Tracie D. Locklear

Effects of cranberry extracts and ursolic acid derivatives on P-fimbriated Escherichia coli, COX-2 activity, pro-inflammatory cytokine release and the NF-κβ transcriptional response in vitro

Cranberry, the fresh or dried ripe fruit of Vaccinium macrocarpon Ait. (Ericaceae), is currently used as adjunct therapy for the prevention and symptomatic treatment of urinary tract infections. Data from clinical trials suggest that extracts of cranberry or cranberry juice reduce the bacterial load of E. coli and also suppress the inflammatory symptoms induced by E. coli infections. A methanol extract prepared from 10 kg of dehydrated cranberries did not directly inhibit the growth of E coli strains ATCC 700336 or ATCC 25922 in concentrations up to 256 μg/mL in vitro. However, the methanol extract (CR-ME) inhibited the activity of cyclooxygenase-2, with an IC50 of 12.8 μg/mL. Moreover, CR-ME also inhibited the NF-κβ transcriptional activation in human T lymphocytes with an IC50 of 19.4 μg/mL, and significantly (p < 0.01) inhibited the release of interleukin (IL)-1β, IL-6, IL-8 and tumor necrosis factor-α from E. coli lipopolysaccharide (LPS)-stimulated human peripheral blood mononuclear cells in vitro, at a concentration of 50 μg/mL. The extract had no effect on inducible nitric oxide synthase activity in the murine macrophage cell line RAW 264.7. The compounds responsible for this activity were identified using a novel LC-MS based assay as ursolic acid and ursolic acid derivatives. Taken together, these data suggest CR-ME and its constituent chemical compounds target specific pathways involved in E. coli-induced inflammation.

Estrogenic effects of herbal medicines from Costa Rica used for the management of menopausal symptoms

Objective:Outcomes from the Womens Health Initiative have demonstrated adverse effects associated with hormone therapy and have prioritized the need to develop new alternative treatments for the management of menopause and osteoporosis. To this end, we have been investigating natural herbal medicines used by Costa Rican women to manage menopausal symptoms. Methods:Seventeen plant species were collected and extracted in Costa Rica. To establish possible mechanisms of action and to determine their potential future use for menopause or osteoporosis, we investigated the estrogenic activities of the herbal extracts in an estrogen-reporter gene estrogen receptor (ER) &bgr;-Chemically Activated Luciferase Expression assay in U2-OS cells and in reporter and endogenous gene assays in MCF-7 cells. Results:Six of the plant extracts bound to the ERs. Four of the six extracts stimulated reporter gene expression in the ER-&bgr;-Chemically Activated Luciferase Expression assay. All six extracts modulated expression of endogenous genes in MCF-7 cells, with four extracts acting as estrogen agonists and two extracts, Pimenta dioica and Smilax domingensis, acting as partial agonist/antagonists by enhancing estradiol-stimulated pS2 mRNA expression but reducing estradiol-stimulated PR and PTGES mRNA expression. Both P. dioica and S. domingensis induced a 2ERE-luciferase reporter gene in transient transfected MCF-7 cells, which was inhibited by the ER antagonist ICI 182,780. Conclusions:This work presents a plausible mechanism of action for many of the herbal medicines used by Costa Rican women to treat menopausal symptoms. However, it further suggests that studies of safety and efficacy are needed before these herbs should be used as alternative therapies to hormone therapy.

Natural Products As Antibacterial Agents

Abstract For thousands of years medicinal plants have played a significant role in the treatment of a wide range of medical conditions, including infectious diseases. Some naturally occurring chemical compounds serve as models for a large percentage clinically proven drugs, and many are now being re-assessed as antimicrobial agents. The primary reason for this renaissance is the fact that infectious disease remains a significant cause of morbidity and mortality worldwide, accounting for approximately 50% of all deaths in tropical countries and as much as 20% of deaths in the Americas. Despite the significant progress made in microbiology and the control of microorganisms, sporadic incidents of epidemics due to drug resistant microorganisms and previously unknown disease-causing microbes pose an enormous threat to global public health. These negative health trends call for a global initiative for the development of new strategies for the prevention and treatment of infectious disease, including natural products. Literally thousands of plant species have been tested against hundreds of bacterial strains in vitro, and many medicinal plants are active against a wide range of gram-positive and gram-negative bacteria. However, very few of these medicinal plant extracts have been tested in animal or human studies to determine safety and efficacy. This review focuses on the medicinal plants and phytochemical for which there is significant published in vitro, in vivo and clinical data available. The examples provided in this review such as St. Johns wort, tree tea oil, and green tea demonstrate that even commonly used plant extracts may offer prospective new treatment of bacterial infections, including multi-drug resistant bacteria. One interesting example is St. Johns wort (Hypericum perforatum) and its active constituent hyperforin, both of which have significant activity against MRSA in microgram concentrations. This antibacterial discovery was based on the ethnomedical use of St. Johns wort to treat skin infections and wounds. Review of the published data indicates that medicinal plants offer significant potential for the development of novel antibacterial therapies and adjunct treatments (i.e. MDR pump inhibitors). However, new investigations should employ modern methodology, including using nationally recognized protocols and standards for microbial testing, the generation of minimum inhibitory concentrations, as well as standardization of the quality of plant materials used for testing.

