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Purpose: We aimed to estimate health state utility values (HSUVs) for the key health states found in opioid use disorder (OUD) cost-effectiveness models in the published literature., Methods: Data obtained from six trials representing 1,777 individuals with OUD. We implemented mapping algorithms to harmonize data from different measures of quality of life (the SF-12 Versions 1 and 2 and the EQ-5D-3 L). We performed a regression analysis to quantify the relationship between HSUVs and the following variables: days of extra-medical opioid use in the past 30 days, injecting behaviors, treatment with medications for OUD, HIV status, and age. A secondary analysis explored the impact of opioid withdrawal symptoms., Results: There were statistically significant reductions in HSUVs associated with extra-medical opioid use (-0.002 (95% CI [-0.003,-0.0001]) to -0.003 (95% CI [-0.005,-0.002]) per additional day of heroin or other opiate use, respectively), drug injecting compared to not injecting (-0.043 (95% CI [-0.079,-0.006])), HIV-positive diagnosis compared to no diagnosis (-0.074 (95% CI [-0.143,-0.005])), and age (-0.001 per year (95% CI [-0.003,-0.0002])). Parameters associated with medications for OUD treatment were not statistically significant after controlling for extra-medical opioid use (0.0131 (95% CI [-0.0479,0.0769])), in line with prior studies. The secondary analysis revealed that withdrawal symptoms are a fundamental driver of HSUVs, with predictions of 0.817 (95% CI [0.768, 0.858]), 0.705 (95% CI [0.607, 0.786]), and 0.367 (95% CI [0.180, 0.575]) for moderate, severe, and worst level of symptoms, respectively., Conclusion: We observed HSUVs for OUD that were higher than those from previous studies that had been conducted without input from people living with the condition., (© 2024. The Author(s).)

Background: Opioid tapering in the general population is linked to increases in hospitalizations or emergency department visits related to psychiatric or drug-related diagnoses. Cancer survivors represent a unique population with different opioid indications, prescription patterns, and more frequent follow-up care. This study sought to describe patterns of opioid tapering among older cancer survivors and to test the hypothesis of whether older cancer survivors face increased risks of adverse events with opioid tapering., Methods: Using the Surveillance, Epidemiology and End Results Medicare-linked database, we identified 15 002 Medicare-beneficiary cancer survivors diagnosed between 2010 and 2017 prescribed opioids consistently for at least 6 months after their cancer diagnosis. Tapering was defined as a binary time-varying event occurring with any monthly oral morphine equivalent reduction of 15% or more from the previous month. Primary diagnostic billing codes associated with emergency room or hospital admissions were used for the composite endpoint of psychiatric- or drug-related event(s)., Results: There were 3.86 events per 100 patient-months, with 97.8% events being mental health emergencies, 1.91% events being overdose emergencies, and 0.25% involving both. Using a generalized estimating equation for repeated measure time-based analysis, opioid tapering was not statistically associated with acute events in the 3-month posttaper period (odds ratio [OR] = 1.02; P = .62) or at any point in the future (OR = 0.96; P = .46)., Conclusions: Opioid tapering in older cancer survivors does not appear to be linked to a higher risk of acute psychiatric- or drug-related events, in contrast to prior research in the general population., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Adverse childhood experiences (ACEs) are associated with mental health issues and substance use. Having a substance use disorder increases the risk of overdose (OD). Research on ACEs and risk of OD is limited. This study examined the relationship between ACE scores and a self-reported history of OD among patients in an addiction and mental health outpatient setting., Methods: This single-center, cross-sectional design included adults in a dual-diagnosis addiction and mental health outpatient recovery and treatment program from November 2017 to August 2020. Patients (N = 115) were assessed with self-report questionnaires, which included ACEs and history of OD. Bivariate and multivariable logistic regression was used to determine factors associated with self-reported OD history. We assessed the reliability and validity of the ACEs scale., Results: Of the 115 participants, 26 (22.6%) reported a past OD at intake. The mean ACE score for participants with an OD history, as compared with those with no history of OD, was 4.0 (standard deviation, 2.7) vs 2.3 (standard deviation, 2.2). In the multivariable regression, a higher ACE score was associated with history of OD (adjusted odds ratio, 1.23; 95% confidence interval, 1.00-1.50; P = 0.0456)., Conclusions: Given the observed association between OD and higher ACE scores, patients presenting for treatment in outpatient dual-diagnosis clinics should be screened for ACEs and OD history, providing the opportunity for treatment with trauma-informed care and/or referral to appropriate services., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Addiction Medicine.)

