Did Medicaid expansion close African American-white health care disparities nationwide? A scoping review.

OBJECTIVES: To investigate the impact of the Affordable Care Act's (ACA) Medicaid expansion on African American-white disparities in health coverage, access to healthcare, receipt of treatment, and health outcomes. DESIGN: A search of research reports, following the PRISMA-ScR guidelines, identified twenty-six national studies investigating changes in health care disparities between African American and white non-disabled, non-elderly adults before and after ACA Medicaid expansion, comparing states that did and did not expand Medicaid. Analysis examined research design and findings. RESULTS: Whether Medicaid eligibility expansion reduced African American-white health coverage disparities remains an open question: Absolute disparities in coverage appear to have declined in expansion states, although exceptions have been reported. African American disparities in health access, treatment, or health outcomes showed little evidence of change for the general population. CONCLUSIONS: Future research addressing key weaknesses in existing research may help to uncover sources of continuing disparities and clarify the impact of future Medicaid expansion on African American health care disparities.

Gestational weight gain below instead of within the guidelines per class of maternal obesity: a systematic review and meta-analysis of obstetrical and neonatal outcomes.

OBJECTIVE: This study aimed to systematically investigate a wide range of obstetrical and neonatal outcomes as they relate to gestational weight gain less than the current Institute of Medicine and the American College of Obstetricians and Gynecologists guidelines when compared with weight gain within the guideline range and to stratify outcomes by the class of obesity and by the type of study analysis. DATA SOURCES: We systematically searched studies on PubMed, Scopus, Embase, and the Cochrane Library from 2009 to April 30, 2021. STUDY ELIGIBILITY CRITERIA: Studies reporting on obstetrical and neonatal outcomes of singleton pregnancies related to gestational weight gain less than the current Institute of Medicine and the American College of Obstetricians and Gynecologists guidelines in comparison with weight gain within the guidelines among women with obesity overall (body mass index >30 kg/m2) and/or a specific class of obesity (I: body mass index, 30-34.9 kg/m2; II: body mass index, 35-39.9 kg/m2; and III: body mass index >40 kg/m2). METHODS: Among the studies that met the inclusion criteria, multiple obstetrical and neonatal outcomes were tabulated and compared between pregnancies with weight gain less than recommended in the guidelines and those with weight gain within the guidelines, further classified by the class of obesity if applicable. Primary outcomes included small for gestational age neonates, large for gestational age neonates, preeclampsia, and gestational diabetes mellitus. Secondary outcomes included cesarean delivery, preterm birth, postpartum weight retention, and composite neonatal morbidity. A meta-analysis of univariate and adjusted multivariate analysis studies was conducted. The random-effect model was used to pool the mean differences or odds ratios and the corresponding 95% confidence intervals. Heterogeneity was assessed using the I2 value. The Newcastle-Ottawa Scale was used to assess individual study quality. RESULTS: A total of 54 studies reporting on 30,245,946 pregnancies were included of which 11,515,411 pregnancies were in the univariate analysis and 18,730,535 pregnancies were in the adjusted multivariate analysis. In the meta-analysis of univariate studies, compared with women who gained weight as recommended in the guidelines, those who gained less than the weight recommended in