Andrew Courtwright

Secreted Frizzle-Related Protein 2 Stimulates Angiogenesis via a Calcineurin/NFAT Signaling Pathway

Secreted frizzle-related protein 2 (SFRP2), a modulator of Wnt signaling, has recently been found to be overexpressed in the vasculature of 85% of human breast tumors; however, its role in angiogenesis is unknown. We found that SFRP2 induced angiogenesis in the mouse Matrigel plug assay and the chick chorioallantoic membrane assay. SFRP2 inhibited hypoxia induced endothelial cell apoptosis, increased endothelial cell migration, and induced endothelial tube formation. The canonical Wnt pathway was not affected by SFRP2 in endothelial cells; however, a component of the noncanonical Wnt/Ca2+ pathway was affected by SFRP2 as shown by an increase in NFATc3 in the nuclear fraction of SFRP2-treated endothelial cells. Tacrolimus, a calcineurin inhibitor that inhibits dephosphorylation of NFAT, inhibited SFRP2-induced endothelial tube formation. Tacrolimus 3 mg/kg/d inhibited the growth of SVR angiosarcoma xenografts in mice by 46% (P = 0.04). In conclusion, SFRP2 is a novel stimulator of angiogenesis that stimulates angiogenesis via a calcineurin/NFAT pathway and may be a favorable target for the inhibition of angiogenesis in solid tumors.

Marijuana Use Patterns Among Patients with Inflammatory Bowel Disease

Background:The prevalence and perceived effectiveness of marijuana use has not been well studied in inflammatory bowel disease (IBD) despite increasing legal permission for its use in Crohns disease. Health care providers have little guidance about the IBD symptoms that may improve with marijuana use. The aim of this study was to assess the prevalence, sociodemographic characteristics, and perceived benefits of marijuana use among patients with IBD. Methods:Prospective cohort survey study of marijuana use patterns in patients with IBD at an academic medical center. Results:A total of 292 patients completed the survey (response rate = 94%); 12.3% of patients were active marijuana users, 39.0% were past users, and 48.6% were never users. Among current and past users, 16.4% of patients used marijuana for disease symptoms, the majority of whom felt that marijuana was “very helpful” for relief of abdominal pain, nausea, and diarrhea. On multivariate analysis, age and chronic abdominal pain were associated with current marijuana use (odds ratio [OR], 0.93; 95% confidence interval [CI], 0.89–0.97; P < 0.001 and OR, 3.5; 95% CI, 1.24–9.82; P = 0.02). Age and chronic abdominal pain were also multivariate predictors of medicinal use of marijuana (OR, 0.93; 95% CI, 0.89–0.97; P < 0.001 and OR, 4.7; 95% CI, 1.8–12.2; P = 0.001). Half of the never users expressed an interest in using marijuana for abdominal pain, were it legally available. Conclusions:A significant number of patients with IBD currently use marijuana. Most patients find it very helpful for symptom control, including patients with ulcerative colitis, who are currently excluded from medical marijuana laws. Clinical trials are needed to determine marijuanas potential as an IBD therapy and to guide prescribing decisions.

The Role of Calcineurin/NFAT in SFRP2 Induced Angiogenesis—A Rationale for Breast Cancer Treatment with the Calcineurin Inhibitor Tacrolimus

Tacrolimus (FK506) is an immunosuppressive drug that binds to the immunophilin FKBPB12. The FK506-FKBP12 complex associates with calcineurin and inhibits its phosphatase activity, resulting in inhibition of nuclear translocation of nuclear factor of activated T-cells (NFAT). There is increasing data supporting a critical role of NFAT in mediating angiogenic responses stimulated by both vascular endothelial growth factor (VEGF) and a novel angiogenesis factor, secreted frizzled-related protein 2 (SFRP2). Since both VEGF and SFRP2 are expressed in breast carcinomas, we hypothesized that tacrolimus would inhibit breast carcinoma growth. Using IHC (IHC) with antibodies to FKBP12 on breast carcinomas we found that FKBP12 localizes to breast tumor vasculature. Treatment of MMTV-neu transgenic mice with tacrolimus (3 mg/kg i.p. daily) (n = 19) resulted in a 73% reduction in the growth rate for tacrolimus treated mice compared to control (n = 15), p = 0.003; which was associated with an 82% reduction in tumor microvascular density (p<0.001) by IHC. Tacrolimus (1 µM) inhibited SFRP2 induced endothelial tube formation by 71% (p = 0.005) and inhibited VEGF induced endothelial tube formation by 67% (p = 0.004). To show that NFATc3 is required for SFRP2 stimulated angiogenesis, NFATc3 was silenced with shRNA in endothelial cells. Sham transfected cells responded to SFRP2 stimulation in a tube formation assay with an increase in the number of branch points (p<0.003), however, cells transfected with shRNA to NFATc3 showed no increase in tube formation in response to SFRP2. This demonstrates that NFATc3 is required for SFRP2 induced tube formation, and tacrolimus inhibits angiogenesis in vitro and breast carcinoma growth in vivo. This provides a rationale for examining the therapeutic potential of tacrolimus at inhibiting breast carcinoma growth in humans.