Background: The objectives of this study were to describe trends in the prevalence of postpartum suicidal behaviors in California, 2013-2018, and to estimate associations between adverse perinatal outcomes and suicidal behaviors. Materials and Methods: We used data from a population-based cohort derived from all birth and fetal death certificates. Records were individually linked to maternal hospital discharge records for the years before and after delivery. We estimated the prevalence of postpartum suicidal ideation and attempt by year. Then, we estimated crude and adjusted associations between adverse perinatal outcomes and these suicidal behaviors. The sample included 2,563,288 records. Results: The prevalence of postpartum suicidal ideation and attempt increased from 2013 to 2018. People with postpartum suicidal behavior were younger, had less education, and were more likely to live in rural areas. A greater proportion of those with postpartum suicidal behavior were Black and publicly insured. Severe maternal morbidity, neonatal intensive care unit admission, and fetal death were associated with greater risk of ideation and attempt. Major structural malformation was not associated with either outcome. Conclusions: The burden of postpartum suicidal behavior has increased over time and is unequally distributed across population subgroups. Adverse perinatal outcomes may help identify individuals that could benefit from additional care during the postpartum period.

This article aimed to evaluate whether a substance-related diagnosis (SRD; i.e., alcohol, opioids, cannabis, stimulants, nicotine) predicts the likelihood and co-occurrence of preterm (20-37 weeks' gestation) and cesarean delivery., This study reviewed electronic health record data on women (aged 18-44 years) who delivered a single live or stillbirth at ≥ 20 weeks of gestation from 2012 to 2019. Women with and without an SRD were matched on key demographic characteristics at a 1:1 ratio. Adjusting for covariates, odds ratios and 95% confidence intervals were calculated., Of the 19,346 deliveries, a matched cohort of 2,158 deliveries was identified. Of these, 1,079 (50%) had an SRD, 280 (13%) had a preterm delivery, 833 (39%) had a cesarean delivery, and 166 (8%) had a co-occurring preterm and cesarean delivery. An SRD was significantly associated with preterm and cesarean delivery (AOR = 1.84 [95% CI, 1.41-2.39], p -value= <0.0001; AOR = 1.51 [95% CI, 1.23-1.85], p -value= <0.0001). An alcohol-related diagnosis (AOR = 1.82 [95% CI, 1.01-3.28], p -value= 0.0471), opioid-related diagnosis (AOR = 1.94 [95% CI, 1.26-2.98], p -value= 0.0027), stimulant-related diagnosis (AOR = 1.65 [95% CI, 1.11-2.45], p -value= 0.0142), and nicotine-related diagnosis (AOR = 1.54 [95% CI, 1.05-2.26], p -value= 0.0278) were associated with co-occurring preterm and cesarean delivery., Pregnant women with an SRD experienced disproportionally higher odds of preterm and cesarean delivery compared to pregnant women without an SRD. Substance-type predicts the type of delivery outcome. An SRD in pregnant women should be identified early to reduce potential harm through intervention and treatment.

