21% of adolescents with common NCP conditions in HealthCore and 40.2% of adolescents with NCP in Arkansas Medicaid had received prescription opioids. The majority of opioid prescriptions in both 2001 and 2005 were for DEA Schedule II and III short acting opioids. In both samples, rates of prescription were higher for adolescents with comorbid mental health diagnoses compared to those without and for adolescents with multiple pain conditions compared to a single pain condition.
Prescription of opioids among adolescents with NCP is common and the prescription rate is higher among adolescents with multiple pain conditions and comorbid mental health disorders. Further research is necessary to determine risk factors for abuse and misuse of opioids in adolescents to help develop guidelines for use in this age group.
Pain; Adolescents; Opioids
Preterm survivors from the neonatal intensive care unit (NICU) are considered to be at risk for some neurobehavioral disorders such as attention-deficit/hyperactivity disorder (ADHD). The current study aimed to explore the relationship between ADHD and premature infants in Taiwan.
A total of 195 children (157 males and 38 females) diagnosed with ADHD based on DSM-IV and aged between 6 to 12 years and a control group of 212 (164 males, 48 females) age- and sex-matched healthy children were enrolled. The ADHD-Rating scale and CGI severity were performed by child psychiatrists. Demographic data of the children, including birth history, perinatal neurological and respiratory problems were collected to facilitate the investigation of whether a correlation exists between ADHD and prematurity.
The ADHD group had a significantly higher rate of prematurity and significantly higher rate of low birth body weight (defined as <2500 g) than the control group (both P = 0.003). Pearson correlation showed a significantly negative correlation between gestational age and ADHD-RS score, inattentive score, hyperactivity and CGI-S score (P = 0.004, 0.013, 0.015 and 0.002, respectively). However, only a CGI-S score (P = 0.018) showed a significantly correlation between low birth weight and ADHD.
Premature infants have significantly more severe symptoms of ADHD at school age and they were highly correlated. Further study is necessary to determine the main effect and pathogenesis of moderate as well as extreme preterm birth on the development of ADHD.
Premature infant; Attention-deficit/hyperactivity disorder; Behavioral disorder; DSM-IV; Gestational age
With rapid advances in the development of DNA sequencing technologies, a plethora of high-throughput genome and proteome data from a diverse spectrum of organisms have been generated. The functional annotation and evolutionary history of proteins are usually inferred from domains predicted from the genome sequences. Traditional database-based domain prediction methods cannot identify novel domains, however, and alignment-based methods, which look for recurring segments in the proteome, are computationally demanding. Here, we propose a novel genome-wide domain prediction method, SECOM. Instead of conducting all-against-all sequence alignment, SECOM first indexes all the proteins in the genome by using a hash seed function. Local similarity can thus be detected and encoded into a graph structure, in which each node represents a protein sequence and each edge weight represents the shared hash seeds between the two nodes. SECOM then formulates the domain prediction problem as an overlapping community-finding problem in this graph. A backward graph percolation algorithm that efficiently identifies the domains is proposed. We tested SECOM on five recently sequenced genomes of aquatic animals. Our tests demonstrated that SECOM was able to identify most of the known domains identified by InterProScan. When compared with the alignment-based method, SECOM showed higher sensitivity in detecting putative novel domains, while it was also three orders of magnitude faster. For example, SECOM was able to predict a novel sponge-specific domain in nucleoside-triphosphatase (NTPases). Furthermore, SECOM discovered two novel domains, likely of bacterial origin, that are taxonomically restricted to sea anemone and hydra. SECOM is an open-source program and available at http://sfb.kaust.edu.sa/Pages/Software.aspx.
In our previous study, we detected decreased expression of phospho-Smad1/5/8 and its upstream signaling molecule, bone morphogenetic protein receptor IB subunit (BMPR-IB), in certain glioblastoma tissues, unlike normal brain tissues. In order to clarify the functional roles and mechanism of BMPR-IB in the development of glioblastoma, we studied the effects of BMPR-IB overexpression on glioblastoma cell lines in vitro and in vivo.
We selected glioblastoma cell lines U251, U87, SF763, which have different expression of BMPR-IB to be the research subjects. Colony formation analysis and FACS were used to detect the effects of BMPR-IB on the growth and proliferation of glioblastoma cells in vivo. Immunofluresence was used to detect the differentiation changes after BMPR-IB overexpression or knocking-down. Then we used subcutaneous and intracranial tumor models to study the effect of BMPR-IB on the growth and differentiation of glioblastoma cells in vivo. The genetic alterations involved in this process were examined by real-time PCR and western blot analysis.ed.