the guidelines had higher odds of having a small for gestational age neonate among those with obesity class I and II (odds ratio, 1.30; 95% confidence interval, 1.17-1.45; I2=0%; P<.00001; and odds ratio, 1.56; 95% confidence interval, 1.31-1.85; I2=0%; P<.00001, respectively). However, the incidence of small for gestational age neonates was below the expected limits (<10%) and was not associated with increased neonatal morbidity. Furthermore, after adjusting for covariates, that difference was not statistically significant anymore. The difference was not statistically significant for class III obesity. Following adjusted multivariate analysis, no significant differences in small for gestational age rates were noted for any classes of obesity between groups. Significantly lower odds for large for gestational age neonates were seen in the group with gestational weight gain less than the recommended guidelines among those with obesity class I, II, and III (odds ratio, 0.69; 95% confidence interval, 0.64-0.73; I2=0%; P<.00001; odds ratio, 0.68; 95% confidence interval, 0.63-0.74; I2=0%; P<.00001; and odds ratio, 0.65; 95% confidence interval, 0.57-0.75; I2=34%; P<.00001, respectively), and similar findings were seen in the adjusted multivariate analysis. Women with weight gain less than the recommended guidelines had significantly lower odds for preeclampsia among those with obesity class I, II, and III (odds ratio, 0.71; 95% confidence interval, 0.63-0.79; I2=0%; P<.00001; odds ratio, 0.82; 95% confidence interval, 0.73-0.91; I2=0%; P<.00001; and odds ratio, 0.82; 95% confidence interval, 0.70-0.94; I2=0%; P=.006, respectively), and similar findings were seen in the adjusted multivariate analysis. No significant differences were seen in gestational diabetes mellitus between groups. Regarding preterm birth, available univariate analysis studies only reported on overall obesity and mixed iatrogenic and spontaneous preterm birth showing a significant increase in the odds of preterm birth (odds ratio, 1.42; 95% confidence interval, 1.40-1.43; I2=0%; P<.00001) among women with low weight gain, whereas the adjusted multivariate studies in overall obesity and in all 3 classes showed no significant differences in preterm birth between groups. Women with low weight gain had significantly lower odds for cesarean delivery in obesity class I, II, and III (odds ratio, 0.76; 95% confidence interval, 0.72-0.81; I2=0%; P<.00001; odds ratio, 0.82; 95% confidence interval, 0.77-0.87; I2=0%; P<.00001; and odds ratio, 0.87; 95% confidence interval, 0.82-0.91; I2=0%; P<.00001, respectively), and similar findings were seen in the adjusted multivariate analysis. There was significantly lower odds for postpartum weight retention (odds ratio, 0.20; 95% confidence interval, 0.05-0.82; I2=0%; P=.03) and lower odds for composite neonatal morbidity in the overall obesity group with low gestational weight gain (odds ratio, 0.93; 95% confidence interval, 0.87-0.99; I2=19.6%; P=.04). CONCLUSION: Contrary to previous reports, the current systematic review and meta-analysis showed no significant increase in small for gestational age rates in pregnancies with weight gain below the current guidelines for all classes of maternal obesity. Furthermore, gaining less weight than recommended in the guidelines was associated with lower large for gestational age, preeclampsia, and cesarean delivery rates. Our study provides the evidence that the current recommended gestational weight gain range is high for all classes of obesity. These results provide pertinent information supporting the notion to revisit the current gestational weight gain recommendations for women with obesity and furthermore to classify them by the class of obesity rather than by an overall obesity category as is done in the current recommendations.

