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Chemically activated luciferase expression (CALUX) cell bioassays are popular tools for assessing endocrine activity of chemicals such as certain environmental contaminants. Although activity equivalents can be obtained from CALUX analysis, directly comparing these equivalents to those obtained from analytical chemistry methods can be problematic due to the complexity of endocrine active pathways. We explored the suitability of two estrogen CALUX bioassays (the OECD-approved VM7Luc4E2 cell bioassay and the VM7LucERβc9 cell bioassay) for quantitation of estrogen. Quadrupole-time of flight ultraperformance liquid chromatography/mass spectrometry (LC/MS) was selected as a comparative method. Regression analysis of measured estrone (E1) calibration samples showed all three methods as highly predictive of nominal concentrations (p ≤ 7.5 x 10

BACKGROUND: No prior studies have characterized long-term patterns of opioid use regardless of source or reason for use among patients with HIV (PWH). We sought to identify trajectories of self-reported opioid use and their correlates among a national sample of PWH engaged in care. SETTING: Veterans Aging Cohort Study, a prospective cohort including PWH receiving care at eight US Veterans Health Administration (VA) sites. METHODS: Between 2002 and 2018, we assessed past year opioid use frequency based on self-reported “prescription painkillers” and/or heroin use at baseline and follow-up. We used group-based trajectory models to identify opioid use trajectories and multinomial logistic regression to determine baseline factors independently associated with escalating opioid use compared to stable, infrequent use. RESULTS: Among 3,702 PWH, we identified four opioid use trajectories: 1) no lifetime use (25%); 2) stable, infrequent use (58%); 3) escalating use (7%); and 4) de-escalating use 11%). In bivariate analysis, anxiety; pain interference; prescribed opioids, benzodiazepines and gabapentinoids; and marijuana use were associated with escalating opioid group membership compared to stable, infrequent use. In multivariable analysis, illness severity, pain interference, receipt of prescribed benzodiazepine medications and marijuana use were associated with escalating opioid group membership compared to stable, infrequent use. CONCLUSION: Among PWH engaged in VA care, one in 15 reported escalating opioid use. Future research is needed to understand the impact of psychoactive medications and marijuana use on opioid use and whether enhanced uptake of evidence-based treatment of pain and psychiatric symptoms can prevent escalating use among PWH.

Objectives. To describe trends in suicides with opioid poisoning noted as a contributing cause of death. Methods. Using National Vital Statistics data (1999–2014), we calculated age-adjusted rates of suicide with opioid poisoning (International Classification of Diseases, Tenth Revision codes T40.0–T40.4) per 100 000 population per year and annual percentage change (APC) in rates. We used Joinpoint regression to examine trends in suicide rates and proportion of suicides involving opioids. Results. The annual age-adjusted death rate from suicide with opioid poisoning as a contributing cause of death increased from 0.3 per 100 000 in 1999 to 0.7 per 100 000 in 2009 (APC = 8.1%; P Conclusions. Opioid involvement in suicides has doubled since 1999. These analyses underscore the need for health care providers to assess suicidal risk in patients receiving opioids.

Pain complaints are commonly reported symptoms among postmenopausal women and can have significant effects on health-related quality of life. We sought to identify medical and psychosocial factors that predict changes in pain and overall physical functioning over a 3-year period among postmenopausal women with recurrent pain conditions. We examined data from postmenopausal women age 50 to 79 with recurrent pain conditions (low back pain, neck pain, headache or migraines, or joint pain or stiffness) over a 3-year period using the Women’s Health Initiative Observational Study Cohort (N = 67,963). Multinomial logistic regression models controlling for demographic and clinical characteristics were used to identify baseline predictors of change in the SF-36 subscales for pain and physical functioning between baseline and 3-year follow-up. Body mass index (BMI) was associated with worsening of pain (OR [95% CI] 1.54 [1.45-1.63] for BMI ≥30) and physical functioning (1.83 [1.71-1.95] for BMI ≥30). A higher reported number of nonpain symptoms, higher medical comorbidity, and a positive screen for depression (1.13 [1.05-1.22] for worsened pain) were also associated with worsening of pain and physical functioning. Baseline prescription opioid use was also associated with lack of improvement in pain (OR .42, 95% CI .36-.49) and with worsened physical functioning (1.25 [1.04-1.51]). Perspective This study presents prospective data on change in pain and physical functioning in postmenopausal women over a 3-year period. Our results suggest depression, nonpain physical symptoms, obesity, and possibly opioid treatment are associated with worse long-term pain outcomes in this population.