Background: As a vulnerable population, pregnant women with a substance-related diagnosis (ie, substance use, misuse, or dependence) may use healthcare disproportionately., Objective: The primary goal of this study was to evaluate the differences in the use of outpatient clinical visits, emergency department visits, and inpatient days in the hospital among women with and without a substance-related diagnosis during the antepartum period., Study Design: This retrospective study retrieved electronic health record data on women (age, 18-44 years) who delivered a single live birth or stillbirth at ≥20 weeks of gestation from April 1, 2012, to September 30, 2019. Imbalance in measured maternal sociodemographic and obstetrical characteristics between women with and without a substance-related diagnosis was attenuated using propensity score matching on key demographic characteristics (eg, age), yielding a matched 1:1 sample. Unadjusted and adjusted logistic regressions models were used to determine the association between a substance-related diagnosis and outpatient visits, emergency visits, and inpatient days., Results: From the total sample (n=16,770), the matched cohort consisted of 1986 deliveries. Of these, most were White (51.0%), or mixed or of some other race (31.1%). The mean age was 29.8 (standard deviation, 5.6). A substance-related diagnosis was identified in 993 women (50%) because of matching. Women with a substance-related diagnosis were more likely to have ≤10 outpatient visits than women without a substance-related diagnosis (adjusted odds ratio, 1.81 [95% confidence interval, 1.44-2.28]; P<.0001). Alcohol-, opioid-, and stimulant-related diagnoses were independently associated with ≤10 outpatient visits (adjusted odds ratio, 3.16 [95% confidence interval, 1.67-6.04]; P=.0005; adjusted odds ratio, 3.02 [95% confidence interval, 1.79-5.09]; P<.0001; adjusted odds ratio, 2.18 [95% confidence interval, 1.39-3.41]; P=.0007, respectively). Women with a substance-related diagnosis were more likely to have ≥1 emergency visit than women without a substance-related diagnosis (adjusted odds ratio, 1.36 [95% confidence interval, 1.00-1.85]; P<.0001). Opioid-, stimulant-, and nicotine-related diagnoses were independently associated with ≥1 emergency visit (adjusted odds ratio, 2.28 [95% confidence interval, 1.09-4.77]; P=.0287; adjusted odds ratio, 2.01 [95% confidence interval, 1.07-3.78]; P=.0301; adjusted odds ratio, 3.38 [95% confidence interval, 1.90-6.02]; P<.0001, respectively). Women with a substance-related diagnosis were more likely to have ≥3 inpatient days than women without a substance-related diagnosis (adjusted odds ratio, 1.69 [95% confidence interval, 1.07-2.67]; P=.0256). Opioid-, stimulant-, and nicotine-related diagnosis were independently associated with ≥3 inpatient days (adjusted odds ratio, 3.52 [95% confidence interval, 1.42-8.75]; P=.0067; adjusted odds ratio, 3.51 [95% confidence interval, 1.31-9.34]; P=.0123; adjusted odds ratio, 2.74 [95% confidence interval, 1.11-6.73]; P=.0285, respectively)., Conclusion: Women with a substance-related diagnosis during the antepartum period who delivered a single live birth or stillbirth at ≥20 weeks of gestation were experiencing fewer outpatient visits, more emergency department visits, and more inpatient days than women without a substance-related diagnosis. The type of substance-related diagnosis (eg, alcohol, opioids, stimulants, or nicotine) was associated with different patterns of healthcare use. The results from this study have reinforced the need to identify substance-related diagnoses in pregnant women early to minimize disproportionate healthcare service utilization through intervention and treatment., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Cannabis use and cannabis use disorders are increasing in prevalence, including among pregnant women. The objective was to evaluate the association of a cannabis-related diagnosis (CRD) in pregnancy and adverse maternal and infant outcomes., Methods: We queried an administrative birth cohort of singleton deliveries in California between 2011-2017 linked to maternal and infant hospital discharge records. We classified pregnancies with CRD from International Classification of Disease codes. We identified nicotine and other substance-related diagnoses (SRD) in the same manner. Outcomes of interest included maternal (hypertensive disorders) and infant (prematurity, small for gestational age, NICU admission, major structural malformations) adverse outcomes., Results: From 3,067,069 pregnancies resulting in live births, 29,112 (1.0 %) had a CRD. CRD was associated with an increased risk of all outcomes studied; the strongest risks observed were for very preterm birth (aRR 1.4, 95 % CI 1.3, 1.6) and small for gestational age (aRR 1.4, 95 % CI 1.3, 1.4). When analyzed with or without co-exposure diagnoses, CRD alone conferred increased risk for all outcomes compared to no use. The strongest effects were seen for CRD with other SRD (preterm birth aRR 2.3, 95 % CI 2.2, 2.5; very preterm birth aRR 2.6, 95 % CI 2.3, 3.0; gastrointestinal malformations aRR 2.0, 95 % CI 1.6, 2.6). The findings were generally robust to unmeasured confounding and misclassification analyses., Conclusions: CRD in pregnancy was associated with increased risk of adverse maternal and infant outcomes. Providing education and effective treatment for women with a CRD during prenatal care may improve maternal and infant health., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and Objectives: We implemented a naloxone education and distribution program in our academic health system. Despite the program, naloxone prescribing was not fully realized. This study aimed to identify the barriers to prescribing., Methods: We conducted a prospective, cross-sectional, mixed-methods study of naloxone prescribers. Participants completed a questionnaire regarding their prescribing practices, attitudes, facilitators, and barriers to prescribing naloxone. Participants were then invited for an interview to further explore these topics and elicit more in-depth explanations., Results: Sixty-four physicians and eight pharmacists completed the questionnaire (n = 72). The most commonly reported barrier to prescribing naloxone was time constraints (33%). During the interviews, 14 subthemes emerged within four themes: provider competency, provider beliefs, health care system, and patient factors/social climate., Discussion: Prescribers identified barriers to naloxone prescribing despite implementation of an institutional overdose education and naloxone distribution (OEND) program. The results were similar to those previously reported prior to initiation of such programs., Conclusion: In this study, we examined barriers and facilitators to naloxone prescribing. Although previous studies have shown that health care providers endorsed similar barriers, our study indicates that some of those barriers persist despite a concerted effort to educate and promote prescribing via an OEND. While our study is limited by a small, selective sample size the results indicate that improvements to our OEND program are warranted., Scientific Significance: Our study addressed an unexplored area of OEND research and may inform future program development. (Am J Addict 2019;00:00-00)., (© 2019 American Academy of Addiction Psychiatry.)