The Daalbirrwirr Gamambigu (Safe Children) Model: Embedding Cultural Safety in Child Protection Responses for Australian Aboriginal Children in Hospital Settings.

The aim of this paper is to describe the development of a model of care to embed cultural safety for Aboriginal children into paediatric hospital settings. The Daalbirrwirr Gamambigu (pronounced "Dahl-beer-weer gum-um-be-goo" in the Gumbaynggirr language means 'safe children') model encompasses child protection responses at clinical, managerial and organisational levels of health services. A review of scholarly articles and grey literature followed by qualitative interviews with Aboriginal health professionals formed the evidence base for the model, which then underwent rounds of consultation for cultural suitability and clinical utility. Culturally appropriate communication with children and their families using clinical yarning and a culturally adapted version of ISBAR (a mnemonic for Identify, Situation, Background, Assessment and Recommendation) for interprofessional communication is recommended. The model guides the development of a critical consciousness about cultural safety in health care settings, and privileges the cultural voices of many diverse Aboriginal peoples. When adapted appropriately for local clinical and cultural contexts, it will contribute to a patient journey experience of respect, dignity and empowerment.

Urine lipoarabinomannan for rapid tuberculosis diagnosis in HIV-infected adult outpatients in Khayelitsha.

BACKGROUND: Decreasing tuberculosis (TB) mortality is constrained by diagnostic and treatment delays. The World Health Organization (WHO) recently actively recommended the point-of-care Alere Determine Lipoarabinomannan Ag assay (AlereLAM) to assist in the diagnosis of tuberculosis in specific HIV-infected outpatients. OBJECTIVES: The primary objective of this study was to compare time to ambulatory TB treatment in HIV-infected adults with CD4 ≤ 100 cells/µL before and after ('primary comparison groups') availability of AlereLAM. In pre-specified subgroups, we prospectively assessed AlereLAM-positive prevalence. METHOD: Clinicians prospectively performed AlereLAM in HIV-infected adults with TB symptoms and either CD4 ≤ 100 cells/µL or 'seriously ill' criteria. In a retrospective arm of equal duration, clinicians retrospectively collected data on HIV-infected adults with CD4 ≤ 100 cells/µL who initiated TB treatment. RESULTS: A total of 115 prospectively eligible adults (of whom 55 had CD4 ≤ 100 cells/µL) and 77 retrospectively eligible patients were included. In the primary comparison groups, the retrospective and prospective arms had similar age and sex distribution. With availability of AlereLAM, the time to TB treatment decreased from a median of 4 to 3 days (p = 0.0557). With availability of AlereLAM, same-day TB treatment initiation rose from 9.1% to 32.7% (p = 0.0006). In those with CD4 ≤ 100 only, those with 'seriously ill' criteria only, and in those meeting either, or both, of these criteria, AlereLAM was positive in 10.5%, 21.9%, 34.8% and 48.4% respectively. CONCLUSION: Availability of AlereLAM led to more patients initiating same-day TB treatment. Using both CD4 ≤ 100 and 'seriously ill' criteria gave the greatest yield. Results of this study have informed local policy design.

Emergency Nurses' Experiences in Treating Patients With Mental Illness: A Qualitative, Interpretive Metasynthesis.

INTRODUCTION: Each year, emergency departments are seeing an increase in the number of patients with mental illness. Nurses often do not feel equipped with the knowledge or skills for this patient population while caring for them. Although there is published literature about nurses caring for patients with mental illness, there is a gap in knowledge about the lived experiences of these frontline workers. METHODS: To gain a better understanding of the experiences of emergency nurses in treating patients presenting with psychiatric issues, a qualitative interpretive metasynthesis of 5 qualitative articles was conducted. RESULTS: Three themes emerged from the synthesis: (1) feeling unprepared and unqualified, (2) feeling anxious and hesitant, and (3) the need to keep the patient environment safe. DISCUSSION: The overarching finding in our QIMS was the prevalent feeling of general concern regarding treating patients with mental illness despite the nurses' own preconceptions and apprehensions. It is important to understand the lived experiences of nurses treating patients with mental illness to learn be better prepared for future encounters.

Intervention Response to the Trauma-Exposed, Justice-Involved Female Youth: A Narrative Review of Effectiveness in Reducing Recidivism.

This study aims to examine current research about trauma-exposed, justice-involved (TEJI) female youth, and evaluate the current literature regarding the effectiveness of gender-specific interventions aimed at reducing their recidivism. Preferred reporting items for systematic reviews and meta-analyses (PRISMA) methodology was utilized to examine quantitative and qualitative literature, published from 2000 through March 2020, about interventions for female justice-involved youth with trauma exposure. Analysis of selected studies utilized an integrated framework based on Andrew's Risk-Need-Responsivity (RNR) model and Lipsey's factors of effectiveness, which reviewed studies showing the relationship between female justice-involved youth with mental health symptomologies and trauma. The findings show that effective intervention for this population targets the youth's negative internal mechanisms related to trauma-subsequent psychosocial problems. These studies suggest that trauma-sensitive modalities have the potential to mitigate the further risk of problematic external behaviors. All studies had limited sample sizes, low follow-up rates, and unknown long-term outcomes. Future research should explore dimensions of sustainability and achieving stability in relation to intervention setting. Selecting the proper venue and facilitator for quality implementation and stability of setting is critical in delivering effective therapies. Modifications in public expectations of juvenile justice policy and practice, from disciplinary to therapeutic approaches, is needed.

Use of Medicare Administrative Claims to Identify a Population at High Risk for Adverse Drug Events and Hospital Use for Quality Improvement.