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.

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 the 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. A total of 21,685 enrollees in commercial insurance plans and 10,159 in Arkansas Medicaid who had at least 90 days of continuous opioid use 2000-2005 were studied for one year. Criteria were developed for possible and probable opioid misuse using administrative claims data concerning excess days supplied of short-acting 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 >120 mg MED per day) and short-acting Schedule II opioids appears to increase the risk of misuse. The consistency of the findings across diverse patient populations and the varying levels of misuse suggest that these results will generalize broadly, but await confirmation in other studies.

Objective. To estimate recent age- and sex-specific changes in long-term opioid prescription among patients with chronic pain in two large American Health Systems. Design. 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). Patients. Enrollees in HealthCore (N = 2,716,163 in 2000) and Arkansas Medicaid (N = 115,914 in 2000). Results. 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. Conclusions. 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.

Objective We report trends in long-term opioid use among patients with a history of depression from two large health plans. Methods Using claims data, age- and gender-adjusted rates for long-term (>90 days) opioid use episodes were calculated for 1997–2005, comparing those with and without a depression diagnosis in the prior 2 years. Opioid use characteristics were calculated for those with a long-term episode in 2005. Results Incident and prevalent long-term opioid use rates were three times higher in those with a history of depression. Prevalent long-term use per 1000 in patients with a history of depression increased from 69.8 to 125.9 at Group Health and from 84.3 to 117.5 at Kaiser Permanente of Northern California between 1997 and 2005. Those with a history of depression were more likely to receive a higher average daily dose, greater days supply, and Schedule II opioids than nondepressed persons. Conclusion Persons with a history of depression are more likely to receive long-term opioid therapy for noncancer pain than those without a history of depression. Results suggest that long-term opioid therapy for noncancer pain is being prescribed to a different population in clinical practice than the clinical trial populations where opioid efficacy has been established.

Objective Mental health disorders commonly co-occur in patients with chronic pain, but little is known about the role of chronic pain in mental health service use. In this study, the authors explored the role of chronic pain in mental health service use by adults according to age group. Method The authors conducted a cross-sectional analysis of survey data from the second wave of the Health Care for Communities telephone survey collected in 2000–2001. Participants consisted of U.S. civilian adults (N = 6629) from randomly selected U.S. households. Common mental disorders were assessed using the short-form versions of the World Health Organization's Composite International Diagnostic Interview. Chronic pain conditions and mental health services received were identified by self-report. Physical and mental functioning was assessed using the Short Form-12. Results Adults older than age 60 had higher rates of chronic pain and lower rates of mental health service use compared with those aged 18–60 years. In multiple logistic regression models, an interaction effect was found between age and chronic pain (odds ratio: 3.0 [1.1–8.0]) with chronic pain significantly increasing the odds of any mental health care in the past year in adults older than 60 years of age. Conclusions Chronic pain increases the likelihood of mental health service use among older adults. Chronic pain may facilitate the presentation of distress in medical settings for these adults.

The pivotal point of vertebrate sex determination is the development of the gonad into a testis or ovary, which governs phenotypic sex through the production of hormones. The identification of Sry, the genetic switch that controls testis development in mammals, fuelled the race for the discovery of downstream pathways. Comparative analyses of XY versus XX gonadogenesis in both mouse and human genetic mutants have uncovered a burgeoning network of intra- and extra-cellular pathways. Here, we review the old and new players that are involved in the initial steps of testis and ovary development.