Purpose: To explore the acute effect of betel quid (BQ) use on functional network connectivity by comparing the global functional brain networks and their subsets before and immediately after BQ chewing., Materials and Methods: Resting-state functional magnetic resonance imaging (fMRI) was performed in 27 healthy male participants before and just after chewing BQ on a 3.0T scanner with a gradient-echo echo planar imaging sequence. Independent component analysis (ICA) was used to determine components that represent the brain's functional networks and their spatial aspects of functional connectivity. A paired t-test was used for exploring the connectivity differences in each network before and after BQ chewing., Results: Sixteen networks were identified by ICA. Nine of them showed connectivity differences before and after BQ chewing (P < 0.05 false discovery rate corrected): (A) orbitofrontal, (B) left frontoparietal, (C) visual, (D) right frontoparietal, (E) anterior default mode, (F) medial frontal/anterior cingulate (G) frontotemporal, (H) occipital/parietal, (I) occipital/temporal/cerebellum. Moreover, networks A, B, C, D, G, H, and I showed increased connectivity, while networks E and F showed decreased connectivity in participants after BQ chewing compared to before chewing., Conclusion: The acute effects of BQ use appear to actively alter functional connectivity of frontal and default networks that are known to play a key role in addictive behavior., Level of Evidence: 2 J. Magn. Reson. Imaging 2017;45:157-166., (© 2016 International Society for Magnetic Resonance in Medicine.)

Objective An innovative course was developed for fellows enrolled in the Yale School of Medicine Addiction Psychiatry program to educate them in key principles of adult learning, apply these principles in a case conference presentation, and to improve skills in providing and receiving feedback. Methods An initial training module on educational skills was followed by individual mentorship to prepare a case presentation. A feedback module provided space to learn and practice skills in feedback delivery. Results The program showed positive results and improved confidence levels of the participants in presenting and providing/receiving feedback. Conclusions Implementing a course designed to improve teaching and feedback skills is feasible in a 1-year Addiction Psychiatry fellowship.