BACKGROUND: A system using administrative claims to monitor medication use patterns and associated adverse events is not currently available. Establishment of a standardized method to identify Medicare beneficiaries at high risk for adverse events, by assessing Medicare Part D medication claim patterns and associated outcomes, including outpatient adverse drug events (ADEs) and hospital use, enhances prevention efforts and monitoring for quality improvement efforts. OBJECTIVES: To (a) demonstrate that Medicare claims data can be used to identify a population of beneficiaries at high risk for adverse events for quality improvement and (b) define trends associated with adverse health outcomes in identified high-risk beneficiaries for quality improvement opportunities. METHODS: We used Medicare fee-for-service Part D claims data to identify a population at high risk for adverse events by evaluating medication use patterns. This population was taking at least 3 medications, 1 of which was an anticoagulant, an opioid, or an antidiabetic agent. Next, we used associated Part A claims to calculate rates of outpatient ADEs, looking for specific ICD-9-CM or ICD-10-CM codes in the principal diagnosis code position. Rates of hospital use (inpatient hospitalization, observation stays, emergency department visits, and 30-day rehospitalizations) were also evaluated for the identified high-risk population. The data were then shared for targeted quality improvement. RESULTS: We identified 8,178,753 beneficiaries at high risk for adverse events, or 20.7% of the total eligible fee-for-service population (time frame of October 2016-September 2017). The overall rate of outpatient ADEs for beneficiaries at high risk was 46.28 per 1,000, with anticoagulant users demonstrating the highest rate of ADEs (68.52/1,000), followed by opioid users (42.11/1,000) and diabetic medication users (20.72/1,000). As expected, the primary setting for beneficiaries at high risk to seek care for outpatient ADEs was the emergency department, followed by inpatient hospitalizations and observation stays. CONCLUSIONS: Medicare claims are an accessible source of data, which can be used to establish for quality improvement a population at high risk for ADEs and increased hospital use. Using medication use patterns to attribute risk and associated outcomes, such as outpatient ADEs and hospital use, is a simple process that can be readily implemented. The described method has the potential to be further validated and used as a foundation to monitor population-based quality improvement efforts for medication safety. DISCLOSURES: This work was performed under contract HHSM-500-2014-QINNCC, Modification No. 000004, funded by Centers for Medicare & Medicaid Services (CMS), an agency of the U.S. Department of Health and Human Services. CMS did not have a role in the analysis. At the time of this analysis, Digmann, Peppercorn, Zhang, Irby, and Brock were employees of Telligen, which was awarded the National Coordinating Center-Quality Improvement Organization contract from CMS, which supported the work. Ryan was an employee at Qsource, which was awarded the Quality Innovation Network-Quality Improvement Organization contract from CMS, which supported the work. Thomas was employed by CMS. The content is solely the responsibility of the authors and does not necessarily represent the official views or policies of the CMS. This work is posted on the QIOprogram.org website, as recommended in the Common Rule ( https://www.hhs.gov/ohrp/regulations-and-policy/regulations/common-rule/index.html ).

Rewinding the waves: tracking underwater signals to their source.

Analysis of data, recorded on March 8th 2014 at the Comprehensive Nuclear-Test-Ban Treaty Organisation's hydroacoustic stations off Cape Leeuwin Western Australia, and at Diego Garcia, reveal unique pressure signatures that could be associated with objects impacting at the sea surface, such as falling meteorites, or the missing Malaysian Aeroplane MH370. To examine the recorded signatures, we carried out experiments with spheres impacting at the surface of a water tank, where we observed almost identical pressure signature structures. While the pressure structure is unique to impacting objects, the evolution of the radiated acoustic waves carries information on the source. Employing acoustic-gravity wave theory we present an analytical inverse method to retrieve the impact time and location. The solution was validated using field observations of recent earthquakes, where we were able to calculate the eruption time and location to a satisfactory degree of accuracy. Moreover, numerical validations confirm an error below 0.02% for events at relatively large distances of over 1000 km. The method can be developed to calculate other essential properties such as impact duration and geometry. Besides impacting objects and earthquakes, the method could help in identifying the location of underwater explosions and landslides.