Puma encodes a BH3-only protein that is induced by the p53 tumor suppressor and other apoptotic stimuli. To assess its physiological role in apoptosis, we generated Puma knockout mice by gene targeting. Here we report that Puma is essential for hematopoietic cell death triggered by ionizing radiation (IR), deregulated c-Myc expression, and cytokine withdrawal. Puma is also required for IR-induced death throughout the developing nervous system and accounts for nearly all of the apoptotic activity attributed to p53 under these conditions. These findings establish Puma as a principal mediator of cell death in response to diverse apoptotic signals, implicating Puma as a likely tumor suppressor.

Myc and E2f1 promote cell cycle progression, but overexpression of either can trigger p53-dependent apoptosis. Mice expressing an Eμ- Myc transgene in B lymphocytes develop lymphomas, the majority of which sustain mutations of either the Arf or p53 tumor suppressors. Eμ- Myc transgenic mice lacking one or both E2f1 alleles exhibited a slower onset of lymphoma development associated with increased expression of the cyclin-dependent kinase inhibitor p27 Kip1 and a reduced S phase fraction in precancerous B cells. In contrast, Myc-induced apoptosis and the frequency of Arf and p53 mutations in lymphomas were unaffected by E2f1 loss. Therefore, Myc does not require E2f1 to induce Arf, p53, or apoptosis in B cells, but depends upon E2f1 to accelerate cell cycle progression and downregulate p27 Kip1 .