Background: Methadone maintenance treatment (MMT) reduces the harms of opioid use disorder and is being rapidly scaled-up in China. This study evaluated the real-world implementation of MMT system in Wuhan, China., Methods: Data extracted from electronic medical records collected in 2010 on 8811 patients were used to compute for each patient indices of the prescribed and consumed daily methadone doses, an adherence index, dose adjustments following missed doses, the rates of opiate positive urine tests, self-reported drug use, injection drug use (IDU), and the duration of MMT exposure., Findings: The modal daily doses prescribed were 60 mg and above for 68.5% of patients. Adherence was variable: 51% of patients attended less than 60% and 26% attended 80-100% of their treatment days; and patients with long MMT exposure had significantly higher adherence rates than patients with short MMT exposure. The differences between doses dispensed immediately before and after the interruption in dosing days ranged from 0 to 7 mg, independently of the length of the interruption or the prescribed dosing level. The overall rate of opiate positive tests was 20%; 45% of patients had at least one opiate positive test; 29% reported past month drug use and 53% of them reported past month IDU. Adherence and MMT exposure duration correlated significantly with the proportion of opiate negative urine tests (r=0.355, p<0.001; r=0.351, p<0.001, respectively). Treatment for males and females was comparable., Conclusions: Provision of safe methadone dosing after absences and improving daily attendance are identified as priority improvement areas., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: Comorbidity and co-prescription patterns of people with serious mental illness in methadone maintenance may complicate their treatment and have not been studied. The goal of this study was to examine the care and characteristics of people with serious mental illness in methadone maintenance treatment nationally in the Veterans Health Administration (VHA)., Methods: Using national VHA data from FY2012, bivariate and multiple logistic regression analyses were used to compare veterans in methadone maintenance treatment wo had a serious mental illness (schizophrenia, bipolar disorder, or major affective disorder) to patients in methadone maintenance treatment without serious mental illness and patients with serious mental illness who were not in methadone maintenance treatment., Results: Only a small fraction of patients with serious mental illness were receiving methadone maintenance treatment (0.65%), but a relatively large proportion in methadone maintenance treatment had a serious mental illness (33.2%). Compared to patients without serious mental illness, patients with serious mental illness in methadone maintenance treatment were more likely to have been homeless, to have had a recent psychiatric hospitalization, to be over 50% disabled, and to have had more fills for more classes of psychotropic drugs. Compared to other patients with serious mental illness, patients with serious mental illness in methadone maintenance treatment were more likely to have a drug abuse diagnosis and to reside in large urban areas., Conclusions: One-third of patients in methadone maintenance treatment have serious mental illness and more frequent psychiatric comorbidity, and they are more likely to use psychiatric and general health services and fill more types of psychiatric prescriptions. Further study and clinical awareness of potential drug-drug interactions in this high medication and service using population are needed.

Objective: This study assessed beliefs about mental disorders and changes in those beliefs following an educational intervention for a convenience sample of Nigerian medical and nursing students., Methods: A 43-item questionnaire was used to assess perceptions regarding mental disorders and attitudes toward people with mental illness before and after a 4-day educational intervention., Results: Factor analysis identified four domains: (1) socializing with people with mental illness, (2) belief in witchcraft or curses as causes of mental illness, (3) favorable attitudes toward normalization of the lives of people with mental illness, and (4) biopsychosocial approaches to mental illness. The greatest changes were in attitudes favoring normalization of the lives of people with mental illness (p = 0.0002), socializing with the mentally ill (p = 0.01), and biopsychosocial perspectives on mental illness (p = 0.01)., Conclusion: Brief educational interventions may alter some stigmatizing negative attitudes toward mental illness in healthcare trainees in low- and middle-income countries.