Prolonged gonadotropin stimulation for assisted reproductive technology cycles is associated with decreased pregnancy rates for all women except for women with polycystic ovary syndrome.

PURPOSE: To determine if etiology of infertility modifies the relationship between the duration of ovarian stimulation and success during assisted reproductive technology (ART) cycles. METHODS: A prospectively collected database was analyzed in an academic infertility practice. Eight hundred and twelve infertile women undergoing their initial fresh embryo, non-donor in vitro fertilization (IVF) or Intracytoplasmic Sperm Injection ICSI) cycle between January 1999 and December 2010 were evaluated. Clinical pregnancy was the main outcome measured. RESULTS: Out of 663 cycles resulting in oocyte retrieval, 299 produced a clinical pregnancy (45.1%). Women who achieved a clinical pregnancy had a significantly shorter stimulation length (11.9 vs. 12.1 days, p = 0.047). Polycystic ovary syndrome (PCOS) was the only etiology of infertility that was significantly associated with a higher chance for clinical pregnancy and was a significant confounder for the association of duration and success of treatment. Women with 13 days or longer of stimulation had a 34 % lower chance of clinical pregnancy as compared to those who had a shorter cycle (OR 0.66, 95% CI:0.46-0.95) after adjustment for age, ovarian reserve, number of oocytes retrieved, embryos transferred and PCOS diagnosis. CONCLUSION: Prolonged duration of stimulation is associated with decreased ART success for all couples, except for women with PCOS.

Clomiphene citrate in the management of male infertility.

Clomiphene citrate, a selective estrogen receptor modulator, has been used to treat infertility in women and men for 50 years. In men, clomiphene citrate has been employed in the management of unexplained infertility, oligo and asthenospermia, hypogonadism, and nonobstructive azoospermia. The available evidence reveals mixed results and suggests that clomiphene citrate may be appropriate for the management of male infertility in specific clinical scenarios. Further research is needed to clarify when clomiphene citrate is indicated in the treatment of male infertility.

A qualitative study of service user experiences of occupation in forensic mental health.

BACKGROUND/AIM: This qualitative study explored occupational engagement of those detained in forensic units. Legal and institutional restrictions on occupation have implications for their health and wellbeing. METHOD: Twenty-six current forensic mental health service users participated in five focus groups, which were audio-recorded, transcribed verbatim and subjected to constant comparative analysis. FINDINGS: The participants highlighted previous occupations, current occupations and hopes. Key aspects were control over decision-making, motivation and support, generating suggestions alongside positive experiences of occupational therapy. CONCLUSIONS: Institutional barriers could be overcome with a dynamic balance between risk management and mental health promotion through occupation. This demands a sustained focus on occupation for everyone involved in providing care and treatment in these settings.

The Health Service Bus: an architecture and case study in achieving interoperability in healthcare.

Interoperability in healthcare is a requirement for effective communication between entities, to ensure timely access to up to-date patient information and medical knowledge, and thus facilitate consistent patient care. An interoperability framework called the Health Service Bus (HSB), based on the Enterprise Service Bus (ESB) middleware software architecture is presented here as a solution to all three levels of interoperability as defined by the HL7 EHR Interoperability Work group in their definitive white paper "Coming to Terms". A prototype HSB system was implemented based on the Mule Open-Source ESB and is outlined and discussed, followed by a clinically-based example.

Compensation patterns following occupational injuries in Zambia: results from the 2009 Labour Survey.

BACKGROUND: Occupational injuries have received limited research attention in the Southern African Development Community. Much of the published data come from South Africa and little has been reported elsewhere within the region. The present study was conducted to estimate the prevalence rates of occupational injuries and compensation; and to determine factors associated with occupational injuries and compensation. METHODS: Data were obtained from occupational health and injury questions added to the Zambian Labour Force Survey of 2009 by the Work and Health in Southern Africa programme. Logistic regression analyses were conducted to determine the degree of association between demographic, social and economic factors on one hand and injury and compensation on the other. RESULTS: Data on 61871 study participants were available for analysis, of whom 4998 (8.1%) reported having been injured (10.0% of males, and 6.2% of females) due to work in the previous 12 months to the survey. Of those injured, 60.5% reported having stayed away from work as a result. The commonest type of injury was "open wound" (81.6%). Male gender, being married or married before, being a paid employee, working for a private company and household were positively associated with serious injuries. Injuries also varied by geographical area. Factors positively associated with receiving compensation for work-related injuries were: male gender, Copperbelt and North-Western provinces, and unpaid family worker. Employer/self employed and having less than 5 employees in a workplace were negatively associated with compensation. CONCLUSION: The prevalence of reported injury and its association with a significant level of absence from work, indicate that occupational hazards in Zambia have significant health and economic effects. Female workers should equally be compensated for injuries suffered as their male counterparts.