Results and conclusion
Forced BMPR-IB expression in malignant human glioma cells, which exhibit lower expression of BMPR-IB, induced the phosphorylation and nuclear localization of smad1/5/8 and arrested the cell cycle in G1. Additionally, BMPR-IB overexpression could suppress anchorage-independent growth and promote differentiation of theses glioblastoma cells. Furthermore, overexpression of BMPR-IB inhibited the growth of subcutaneous and intracranial tumor xenografts and prolonged the survival of mice injected intracranially with BMPR-IB-overexpressing glioblastoma cells. Conversely, inhibition of BMPR-IB caused SF763 malignant glioma cells, a line known to exhibit high BMPR-IB expression that does not form tumors when used for xenografts, to show increased growth and regain tumorigenicity in a nude mouse model system, ultimately shortening the survival of these mice. We also observed significant accumulation of p21 and p27kip1 proteins in response to BMPR-IB overexpression. Our study suggests that overexpression of BMPR-IB may arrest and induce the differentiation of glioblastoma cells due to upregulation of p21 and p27kip1 in vitro and that in vivo and decreased expression of BMPR-IB in human glioblastoma cells contributes to glioma tumorigenicity. BMPR-IB could represent a new potential therapeutic target for malignant human gliomas.
1. BMPR-IB; 2. Glioblastoma; 3. Growth inhibition; 4. Differentiation
The irreversible airflow limitation characterised by chronic obstructive pulmonary disease (COPD) causes a decrease in the oxygen supply to the brain. The aim of the present study was to investigate brain structural damage in COPD.
Retrospective case–control study. Patients with COPD and healthy volunteers were recruited. The two groups were matched in age, gender and educational background.
A hospital and a number of communities: they are all located in southern Fujian province, China.
25 stable patients and 25 controls were enrolled from December 2009 to May 2011.
Using voxel-based morphometry and tract-based spatial statistics based on MRI to analyse grey matter (GM) density and white matter fractional anisotropy (FA), respectively, and a battery of neuropsychological tests were performed.
Patients with COPD (vs controls) showed decreased GM density in the limbic and paralimbic structures, including right gyrus rectus, left precentral gyrus, bilateral anterior and middle cingulate gyri, bilateral superior temporal gyri, bilateral anterior insula extending to Rolandic operculum, bilateral thalamus/pulvinars and left caudate nucleus. Patients with COPD (vs controls) had decreased FA values in the bilateral superior corona radiata, bilateral superior and inferior longitudinal fasciculus, bilateral optic radiation, bilateral lingual gyri, left parahippocampal gyrus and fornix. Lower FA values in these regions were associated with increased radial diffusivity and no changes of longitudinal diffusivity. Patients with COPD had poor performances in the Mini-Mental State Examination, figure memory and visual reproduction. GM density in some decreased regions in COPD had positive correlations with arterial blood Po2, negative correlations with disease duration and also positive correlations with visual tasks.
The authors demonstrated that COPD exhibited loss of regional GM accompanied by impairment of white matter microstructural integrity, which was associated with disease severity and may underlie the pathophysiological and psychological changes of COPD.
Decreased oxygen supply to brain may cause neuronal damage in COPD. However, the damage remains largely uninvestigated.
We found that COPD extends to the brain, with the loss of regional cortical grey matter accompanied by impairment in the white matter microstructural integrity.
Our findings would be help for clinical therapy of COPD.
Strengths and limitations of this study
Multiple analyses were used based on MR images. The statistic power for FA analysis was weak.
Our previous study showed that pretreatment with 5-hydroxymethyl-2-furfural (5-HMF) led to protection against hypoxic injury via a p-ERK-mediated pathway in vitro. Whether the protection of 5-HMF against hypoxia is effective in vivo is unknown. The present study is aimed to verify the role of 5-HMF in acute hypobaric hypoxia using Kunming mice as an in vivo model and further investigate the underlying mechanisms. Mice pretreated with or without 5-HMF for 1 h were exposed to acute hypobaric hypoxic condition for 6 h and then the survival time, the survival rate, the permeability of blood–brain barrier (BBB), the histological analysis in hippocampus and cortex, and the phosphorylation level of mitogen-activated protein kinases (ERK, JNK, and p38) were investigated. The results showed that 5-HMF significantly increased the survival time and the survival rate of mice. Accordingly, pretreatment with 5-HMF markedly attenuated acute hypobaric hypoxia-induced permeability of BBB (P < 0.01). In addition, the cellular damage extent of the hippocampus and the cortex induced by hypoxia for 6 h was also attenuated by pretreatment with 5-HMF, especially in the hippocampus CA1 region. Furthermore, the activation of ERK rather than JNK and p38 was involved in the protection of 5-HMF against acute hypobaric hypoxia. In summary, 5-HMF enhanced the survival capability of mice and decreased acute hypoxic damage to the brain, which may be associated with the effects on BBB and p-ERK.