Patient-Reported Outcomes After Choice for Contralateral Prophylactic Mastectomy

PURPOSE The rate of contralateral prophylactic mastectomies (CPMs) continues to rise, although there is little evidence to support improvement in quality of life (QOL) with CPM. We sought to ascertain whether patient-reported outcomes and, more specifically, QOL differed according to receipt of CPM. METHODS Volunteers recruited from the Army of Women with a history of breast cancer surgery took an electronically administered survey, which included the BREAST-Q, a well-validated breast surgery outcomes patient-reporting tool, and demographic and treatment-related questions. Descriptive statistics, hypothesis testing, and regression analysis were used to evaluate the association of CPM with four BREAST-Q QOL domains. RESULTS A total of 7,619 women completed questionnaires; of those eligible, 3,977 had a mastectomy and 1,598 reported receipt of CPM. Women undergoing CPM were younger than those who did not choose CPM. On unadjusted analysis, mean breast satisfaction was higher in the CPM group (60.4 v 57.9, P < .001) and mean physical well-being was lower in the CPM group (74.6 v 76.6, P < .001). On multivariable analysis, the CPM group continued to report higher breast satisfaction (P = .046) and psychosocial well-being (P = .017), but no difference was reported in the no-CPM group in the other QOL domains. CONCLUSION Choice for CPM was associated with an improvement in breast satisfaction and psychosocial well-being. However, the magnitude of the effect may be too small to be clinically meaningful. Such patient-reported outcomes data are important to consider when counseling women contemplating CPM as part of their breast cancer treatment.

Estrogenic and Progestagenic effects of extracts of Justicia pectoralis Jacq., an herbal medicine from Costa Rica used for the treatment of Menopause and PMS

OBJECTIVES To investigate the biological activities of Justicia pectoralis Jacq. (Acanthaceae), an herbal medicine used in Costa Rica (CR) for the management of menopausal symptoms and dysmenorrhea. STUDY DESIGN The aerial parts of J. pectoralis were collected, dried and extracted in methanol. To establish possible mechanisms of action of JP for the treatment of menopausal symptoms, the estrogenic and progesterone agonists, and antiinflammatory activities were investigated. MAIN OUTCOME MEASURES The methanol extract (JP-M) was tested in ER and PR binding assays, a COX-2 enzyme inhibition assay, the ERbeta-CALUX assay in U2-OS cells, as well as reporter and endogenous gene assays in MCF-7 K1 cells. RESULTS The JP-M extract inhibited COX-2 catalytic activity (IC(50) 4.8 microg/mL); bound to both ERalpha and ERbeta (IC(50) 50 microg/mL and 23.1 microg/mL, respectively); induced estrogen-dependent transcription in the ERbeta-CALUX; and bound to the progesterone receptor (IC(50) 22.8 microg/mL). The extract also modulated the expression of endogenous estrogen responsive genes pS2, PR, and PTGES in MCF-7 cells at a concentration of 20 microg/mL. Activation of a 2 ERE-construct in transiently transfected MCF-7 cells by the extract was inhibited by the estrogen receptor antagonist ICI 182,780, indicating that the effects were mediated through the estrogen receptor. Finally, the extract weakly enhanced the proliferation of MCF-7 cells, however this was not statistically significant as compared with DMSO controls. CONCLUSIONS Extracts of J. pectoralis have estrogenic, progestagenic and anti-inflammatory effects, and thus have a plausible mechanism of action, explaining its traditional use for menopause and PMS.

Women's Health in Central America: The Complexity of Issues and the Need to Focus on Indigenous Healthcare

The Central American (CA) isthmus consists of seven countries including Belize, Costa Rica, El Salvador, Guatemala, Honduras, Nicaragua and Panama, some of the poorest countries in the world. Over the past twenty years, CA has made good progress in improving the health status of their populations. Analysis of the peer-reviewed literature, as well as national and international reports show that life expectancy at birth has increased and child mortality rates have fallen. Maternal mortality ratios (MMR) have declined by approximately 33%, however the MMRs for indigenous women remain at unacceptable levels. Despite the advances, made in many CA countries, the overall health status remains well below Latin American averages. In fact, in most CA countries, poor health outcomes are increasingly concentrated geographically among the poor and indigenous populations. Considering indigenous people make up the second largest population group in CA, any improvements in healthcare should significantly improve the health statistics for these countries. For these populations, the integration of local cultural practices and traditional healing methods with modern medicine and healthcare facilities is critical for acceptance. Investigations and analyses of local cultures, knowledge and traditional medicine practices should be used to determine the factors that contribute to poor health in these populations. Local health educational programs are needed, especially those that would involve men (spouses), families and entire communities. Furthermore, manywomens reproductive issues still need to be addressed, particularly those that focus specifically on maternal mortality and cancer. For reductions in maternal mortality, El Salvador and Costa Rica may be good examples to follow. Access to inexpensive (or free) healthcare that is culturally sensitive and community based, particularly for indigenous women, would greatly improve the overall health. The major stumbling blocks to progress are that the funding for programs to reduce maternal mortality is woefully inadequate and that there has not been a focus on improving healthcare for indigenous women.