A framework for semantic interoperability in healthcare: a service oriented architecture based on health informatics standards.

Healthcare information is composed of many types of varying and heterogeneous data. Semantic interoperability in healthcare is especially important when all these different types of data need to interact. Presented in this paper is a solution to interoperability in healthcare based on a standards-based middleware software architecture used in enterprise solutions. This architecture has been translated into the healthcare domain using a messaging and modeling standard which upholds the ideals of the Semantic Web (HL7 V3) combined with a well-known standard terminology of clinical terms (SNOMED CT).

Toward the interoperability of HL7 v3 and SNOMED CT: a case study modeling mobile clinical treatment.

Semantic interoperability in healthcare can be achieved by a tighter coupling of terminology and HL7 message models. In this paper, we highlight the difficulty of achieving this goal, but show how it can become attainable by basing HL7 message models on SNOMED CT concepts and relationships. We then demonstrate how this methodology has been applied to a set of clinical observations for use in the ePOC project, and discuss our findings.

Serial changes in systolic and diastolic echocardiographic indices as predictors of outcome in patients with decreased left ventricular ejection fraction.

BACKGROUND: Echocardiographic estimation of left ventricular ejection fraction aids in predicting adverse outcomes in coronary artery disease. However, in patients with impaired left ventricular function, further risk stratification is difficult. METHODS: A 2 year retrospective review was performed to identify patients with ejection fraction < or=30%. Echocardiographic measures of systolic and diastolic function were independently performed offline. Outcome information, which included MI, stroke, or death, was obtained. The patient cohort identified those with follow-up having 1) a single echocardiogram and a subset 2) with an initial echocardiogram and a second echocardiogram at greater than one year follow-up. RESULTS: This study included 110 patients, ages 20-94. Mean follow-up time was 29+/-9 months. Ejection fraction did not predict cardiovascular events. LV mass predicted of mortality (p=0.03). Diastolic indexes of mitral inflow E wave was a significant predictor of outcome (p=0.05). Impaired diastolic filling grade 2, 3, or 4 showed a 76% event rate. Decreases in ejection fraction at follow-up were seen in those who had an event, with an average decrease in ejection fraction of 17% versus those who lived with no event of 1%. Changes in mitral inflow E wave and changes in E/A ratio were both significant predictors of outcome. CONCLUSIONS: These data indicate that echocardiographic measures of both systolic and diastolic function aid in risk stratifying patients with decreased ejection fraction. The changed detected in serial echocardiographic information may be important in treatment and secondary prevention of future events.

Bromodomain and histone acetyltransferase domain specificities control mixed lineage leukemia phenotype.

A critical unanswered question about mixed lineage leukemia (MLL) is how specific MLL fusion partners control leukemia phenotype. The MLL-cyclic AMP-responsive element binding protein-binding protein (CBP) fusion requires both the CBP bromodomain and histone acetyltransferase (HAT) domain for transformation and causes acute myelogenous leukemia (AML), often preceded by a myelodysplastic phase. We did domain-swapping experiments to define whether unique specificities of these CBP domains drive this specific MLL phenotype. Within MLL-CBP, we replaced the CBP bromodomain or HAT domain with P300/CBP-associated factor (P/CAF) or TAF(II)250 bromodomains or the P/CAF or GCN5 HAT domains. HAT, but not bromodomain, substitutions conferred enhanced proliferative capacity in vitro but lacked expression of myeloid cell surface markers normally seen with MLL-CBP. Mice reconstituted with domain-swapped hematopoietic progenitors developed different disease from those with MLL-CBP. This included development of lymphoid disease and lower frequency of the myelodysplastic phase in those mice developing AML. We conclude that both the CBP bromodomain and HAT domain play different but critical roles in determining the phenotype of MLL-CBP leukemia. Our results support an important role for MLL partner genes in determining the leukemia phenotype besides their necessity in leukemogenesis. Here, we find that subtleties in MLL fusion protein domain specificity direct cells toward a specific disease phenotype.