Electronic supplementary material
The online version of this article (doi:10.1007/s12192-011-0264-8) contains supplementary material, which is available to authorized users.
5-HMF; Hypobaric hypoxia; Brain injury; BBB
We previously reported that chronic ethanol lowers blood pressure in female rats. In this study, hemodynamic, biochemical, and immunoblot analyses were performed to investigate: (i) the roles of cardiac contractility and autonomic activity in the hypotensive action of ethanol, and (ii) whether endotoxemia-induced upregulation of cardiac and/or vascular nitric oxide synthase (NOS) isoforms underlies the hypotensive and cardiac effects of ethanol. Telemetric monitoring of blood pressure, heart rate, and myocardial contractility (dP/dtmax) was performed in female rats receiving liquid diet with or without ethanol (5% w/v, 13 weeks). Autonomic control was assessed by frequency domain analysis of interbeat intervals (IBI) and systolic blood pressure (SBP). Compared with pair-fed controls, ethanol caused sustained reductions in blood pressure, heart rate, and +dP/dtmax. Ethanol feeding increased the spectral power of high-frequency band (IBIHF, 0.75–3 Hz) and decreased the low-frequency band (IBILF, 0.25–0.75 Hz) and IBILF/HF ratio, suggesting increased cardiac parasympathetic dominance. In contrast, vascular tone was not affected by ethanol because SBP spectral bands and plasma norepinephrine remained unchanged. Myocardial expressions of eNOS and its upstream regulators, phosphatidylinositol 3-kinase(PI3K) and Akt, and plasma endotoxin and nitrite/nitrate were increased by ethanol. Myocardial iNOS was also increased by ethanol whereas nNOS remained unchanged and aortic levels of all NOS isoforms were not altered by ethanol. These findings suggest that facilitation of myocardial PI3K/Akt/eNOS and iNOS pathways, due possibly to ethanol-induced endotoxemia and/or increased cardiac parasympathetic dominance, might constitute a cellular mechanism for the reduced myocardial contractility and hypotension caused by ethanol in female rats.
Ethanol; blood pressure; myocardial contractility; female rats; nitric oxide synthase; hemodynamic variability
To estimate the prevalence of and risk factors for opioid abuse/dependence in long-term users of opioids for chronic pain, including risk factors for opioid abuse/dependence that can potentially be modified to decrease the likelihood of opioid abuse/dependence, and non-modifiable risk factors for opioid abuse/dependence that may be useful for risk stratification when considering prescribing opioids.
We used claims data from two disparate populations, one national, commercially insured population (HealthCore) and one state-based, publicly insured (Arkansas Medicaid). Among users of chronic opioid therapy, we regressed claims-based diagnoses of opioid abuse/dependence on patient characteristics, including physical health, mental health and substance abuse diagnoses, sociodemographic factors, and pharmacological risk factors.
Among users of chronic opioid therapy, 3% of both the HealthCore and Arkansas Medicaid samples had a claims-based opioid abuse/dependence diagnosis. There was a strong inverse relationship between age and a diagnosis of opioid abuse/dependence. Mental health and substance use disorders were associated with an increased risk of opioid abuse/dependence. Effects of substance use disorders were especially strong, although mental health disorders were more common. Concerning opioid exposure; lower days supply, lower average doses, and use of Schedule III-IV opioids only, were all associated with lower likelihood of a diagnosis of opioid abuse/dependence.