Organogenesis of the gonad is unique in that both the testis and ovary are derived from an initially bipotential tissue, the genital ridge. Development diverges when Sry is expressed during a narrow window of time between 10.5 and 12.5 days postcoitum (dpc) in the XY gonad, resulting in rapid morphological changes that produce a characteristic testis morphology by 12.5 dpc. At this stage, the organization of testis cords defines two compartments of the testis. Inside testis cords are the Sertoli cells, which support the development of primordial germ cells, are the cell type that expresses Sry, and are believed to orchestrate testis organogenesis. Peritubular myoid cells surround the cords and participate with Sertoli cells in the production of basal lamina. The interstitial compartment lies between testis cords and contains steroid-secreting Leydig cells, fibroblasts, and the characteristic vasculature of the testis. Although no direct targets of Sry have been identified, several developmental processes in the gonad depend on Sry and occur soon after Sry is expressed. One early event is an increase in proliferation of cells at the coelomic surface of the XY gonad (Schmahl et al. 2000). Proliferation occurs in two stages. The first stage of proliferation occurs between 11.2 and 11.5 dpc and gives rise to Sertoli cell precursors. The second stage of proliferation occurs between 11.5 and 12.0 dpc and gives rise to other, uncharacterized somatic cells of the testis (Karl and Capel 1998; Schmahl et al. 2000). The adjacent mesonephros is an additional source of cells for the XY gonad. Migration of cells from the mesonephros is dependent on Sry (Capel et al. 1999) and is required for organization of testis cords (Buehr et al. 1993; Merchant-Larios et al. 1993; Martineau et al. 1997; Tilmann and Capel 1999). The migrating cell population includes peritubular myoid cells and many endothelial and perivascular cells that contribute to divergent vascular development in the XY gonad (Brennan et al. 2002). The origin of fetal Leydig cells has not been clarified, but several sources have been suggested, which include the coelomic epithelium (Karl and Capel 1998), a migrating mesonephric population (Merchant-Larios and Moreno-Mendoza 1998; Nishino et al. 2001) that may include neural crest cells (Middendorff et al. 1993; Mayerhofer et al. 1996), or a common early precursor of the adrenal steroid cells (Hatano et al. 1996). Very little is known about the genetic signaling pathways operating downstream of Sry that control the cellular mechanisms of testis organogenesis. Using a candidate approach, we investigated the platelet-derived growth factor (PDGF) family of ligands and receptors, which have well-characterized roles in the proliferation and migration of mesenchymal cell types, particularly smooth muscle and endothelial cells (Betsholtz et al. 2001). There are two identified PDGF receptors, α and β, and four ligands, A, B, C, and D. Different combinations of ligands and receptors can homo- and heterodimerize and activate several distinct and overlapping intracellular pathways (for review, see Heldin and Westermark 1999; Klinghoffer et al. 2001). PDGFR-α has a broader specificity for ligand binding and can bind PDGF-A, PDGF-B, and PDGF-C homodimers as well as PDGF-AB heterodimers, whereas PDGFR-β can bind only PDGF-B and PDGF-D homodimers. Generally, Pdgf ligands are expressed by epithelial or endothelial cells, whereas mesenchymal cells express Pdgf receptors. Proliferation and migration of mesenchymal cells in response to PDGF signaling contribute to the morphogenesis and integrity of epithelial and endothelial structures as shown by genetic disruptions that affect tissues such as the lung, the kidney, and the intestine (Soriano 1994; Bostrom et al. 1996; Lindahl et al. 1998; Karlsson et al. 2000). Previous expression data (Gnessi et al. 1995) and recent genetic data have provided some insight into the involvement of PDGFs in the postnatal development of the testis. In the Pdgf-A−/− testis, very few adult Leydig cells develop, leading to a reduction in testis size and spermatogenic arrest by 32 days postnatal (dpn). Adult Leydig cells are not derived from fetal Leydig cells, but instead arise as a separate, distinct cell population after birth (Ariyaratne et al. 2000). Although fetal stages were not examined, two pieces of evidence implied that fetal Leydig cell development was normal. First, normal numbers of fetal Leydig cells were reported in Pdgf-A−/− gonads at 10–25 dpn, just before they are replaced by adult Leydig cells. Second, testicular descent and masculinization occurred normally, indicating that fetal Leydig cells were present during fetal development and produced testosterone. (Gnessi et al. 2000). The role of PDGF signaling in the embryonic testis has not been investigated in detail. A recent study using the PDGFR tyrosine kinase inhibitor, AG1296, implicated PDGF signaling in rat fetal testis cord development (Uzumcu et al. 2002). Large, dilated cords were noted in the treated samples, although the cellular and molecular basis for the defect was not characterized, and the role of specific PDGF receptors and ligands was not addressed. Our examination of gonads from Pdgfr-β−/− mice (Soriano 1994) revealed no overt defects in early XY or XX development at 11.5–13.5 dpc, ruling out a critical role for this receptor (K. Tilmann, unpubl.). These data led us to focus our study on PDGFR-α and its ligands PDGF-A, PDGF-B, and PDGF-C. We found that Pdgfr-α and Pdgf-A display a sexually dimorphic expression pattern in the gonad. To examine the potential roles of these factors in gonad development, we analyzed gonad development in Pdgfr-α−/− mice. These studies uncovered a sex-specific role for PDGFR-α signaling in promoting cord formation, proliferation, endothelial cell migration, and Leydig cell differentiation. We also provide data placing PDGF signaling in a parallel pathway with Dhh, which is expressed in Sertoli cells and is the only other fetal Leydig cell factor identified thus far (Yao et al. 2002).