Black cohosh (Actaea racemosa) for the mitigation of menopausal symptoms: recent developments in clinical safety and efficacy

The purpose of this article is to assess recent data supporting the safety and efficacy of black cohosh products for the mitigation of menopause-related symptoms. Searches of the published literature in Napralert, Cochrane Library and PubMed databases were performed from 2003 to 2006. Information from drug regulatory agencies from five different countries was obtained to evaluate safety. While there are a few contradictory studies, the majority of the clinical trials indicate that extracts of black cohosh (Actaea racemosa L.) improve menopause-related symptoms. However, to date, at least 50 cases of possible hepatotoxicity have been reported. Although previous safety reviews suggest that black cohosh is well tolerated, the increasing numbers of these case reports indicates that further preclinical toxicological evaluations of black cohosh are urgently needed. At this time, it appears prudent to advise menopausal women with underlying liver disease, autoimmune diseases or those taking medications that may impact liver function not to use products containing black cohosh.

Using patient reported outcomes in oncology clinical practice

Abstract Background and aims Patient reported outcomes (PROs) are increasingly being implemented into the care of patients with cancer. The use of a standard set of PROs (e.g., pain) in cancer is becoming established and there is interest in what additional PROs might provide valuable information. The goal of this observational study was to examine how the PROs of self-efficacy for pain and other symptoms assessed at the point of service were associated with pain, symptom severity and distress, and physical and psychosocial functioning in a sample of breast and gastrointestinal patients. We also sought to examine differences in these relationships by cancer type (breast and gastrointestinal) as well as understand differences in self-assessment mode (paper/pencil or electronic tablet). Methods 178 patients with breast (n = 65) and gastrointestinal cancer (n = 113) completed the Chronic Pain Self Efficacy Scale, M.D. Anderson Symptom Inventory, and Functional Assessment of Cancer Therapy – General questionnaires. Measures were completed with paper and pencil and electronically using a tablet computer while patients waited for their clinical appointment. Responses from the initial completed questionnaires on both the paper and electronic instruments were analyzed. Results Patients’ self-efficacy scores for pain and other symptoms correlated positively with pain, symptom severity and distress, and physical and psychosocial functioning; patients with lower levels of self-efficacy reported poorer outcomes and functioning overall. The results were independent of cancer type and mode of assessment. No statistically significant differences were found in the PROs when collected by electronic technology versus paper-pencil mode; patients were very satisfied with using the tablet computer to complete the PRO measures. Conclusions and implications Our results suggest that self-efficacy for pain and symptom management may be a beneficial addition to clinic-based PRO assessment batteries for patients with cancer and other chronic diseases. Existing short, validated symptom self-efficacy scales could easily be integrated into clinical practice to help healthcare providers identify patients that might benefit from intervention. Study results also support existing research that suggests electronic approaches are a practical way to collect PRO data, including self-efficacy data, in the clinic. Overall, our data suggest that patients who have particularly low levels of self-efficacy for pain and symptom management may be at risk for higher levels of pain and disability. Thus, if self-efficacy for pain and symptom management were routinely collected at the time of clinical service, psychosocial interventions to improve self-efficacy for pain and symptom management, and in turn overall quality of life, could be implemented in a timely fashion.

Partnering with engaged patients accelerates research

DUNYA M. ATISHA, MD,* TRACIE D. LOCKLEAR, PhD, URSULA A. ROGERS, BS, CHRISTEL N. RUSHING, MS, GREGORY P. SAMSA, PhD, AND AMY P. ABERNETHY, MD, PhD Department of Surgery, Division of Plastic Surgery, Morsani College of Medicine, University of South Florida, Tampa, Florida Center for Learning Health Care, Duke University Medical Center, Durham, North Carolina Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina Health Policy and Management Gillings, School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

Black Cohosh for Menopause: Safety and Efficacy Issues and Future Perspectives

Black cohosh [Actaea racemosa L., formerly Cimicifuga racemosa (L.) Nutt.] is an herbal medicine that has been used in the United States for over 100 years for the treatment of many conditions, including menopausal symptoms. To date the clinical data remain controversial. While there are over 20 positive clinical trials, all of the recent NIH-funded studies are negative, casting doubt on its efficacy. In addition, the cases of hepatoxicity are replete, although direct causality to the ingestion of black cohosh has not been demonstrated. In vitro studies have suggested possible chemopreventative effects; however, the in vivo studies to date do not support this hypothesis and suggest enhanced metastases. Unresolved issues of quality, safety, and efficacy remain and until these issues are resolved, the use of black cohosh products cannot be recommended.