Introduction: Alcohol use disorders affect millions, but few utilize medications. This paper examines factors contributing to the use of long-acting injectable depot naltrexone (LADN) in a large patient population., Methods: Bivariate analysis, stepwise multivariate logistic regression, and multivariate logistic regression analysis were used., Results: The sample had 101,026 patients of whom 3180 (3.1%) received any form of naltrexone and 240 (0.24%) received LADN. Of those who received naltrexone, only 7.5% (240/3180) received LADN. The LADN group was more likely to have outpatient mental health service use and a mental health inpatient admission. The LADN group was more likely to have a co-morbid Axis 1 psychiatric disorder and to fill a psychotropic prescription., Conclusion: In order to better serve and understand the implications of LADN treatment for the patient population that uses and may benefit from it, more research is needed on the effectiveness of this medication in the dually-diagnosed and high service use population., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: This study aimed to determine the proportion of patients with alcohol use disorders who were prescribed naltrexone in Veterans Administration (VA) Healthcare system for fiscal year (FY) 2010 and socio-demographic and clinical factors associated with its use., Methods: VA national administrative data were used to identify all veterans who had an alcohol use disorder diagnosis (ICD-9-CM codes 303.9x or305.0x) in fiscal year (FY 2010) and were not prescribed any opioids (n=224,319). Patients in this group who filled a naltrexone prescription during this period were identified. Bivariate analysis was used to evaluate differences between veterans who received naltrexone prescription and those who did not on baseline characteristics and diagnoses. Multivariate logistic regression analysis identified measures that were independently related to receipt of naltrexone., Results: 6172 (2.75%) of the 224,319 patients with a diagnosis of alcohol use disorder who did not receive a prescription for opioid medications received naltrexone prescription. Bivariate analyses showed that patients taking naltrexone were 69 times more likely to have a co-morbid axis I diagnosis. Multivariate logistic regression analysis showed that a history of any substance abuse outpatient visit, any psychiatric outpatient visit or any mental health inpatient hospitalization, were significantly related to filling a prescription for naltrexone., Conclusions: The rate of use of naltrexone by clinicians and patients remains low and having a co-morbid axis I diagnosis and receiving specialty mental health care were strong predictors of receiving a naltrexone prescription. Understanding the reasons for these findings may further naltrexone's clinical usefulness., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Interleukin-6 (IL-6) is a pleiotropic cytokine with diverse biological effects. IL-6 has been implicated in autocrine signaling pathways promoting tumor progression and chemoresistance in some human tumors. However, the mechanisms by which IL-6 modulates these responses are unknown. Aberrant apoptosis has been implicated as a fundamental mechanism of chemotherapeutic resistance. Thus, we investigated whether IL-6 alters the expression of apoptosis regulatory proteins as a mechanism of drug resistance. We provide evidence that IL-6 rapidly phosphorylates the translation initiation factor eukaryotic initiation factor-4E and triggers antiapoptotic responses in cholangiocarcinoma cells. Reduction of cellular eukaryotic initiation factor-4E by RNA interference decreases IL-6-induced effects on cytotoxic drug-induced caspase activation and apoptosis. Furthermore, IL-6 increases expression of the endogenous X-linked inhibitor of apoptosis protein expression by translation at an internal ribosome entry site. Our findings that IL-6 translationally regulates X-linked inhibitor of apoptosis protein expression reveal a novel mechanism by which IL-6 mediates tumor cell survival that may be targeted therapeutically to decrease tumor progression and chemoresistance.

Although the proteasome plays a critical role in the controlled degradation of proteins involved in cell cycle control, the direct modulation of proteasomal function by growth regulatory signaling has not yet been demonstrated. We assessed the effect of transforming growth factor (TGF)-beta, a potent inhibitor of cell growth, on proteasomal function. TGF-beta selectively decreased hydrolysis of the proteasomal substrate Cbz-Leu-Leu-Leu-7-amido-4-methyl-coumarin (z-LLL-AMC) in a concentration-dependent manner but did not inhibit hydrolysis of other substrates Suc-Leu-Leu-Val-Tyr-AMC (suc-LLVY-AMC) or Cbz-Leu-Leu-Glu-AMC (z-LLE-AMC). An increase in intracellular oxidative injury occurred during incubation with TGF-beta. Furthermore, in vitro hydrolysis of z-LLL-AMC, but not suc-LLVY-AMC, was decreased by hydrogen peroxide. TGF-beta did not increase cellular expression of heat shock protein (HSP)90, a potent inhibitor of z-LLL-AMC hydrolysis in vitro. The physiological relevance of TGF-beta inhibition of proteasomal activity was studied by assessing the role of z-LLL-AMC hydrolysis on cyclin-dependent kinase inhibitor expression and cell growth. TGF-beta increased expression of p27KIP1 but did not alter expression of p21WAF1 or p16INK4A. The peptide aldehyde Cbz-Leu-Leu-leucinal (LLL-CHO or MG132) potently inhibited z-LLL-AMC hydrolysis in cell extracts as well as increasing p27KIP1 and decreasing cell proliferation. Thus growth inhibition by TGF-beta decreases a specific proteasomal activity via an HSP90-independent mechanism that may involve oxidative inactivation or modulation of proteasomal subunit composition and results in altered cellular expression of key cell cycle regulatory proteins such as p27KIP1.

The p38 mitogen-activated protein kinase (MAPK) signaling pathway is aberrantly expressed and maintains transformed cell growth in malignant human cholangiocytes. Because cell growth requires and is intimately related to protein synthesis, our aims were to assess the effect of p38 MAPK signaling on protein synthesis during growth of malignant human cholangiocytes. Inhibition of p38 MAPK activity during mitogenic stimulation decreased protein synthesis rates and tumor cell xenograft growth in nude mice. Altered protein synthesis resulted from decreased translational efficiency with impaired initiation of translation. Mitogenic stimulation resulted in phosphorylation of the eukaryotic initiation factor (eIF)-4E. Inhibition of p38 MAPK signaling or functional dysregulation of translation by small interfering double-stranded RNA (siRNA) to eIF-4E decreased anchorage-independent growth of malignant cholangiocytes. In conclusion, these studies identify a relationship between p38 MAPK activity and the regulation of protein synthesis during human cholangiocarcinoma growth. As protein synthesis is intimately linked to cell growth, dysregulation of translation initiation is a mechanism by which cellular p38 MAPK signaling participates in growth regulation of malignant cholangiocytes.