Increasing rates of opioid use disorders (OUDs) (abuse and dependence) among patients prescribed opioids are a significant public health concern. We investigated the association between exposure to prescription opioids and incident OUDs among individuals with a new episode of a chronic noncancer pain (CNCP) condition.We utilized claims data from the HealthCore Database for 2000 to 2005. The dataset included all individuals aged 18 and over with a new CNCP episode (no diagnosis in the prior 6 mo), and no opioid use or OUD in the prior 6 months (n=568,640). We constructed a single multinomial variable describing prescription on opioid days supply (none, acute, and chronic) and average daily dose (none, low dose, medium dose, and high dose), and examined the association between this variable and an incident OUD diagnosis.Patients with CNCP prescribed opioids had significantly higher rates of OUDs compared with those not prescribed opioids. Effects varied by average daily dose and days supply: low dose, acute (odds ratio [OR]=3.03; 95% confidence interval [CI], 2.32, 3.95); low dose, chronic (OR=14.92; 95% CI, 10.38, 21.46); medium dose, acute (OR=2.80; 95% CI, 2.12, 3.71); medium dose, chronic (OR=28.69; 95% CI, 20.02, 41.13); high dose, acute (OR=3.10; 95% CI, 1.67, 5.77); and high dose, chronic (OR=122.45; 95% CI, 72.79, 205.99).Among individuals with a new CNCP episode, prescription opioid exposure was a strong risk factor for incident OUDs; magnitudes of effects were large. Duration of opioid therapy was more important than daily dose in determining OUD risk.

Activation of the Cyclin B/Cdc2 kinase complex triggers entry into mitosis in all eukaryotic cells. Cyclin B1 localization changes dramatically during the cell cycle, precipitously transiting from the cytoplasm to the nucleus at the beginning of mitosis. Presumably, this relocalization promotes the phosphorylation of nuclear targets critical for chromatin condensation and nuclear envelope breakdown. We show here that the previously characterized cytoplasmic retention sequence of Cyclin B1, responsible for its interphase cytoplasmic localization, is actually an autonomous nuclear export sequence, capable of directing nuclear export of a heterologous protein, and able to bind specifically to the recently identified export mediator, CRM1. We propose that the observed cytoplasmic localization of Cyclin B1 during interphase reflects the equilibrium between ongoing nuclear import and rapid CRM1-mediated export. In support of this hypothesis, we found that treatment of cells with leptomycin B, which disrupted Cyclin B1–CRM1 interactions, led to a marked nuclear accumulation of Cyclin B1. In mitosis, Cyclin B1 undergoes phosphorylation at several sites, a subset of which have been proposed to play a role in Cyclin B1 accumulation in the nucleus. Both CRM1 binding and the ability to direct nuclear export were affected by mutation of these phosphorylation sites; thus, we propose that Cyclin B1 phosphorylation at the G2/M transition prevents its interaction with CRM1, thereby reducing nuclear export and facilitating nuclear accumulation.

Opioids are increasingly prescribed, but there are limited data on opioid receipt by HIV status.To describe patterns of opioid receipt by HIV status and the relationship between HIV status and receiving any, high-dose, and long-term opioids.Cross-sectional analysis of the Veterans Aging Cohort Study.HIV-infected (HIV+) patients receiving Veterans Health Administration care, and uninfected matched controls.Pain-related diagnoses were determined using ICD-9 codes. Any opioid receipt was defined as at least one opioid prescription; high-dose was defined as an average daily dose ≥ 120 mg of morphine equivalents; long-term opioids was defined as ≥ 90 consecutive days, allowing a 30 day refill gap. Multivariable models were used to assess the relationship between HIV infection and the three outcomes.Among the HIV+ (n = 23,651) and uninfected (n = 55,097) patients, 31 % of HIV+ and 28 % of uninfected (p 0.001) received opioids. Among patients receiving opioids, HIV+ patients were more likely to have an acute pain diagnosis (7 % vs. 4 %), but less likely to have a chronic pain diagnosis (53 % vs. 69 %). HIV+ patients received a higher mean daily morphine equivalent dose than uninfected patients (41 mg vs. 37 mg, p = 0.001) and were more likely to receive high-dose opioids (6 % vs. 5 %, p 0.001). HIV+ patients received fewer days of opioids than uninfected patients (median 44 vs. 60, p 0.001), and were less likely to receive long-term opioids (31 % vs. 34 %, p 0.001). In multivariable analysis, HIV+ status was associated with receipt of any opioids (AOR 1.40, 95 % CI 1.35, 1.46) and high-dose opioids (AOR 1.22, 95 % CI 1.07, 1.39), but not long-term opioids (AOR 0.94, 95 % CI 0.88, 1.01).Patients with HIV infection are more likely to be prescribed opioids than uninfected individuals, and there is a variable association with pain diagnoses. Efforts to standardize approaches to pain management may be warranted in this highly complex and vulnerable patient population.