Inhibitory effects of 12-O-tetradecanoylphorbol-13-acetate alone or in combination with all-trans retinoic acid on the growth of cultured human pancreas cancer cells and pancreas tumor xenografts in immunodeficient mice.

Treatment of cultured PANC-1, MIA PaCa-2, and BxPC-3 human pancreatic adenocarcinoma cells with 0.1 to 1.6 nM 12-O-tetradecanoylphorbol-13-acetate (TPA) for 96 h inhibited the proliferation of these cells in a dose-dependent manner, and PANC-1 and MIA PaCa-2 cells were more sensitive to TPA than BxPC-3 cells. Inhibition of proliferation by TPA in PANC-1 cells was associated with an increase in the level of p21, but this was not observed in MIA PaCa-2 or BxPC-3 cells. The TPA-induced increase of p21 in PANC-1 cells was blocked by bisindolylmaleimide or rottlerin (inhibitors of protein kinase C). Studies in NCr-immunodeficient mice with well established PANC-1 tumor xenografts indicated that daily i.p. injections of TPA strongly inhibited tumor growth, increased the percentage of caspase-3-positive cells, and decreased the ratio of mitotic cells to caspase-3-positive cells in the tumors. Studies with BxPC-3 tumors in NCr mice receiving daily i.p. injections of vehicle, TPA, all-trans retinoic acid (ATRA), or a TPA/ATRA combination showed that TPA had an inhibitory effect on tumor growth, but treatment of the animals with the TPA/ATRA combination had a greater inhibitory effect on tumor growth than TPA alone. Treatment with the TPA/ATRA combination resulted in a substantially decreased ratio of the percentage of mitotic cells to the percentage of caspase-3-positive cells in the tumors compared with tumors from the vehicle-treated control animals. The inhibitory effects of TPA on tumor growth occurred at clinically achievable blood levels.

Synergistic stimulatory effect of 12-O-tetradecanoylphorbol-13-acetate and capsaicin on macrophage differentiation in HL-60 and HL-525 human myeloid leukemia cells.

Our previous studies demonstrated that 12-O-tetradecanoylphorbol-13-acetate (TPA) had pharmacological activity for the treatment of myeloid leukemia patients. In the present study, we investigated the effects of TPA alone or in combination with capsaicin (8-methyl-N-vanillyl-6-nonenamide) on growth and differentiation in myeloid leukemia HL-60 cells and in a TPA-resistant HL-60 variant cell line termed HL-525. Treatment of HL-60 cells with TPA (0.16-1.6 nM) for 48 h resulted in concentration-dependent growth inhibition and cell differentiation (via the macrophage pathway). Capsaicin (5-50 microM) inhibited the growth of HL-60 cells in a concentration-dependent manner. Treatment of HL-60 cells with capsaicin alone only resulted in a small increase in the number of differentiated cells but treatment of the cells with TPA in combination with capsaicin synergistically increased differentiation. Moreover, inhibitors of protein kinase C (PKC), 7-hydroxystaurosporin (UCN-01; 100 nM) and chelerythrine (0.5 microM), significantly decreased HL-60 cell differentiation induced by the combination of TPA and capsaicin. These results suggest that PKC may be involved in HL-60 cell differentiation induced by TPA in combination with capsaicin. Capsaicin alone caused a very small increase in differentiation in the TPA-resistant HL-525 cells. However, treatment of HL-525 cells with combinations of TPA (0.16 nM) and capsaicin (10-50 microM) caused a strong synergistic increase in differentiation. Results from the present study suggest that a combination of TPA and capsaicin may improve the therapeutic efficacy of TPA and overcome resistance to TPA in some myeloid leukemia patients.