Double-stranded RNA (dsRNA) is produced during replicative viral infection or genotoxic stress. Thus knowledge of the cellular response to dsRNA is necessary to understand the effects of DNA damage or viral infection in biliary epithelia. We assessed the effect of dsRNA on biliary epithelial cell proliferation and apoptosis and the role of the stress-activated p38 MAPK signaling pathway in these responses. dsRNA did not induce apoptosis or proliferation in Mz-ChA-1 human malignant cholangiocytes, but decreased cytotoxicity induced by camptothecin or tumor necrosis factor-related apoptosis inducing ligand and decreased activity of caspases 3, 8, and 9. Furthermore, dsRNA increased p38 MAPK and JNK kinase active site phosphorylation but had no effect on either MAPK kinase (MEK)1/2 or protein kinase R phosphorylation. Inhibition of p38 MAPK with SB-203580 increased basal caspase activity. Thus dsRNA stimulates a p38 MAPK-dependent cell-survival pathway in biliary epithelial cells that may modulate the response of the biliary epithelia to dsRNA produced during genotoxic injury or virus infection.

The aim of this study was to determine whether taurocholate prevents vagotomy-induced cholangiocyte apoptosis. After bile duct ligation (BDL) + vagotomy, rats were fed taurocholate for 1 wk in the absence or presence of wortmannin. Caspase involvement was evaluated by measurement of caspase 8, 9, and 3 activities. Proliferation was determined by morphometry and PCNA immunoblots. Changes in phosphatidylinositol 3-kinase (PI3-kinase) activity were estimated by the expression of the phosphorylated Akt protein. Apically located Na(+)-dependent bile acid transporter (ABAT) expression and activity were evaluated by immunoblots and [(3)H]taurocholate uptake, respectively. Cholangiocyte apoptosis increased, whereas proliferation decreased in BDL + vagotomy rats. Taurocholate feeding prevented vagotomy effects on cholangiocyte functions, which were abolished by wortmannin. ABAT expression and activity as well as phosphorylated Akt protein expression were reduced by vagotomy but restored by taurocholate. The activities of caspase 8, 9, and 3 increased in BDL + vagotomy rats but were restored by taurocholate. The protective effect of taurocholate was associated with maintenance of ABAT activity, downregulation of caspase 8, 9, and 3, and activation of PI3-kinase. Bile acids are important in modulating cholangiocyte proliferation in denervated livers.

St. Louis City and St. Louis County, Missouri share the same public drinking water source, namely the Missouri River. The 'all cancer' and most organ specific cancer mortality rates have been consistently and considerably higher for St. Louis City than for St. Louis County for the period 1960 through 1972. A change in the St. Louis County water treatment process, which included increasing the chlorine dosage and delaying the addition of ammonia to form chloramines until just prior to distribution, was instituted in 1955. St. Louis City has, by contrast, continued the lower chlorine level and early ammoniation. Trend analysis using the period 1960-67 and 1972-76 showed higher percentage as well as net cancer mortality rate per million increases for large bowel, liver and bladder cancers for St. Louis County. An apparent association between a probable increase in trihalomethane production in the St. Louis County water since 1955 and an increase in these specific cancer rates which exceed the increases in the St. Louis City rates appears to have been shown. This does not imply causality but is in general agreement with other studies which have examined water chlorination and cancer mortality.

Mortality rates for specific cancer types and age-sex groups computed for large numbers of cities typically show extreme fluctuation. This is primarily due to the rare occurrence of specific cancer deaths in most of the small and moderate size cities during a fixed time period. Assuming a Poisson death process, we use an empirical Bayes method to obtain adjusted rates that are more stable for comparison of cities and prediction of future mortality. We have chosen stomach and bladder cancers in Missouri cities to illustrate the problems, techniques and results.