There is an ongoing debate on the best way to screen febrile infants for urinary tract infection. We examined the urinanalysis (UA) findings on admission among infants less than 16 weeks old, with and without acute pyelonephritis (APN), as defined by the dimercaptosuccinic acid (DMSA) renal scan findings, performed during a 57-month period. Forty-nine cases with a positive DMSA scan were compared with 79 negative study cases. A negative UA for leukocytes (< 5 white blood cells/high power field) was found in 4 of 49 (8.1%) cases with APN by DMSA, and in 34 of 79 (43%) cases with a negative DMSA (odds ratio 10.88 (95% confidence interval, 2.31 to 70.3; P < 0.001)). Three of the 4 infants not suspected to have APN by their UA findings would have been admitted for a full sepsis workup based on their clinical presentation and/or their laboratory findings on admission. We conclude that a fresh UA may be a sufficient screening method for the exclusion of APN in infants assessed for fever of no obvious origin.

In early phases of human T-cell lymphotrophic virus I-induced adult T-cell leukemia (ATL), the malignant cell proliferation is associated with an autocrine process involving coordinate expression of interleukin (IL) 2 and its receptor. However, during late-phase ATL, leukemic cells no longer produce IL-2 yet continue to express high-affinity IL-2 receptors. During studies to define pathogenic mechanisms that underlie this IL-2-independent proliferation, we demonstrated that the ATL cell line HuT-102 secretes a lymphokine, provisionally designated IL-T, that stimulates T-cell proliferation and the induction of lymphokine-activated killer cells. Conditioned medium from HuT-102, when added to the IL-2-dependent CTLL-2 line, yielded a stimulation index of 230. Since CTLL-2 was purported to be IL-2-specific, we performed a number of studies to exclude IL-2 production by HuT-102. Stimulation of CTLL-2 cells by HuT-102-conditioned medium was not meaningfully inhibited by addition of an antiserum to IL-2. Furthermore, uninduced HuT-102 cells did not express mRNA encoding IL-2 as assessed by Northern blot analysis. No biological activity on CTLL-2 cells was mediated by purified IL-1, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12, IL-13, or granulocyte/macrophage colony-stimulating factor, thus differentiating these factors from IL-T. Based on preliminary biochemical data, IL-T is a protein with a pI value of 4.5 and a molecular mass in SDS gels of 14 kDa. In addition to its action on CTLL-2 cells, 3200-fold-purified IL-T stimulated proliferation of the human cytokine-dependent T-cell line Kit-225. Furthermore, addition of IL-T enhanced cytotoxic activity of large granular lymphocytes (i.e., induced lymphokine-activated killer cells). Thus, IL-T is a lymphokine that plays a role in T-cell proliferation and induction of lymphokine-activated killer cells. Furthermore, IL-T may contribute to IL-2-independent proliferation of select ATL cells and lines.

Background There has been an increase in overdose deaths and emergency department visits (EDVs) involving use of prescription opioids, but the association between opioid prescribing and adverse outcomes is unclear. Methods 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. Results 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). Conclusions 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.