Opioid abuse and dependence are diagnosed in a small minority of patients receiving chronic opioid therapy, but this may underestimate actual misuse. Characteristics of the patients and of the opioid therapy itself are associated with the risk of abuse and dependence.
pain; opioids; abuse; dependence
In an attempt to find new types of anti-hypoxic agents from herbs, we identified 5-hydroxymethyl-2-furfural (5-HMF) as a natural agent that fulfills the criterion. 5-HMF, the final product of carbohydrate metabolism, has favorable biological effects such as anti-oxidant activity and inhibiting sickling of red blood cells. The role of 5-HMF in hypoxia, however, is not yet. Our pilot results showed that pretreatment with 5-HMF markedly increased both the survival time and the survival rate of mice under hypoxic stress. The present study was aimed to further investigate the protective role of 5-HMF and the underlying mechanisms in hypoxic injury using ECV304 cells as an in vitro model. ECV304 cells pretreated with or without 5-HMF for 1 h were exposed to hypoxic condition (0.3% O2) for 24 h and then cell apoptosis, necrosis, the changes of mitochondrial membrane potential (MMP) and the expressions of phosphorylation- extracellular signal-regulated kinase (p-ERK) were investigated. Pretreatment with 5-HMF markedly attenuated hypoxia-induced cell necrosis and apoptosis at late stage (p < 0.01). Furthermore, pretreatment with 5-HMF rescued both the decline of the MMP and the increase of p-ERK protein under hypoxia. In a word, these results indicated that 5-HMF had protective effects against hypoxic injury in ECV304 cells, and its effects on MMP and p-ERK may be involved in the mechanism.
5-HMF; Hypoxic injury; ECV304 cells; MMP
Earlier studies showed that the Val66Met polymorphisms of the brain-derived neurotrophic factor differentially affect gray matter volume and brain region activities. This study used resting positron emission tomography to investigate the relationship between the polymorphisms of Val66Met and the regional cerebral metabolic rate in the brain. We analyzed the positron emission tomography images of 215 patients from the Alzheimer’s Disease Neuroimaging Initiative and found significant differences in the parahippocampal gyrus, superior temporal gyrus, prefrontal cortex, and inferior parietal lobule when comparing Met carriers with noncarriers among both the normal controls and those with mild cognitive impairment. For those with Alzheimer’s disease, we also found additional differences in the bilateral insula between the carriers and noncarriers.
Alzheimer’s disease; brain-derived neurotrophic factor; cerebral metabolic rate for glucose; polymorphism; positron emission tomography
The use of chronic opioid therapy (COT) for chronic non-cancer pain (CNCP) has increased dramatically in the past two decades. There has also been a marked increase in abuse of prescribed opioids and in accidental opioid overdose. Misuse of prescribed opioids may link these trends, but has thus far only been studied in small clinical samples. We therefore sought to validate an administrative indicator of opioid misuse among large samples of recipients of COT and determine the demographic, clinical, and pharmacological risks associated with possible and probable opioid misuse. 21,685 enrollees in commercial insurance plans and 10,159 in Arkansas Medicaid who had at least 90 days of continuous opioid use 2000–5 were studied for one year. Criteria were developed for possible and probable opioid misuse using administrative claims data concerning excess days supplied of shortacting and long-acting opioids, opioid prescribers and opioid pharmacies. We estimated possible misuse at 24% of COT recipients in the commercially insured sample and 20% in the Medicaid sample and probable misuse at 6% in commercially insured and at 3% in Medicaid. Among non-modifiable factors, younger age, back pain, multiple pain complaints and substance abuse disorders identify patients at high risk for misuse. Among modifiable factors, treatment with high daily dose opioids (especially>120mg MED per day) and short-acting Schedule II opioids appears to increase risk of misuse. The consistency of the findings across diverse patient populations and varying levels of misuse suggests that these results will generalize broadly, but awaits confirmation in other studies.
While opioids are increasingly used for chronic non-cancer pain (CNCP), we know little about opioid dosing patterns among individuals with CNCP in usual care settings, and how these are changing over time.
To investigate the distribution of mean daily dose and mean days supply among patients with CNCP in two disparate populations, one national and commercially-insured population (HealthCore) and one state-based and publicly-insured (Arkansas Medicaid), for years 2000 and 2005.
For individuals with any opioid use, we calculated the distribution of mean daily dose (in milligram morphine equivalents), mean days supply in a year, mean annual dose, and patient characteristics associated with heavy utilizers of opioids.
Between 2000 and 2005, across all percentiles, there was little change in the mean daily opioid dose. In HealthCore, mean days supply increased most rapidly at the top end of the days supply distribution, while in Arkansas Medicaid the greatest increases were near the median of days supply. In HealthCore the top 5% of users accounted for 70% of total use (measured in milligram morphine equivalents), and the top 5% of Arkansas Medicaid users accounted for 48% of total use. The likelihood of heavy opioid utilization was increased among individuals with multiple pain conditions, and in HealthCore, among those with mental health and substance use disorders.
Opioid use is heavily concentrated among a small percent of patients. The characteristics of these high utilizers need to be further established, and the benefits and risks of their treatment evaluated.