Use of prescription opioids for chronic pain is increasing, as is abuse of these medications, though the nature of the link between these trends is unclear. These increases may be most marked in patients with mental health (MH) and substance use disorders (SUDs). We analyzed trends between 2000 and 2005 in opioid prescribing among individuals with noncancer pain conditions (NCPC), with and without MH and SUDs.Secondary data analysis of longitudinal administrative data from 2 dissimilar populations: a national, commercially insured population and Arkansas Medicaid enrollees. We examined these opioid outcomes: (1) rates of any prescription opioid use in the past year, (2) rates of chronic use of prescription opioids (greater than 90 d in the past year), (3) mean days supply of opioids, (4) mean daily opioid dose in morphine equivalents, and (5) percentage of total opioid dose that was Schedule II opioids.In 2000, among individuals with NCPC, chronic opioid use was more common among those with a MH or SUD than among those without in commercially insured (8% vs. 3%, P0.001) and Arkansas Medicaid (20% vs. 13%, P0.001) populations. Between 2000 and 2005, in commercially insured, rates of chronic opioid use increased by 34.9% among individuals with an MH or SUD and 27.8% among individuals without these disorders. In Arkansas Medicaid chronic, opioid use increased by 55.4% among individuals with an MH or SUD and 39.8% among those without.Chronic use of prescription opioids for NCPC is much higher and growing faster in patients with MH and SUDs than in those without these diagnoses. Clinicians should monitor the use of prescription opioids in these vulnerable groups to determine whether opioids are substituting for or interfering with appropriate MH and substance abuse treatment.

Objective 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. Methods 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. Results 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. Conclusion Opioid abuse and dependence are diagnosed in a small minority of patients receiving chronic opioid therapy, but this may under-estimate actual misuse. Characteristics of the patients and of the opioid therapy itself are associated with the risk of abuse and dependence.

Context Although opioids are increasingly used for chronic noncancer pain (CNCP), we know little about opioid dosing patterns among individuals with CNCP in usual care settings, and how these are changing over time. Objectives 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. Methods 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. Results 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, whereas 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. Conclusion 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 have been linked to increased risk of fractures, but little is known about how opioid dose affects fracture risk.To assess whether risk of fracture increases with opioid dose among older patients initiating sustained use of opioids for chronic non-cancer pain.A cohort study that uses Cox proportional hazards models to compare fracture risk among current opioid users vs. persons no longer using opioids.Members of an integrated health care plan (N = 2,341) age 60 years and older who received 3+ opioid prescriptions within a 90-day period for chronic, non-cancer pain between 2000 and 2005.Time-varying measures of opioid use and average daily dose in morphine equivalents were calculated from automated data. Fractures were identified from automated data and then validated through medical record review.Compared with persons not currently using opioids, opioid use was associated with a trend towards increased fracture risk (1.28 (95% CI (0.99, 1.64 )). Higher dose opioid use (or=50 mg/day) was associated with a 9.95% annual fracture rate and a twofold increase in fracture risk (2.00 (95% CI (1.24, 3.24)). Of the fractures in the study cohort, 34% were of the hip or pelvis, and 37% were associated with inpatient care.Higher doses (or=50 mg/day) of opioids for chronic non-cancer pain were associated with a 2.00 increase in risk of fracture confirmed by medical record review. Clinicians should consider fracture risk when prescribing higher-dose opioid therapy for older adults.

During testis development, fetal Leydig cells increase their population from a pool of progenitor cells rather than from proliferation of a differentiated cell population. However, the mechanism that regulates Leydig stem cell self-renewal and differentiation is unknown. Here, we show that blocking Notch signaling, by inhibiting γ-secretase activity or deleting the downstream target gene Hairy/Enhancer-of-split 1, results in an increase in Leydig cells in the testis. By contrast, constitutively active Notch signaling in gonadal somatic progenitor cells causes a dramatic Leydig cell loss, associated with an increase in undifferentiated mesenchymal cells. These results indicate that active Notch signaling restricts fetal Leydig cell differentiation by promoting a progenitor cell fate. Germ cell loss and abnormal testis cord formation were observed in both gain- and loss-of-function gonads, suggesting that regulation of the Leydig/interstitial cell population is important for male germ cell survival and testis cord formation.

Objective: This study examined the independent and interactive effects of common mental disorders and chronic pain conditions on employment and work outcomes among individuals under 65 years old. Methods: Cross-sectional data were analyzed from the second wave of Healthcare for Communities (HCC2), a household telephone survey of U.S. civilian adults conducted in 2000-2001 (N=5,328). Common mental disorders were assessed by using the short-form version of the World Health Organization's Composite International Diagnostic Interview. Chronic pain conditions and employment outcomes were identified by self-report. Logistic and linear regression analyses were used to provide estimates for work impairment on the basis of the presence of a mental disorder or a chronic pain condition or both. Results: The interaction between presence of a mental disorder and presence of a chronic pain condition was significantly associated with no work for pay in the past 12 months (odds ratio=2.3,95% confidence interval=1.2-4.2) and number of days of work missed in the past month because of health (regression coefficient=1.47, SE=.59). In stratified analyses this effect persisted for women but not for men. The presence of a mental disorder and the presence of a chronic pain condition were each independently associated with limitations in work and any work missed in the past 30 days because of health, although the interaction was not significant. Conclusions: Mental disorders and chronic pain are each associated with work disability. Mental disorders are more strongly associated with some work disability outcomes when they are accompanied by chronic pain, especially among women.

Opioids are widely prescribed for non-cancer pain conditions (NCPC), but there have been no large observational studies in actual clinical practice assessing patterns of opioid use over extended periods of time. The TROUP (Trends and Risks of Opioid Use for Pain) study reports on trends in opioid therapy for NCPC in two disparate populations, one national and commercially insured (HealthCore Blue Cross and Blue Shield plans) and one state-based and publicly-insured (Arkansas Medicaid) population over a six year period (2000-2005). We track enrollees with the four most common NCPC conditions: arthritis/joint pain, back pain, neck pain, headaches, as well as HIV/AIDS. Rates of NCPC diagnosis and opioid use increased linearly during this period in both groups, with the Medicaid group starting at higher rates and the HealthCore group increasing more rapidly. The proportion of enrollees receiving NCPC diagnoses increased (HealthCore 33%, Medicaid 9%), as did the proportion of enrollees with NCPC diagnoses who received opioids (HealthCore 58%, Medicaid 29%). Cumulative yearly opioid dose (in mg. morphine equivalents) received by NCPC patients treated with opioids increased (HealthCore 38%, Medicaid 37%) due to increases in number of days supplied rather than dose per day supplied. Use of short-acting Drug Enforcement Administration Schedule II opioids increased most rapidly, both in proportion of NCPC patients treated (HealthCore 54%, Medicaid 38%) and in cumulative yearly dose (HealthCore 95%, Medicaid 191%). These trends have occurred without any significant change in the underlying population prevalence of NCPC or new evidence of the efficacy of long-term opioid therapy and thus likely represent a broad-based shift in opioid treatment philosophy.

We sought to examine whether the presence of a noncancer pain condition is independently associated with an increased risk for suicidal ideation, plan, or attempt after adjusting for sociodemographic and psychiatric risk factors for suicide and whether risk differs by specific type of pain. We analyzed data from the National Comorbidity Survey Replication, a household survey of U.S. civilian adults age 18 years and older (n = 5692 respondents). Pain conditions, nonpain medical conditions, and suicidal history were obtained by self-report. DSM-IV mood, anxiety, and substance use disorders were assessed using the World Health Organization's Composite International Diagnostic Interview. Antisocial and borderline personality traits were assessed with the International Personality Disorder Examination screening questionnaire. In unadjusted logistic regression analyses, the presence of any pain condition was associated with lifetime and 12-month suicidal ideation, plan, and attempt. After controlling for demographic, medical, and mental health covariates, the presence of any pain condition remained significantly associated with lifetime suicidal ideation (odds ratio, 1.4; 95% confidence interval, 1.1–1.8) and plan. Among pain subtypes, severe or frequent headaches and “other” chronic pain remained significantly associated with lifetime suicidal ideation and plan; “other” chronic pain was also associated with attempt. Perspective The risk for suicidal thoughts and behaviors that may accompany back, neck, and joint pain can be accounted for by comorbid mental health disorders. There may be additional risk accompanying frequent headaches and “other” chronic pain that is secondary to psychosocial processes not captured by the mental disorders assessed.