Opioids; chronic non-cancer pain; pharmaco-epidemiology
Previous studies have consistently suggested that the ε4 allele of apolipoprotein E (APOE) gene is a major risk factor for Alzheimer’s disease (AD). However, whether the ε2 allele, a possible protective factor for AD, will express its protective effect in terms of cortical thickness in healthy elderly carriers is unclear. The goal of this study is to clarify the effects of APOE genotypes on cortical thickness in nondemented elderly subjects. We used 164 healthy, cognitively normal, elderly subjects, who were grouped into ε2 carriers, ε3 homozygotes, and ε4 carriers respectively. The APOE ε2 carriers had a significant thicker (corrected p < 0.05) cortical thickness in the superior temporal cortex compared with the ε3 homozygotes. In addition to this area, the APOE ε2 carriers had a significantly thicker region in the dorsolateral prefrontal cortex (corrected p < 0.05) than did the ε4 carriers. These findings suggest that the different alleles of the APOE gene have distinct neuroanatomic effects in elderly healthy subjects and may play specific roles in the development of AD.
Cortical thickness; Apolipoprotein E; Alzheimer’s disease
Prediction of conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD) is of major interest in AD research. A large number of potential predictors have been proposed, with most investigations tending to examine one or a set of related predictors. In this study, we simultaneously examined multiple features from different modalities of data, including structural magnetic resonance imaging (MRI) morphometry, cerebrospinal fluid (CSF) biomarkers and neuropsychological and functional measures (NMs), to explore an optimal set of predictors of conversion from MCI to AD in an Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. After FreeSurfer-derived MRI feature extraction, CSF and NM feature collection, feature selection was employed to choose optimal subsets of features from each modality. Support vector machine (SVM) classifiers were then trained on normal control (NC) and AD participants. Testing was conducted on MCIc (MCI individuals who have converted to AD within 24 months) and MCInc (MCI individuals who have not converted to AD within 24 months) groups. Classification results demonstrated that NMs outperformed CSF and MRI features. The combination of selected NM, MRI and CSF features attained an accuracy of 67.13%, a sensitivity of 96.43%, a specificity of 48.28%, and an AUC (area under curve) of 0.796. Analysis of the predictive values of MCIc who converted at different follow-up evaluations showed that the predictive values were significantly different between individuals who converted within 12 months and after 12 months. This study establishes meaningful multivariate predictors composed of selected NM, MRI and CSF measures which may be useful and practical for clinical diagnosis.
There have been several studies on the maternal administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and effects in the reproductive tract of male offspring, subsequent to risk assessments undertaken in 2001. This review compares the methodology and results to examine key methodological features, and consistency in reported outcomes. Maternal dosing at > 0.8 μg TCDD/kg causes lethality and weight loss, and it is difficult to distinguish between direct and indirect effects of TCDD at these dose levels. Statistically-significant effects of maternal doses of <1 μg TCDD/kg (i.e. the dose levels relevant for risk assessment) on prostate weight or epididymal sperm counts in offspring were reported in the minority of studies. The pharmacokinetics of TCDD differs considerably between acute and chronic dosing, and with dose level of TCDD. On the basis of body burden, TCDD had different potency at inducing adverse effects in the only comparison study between acute and chronic dosing. Understanding of the pharmacokinetics of TCDD and relationship to adverse effects in offspring is required. These analyses identify key features of TCDD developmental toxicity in male offspring, and identify data needs for future risk assessment.
Dioxin; TCDD; developmental; reproductive; toxicity; spermatogenesis
Staphylococcus aureus ribonuclease III belongs to the enzyme family known to degrade double-stranded RNAs. It has previously been reported that RNase III cannot influence cell growth but regulates virulence gene expression in S. aureus. Here we constructed an RNase III inactivation mutant (Δrnc) from S. aureus 8325-4. It was found that the extracellular proteins of Δrnc were decreased. Furthermore, we explored how RNase III regulated the production of the extracellular proteins in S. aureus. We found during the lag phase of the bacterial growth cycle RNase III could influence the extracellular protein secretion via regulating the expression of secY2, one component of accessory secretory (sec) pathway. After S. aureus cells grew to exponential phase, RNase III can regulate the expression of extracellular proteins by affecting the level of RNAIII. Further investigation showed that the mRNA stability of secY2 and RNAIII was affected by RNase III. Our results suggest that RNase III could regulate the pathogenicity of S. aureus by influencing the level of extracellular proteins via two different ways respectively at different growth phases.