Stigmatization and Public Health Ethics

Encouraged by the success of smoking denormalization strategies as a tobacco-control measure, public health institutions are adopting a similar approach to other health behaviors. For example, a recent controversial ad campaign in New York explicitly aimed to denormalize HIV/AIDS amongst gay men. Authors such as Scott Burris have argued that efforts like this are tantamount to stigmatization and that such stigmatization is unethical because it is dehumanizing. Others have offered a limited endorsement of denormalization/stigmatization campaigns as being justified on consequentialist grounds; namely, that the potential public health benefits outweigh any stigmatizing side effects. In this paper, I examine and reject the blanket condemnation of stigmatization efforts in public health. I argue that the moral status of such efforts are best evaluated within a contractualist, as opposed to a consequentialist, framework. Contractualism in public health ethics asks whether a particular stigmatizing policy could be justified to reasonable individuals who do not know whether they will be affected by that policy. Using this approach, I argue that it is sometimes permissible for public health institutions to engage in health-related stigmatization.

After the DNR: Surrogates Who Persist in Requesting Cardiopulmonary Resuscitation

Some health care organizations allow physicians to withhold cardiopulmonary resuscitation from a patient, despite patient or surrogate requests that it be provided, when they believe it will be more harmful than beneficial. Such cases usually involve patients with terminal diagnoses whose medical teams argue that aggressive treatments are medically inappropriate or likely to be harmful. Although there is state-to-state variability and a considerable judicial gray area about the conditions and mechanisms for refusals to perform CPR, medical teams typically follow a set of clearly defined procedures for these decisions. The procedures are based on the principle of nonmaleficence and typically include consultation with hospital ethics committees, reflecting the guidelines of relevant professional associations. Ethical debates about when CPR can and should be limited tend to rely more on discussions of theory, principles, and case studies than systematic empirical study of the situations in which such limitations are applied. Sociologists of bioethics call for empirical study, arguing that what ethicists and health professionals believe they are doing when they draft policies or invoke principles does not always mirror what is happening on the ground. In this article, we begin the task of modeling the empirical analyses sociologists call for, focusing on a cohort at Massachusetts General Hospital. We inductively analyzed ethics committee notes and medical records of nineteen patients whose surrogates did not accept the decision to withhold CPR.

Experience with a hospital policy on not offering cardiopulmonary resuscitation when believed more harmful than beneficial

PURPOSE This study investigated the impact of age, race, and functional status on decisions not to offer cardiopulmonary resuscitation (CPR) despite patient or surrogate requests that CPR be performed. METHODS This was a retrospective cohort study of all ethics committee consultations between 2007 and 2013 at a large academic hospital with a not offering CPR policy. RESULTS There were 134 cases of disagreement over whether to provide CPR. In 45 cases (33.6%), the patient or surrogate agreed to a do-not-resuscitate (DNR) order after initial ethics consultation. In 67 (75.3%) of the remaining 89 cases, the ethics committee recommended not offering CPR. In the other 22 (24.7%) cases, the ethics committee recommended offering CPR. There was no significant relationship between age, race, or functional status and the recommendation not to offer CPR. Patients who were not offered CPR were more likely to be critically ill (61.2% vs 18.2%, P < .001). The 90-day mortality rate among patients who were not offered CPR was 90.2%. CONCLUSIONS There was no association between age, race, or functional status and the decision not to offer CPR made in consultation with an ethics committee. Orders to withhold CPR were more common among critically ill patients.

Medical Futility Procedures: What More Do We Need to Know?

Unilateral medical futility policies, which allow health-care providers to limit or withdraw life-sustaining treatment over patient or surrogate objections, are increasingly designed around a procedural approach. Medical or ethics committees follow a prespecified process, the culmination of which is a justified decision about whether ongoing treatment should be withheld or withdrawn. These procedures have three stages. First, health-care providers must decide to refer patients for consideration of whether ongoing treatment is futile. Second, the committees involved must decide whether ongoing treatment is actually futile. Third, there is a clinical outcome that often is, but not always, patient death. We review the available data on procedure-based futility policies, arguing that there is limited information on their potential harms and how these harms are distributed. We consider the ethical implications of policy-making under informational uncertainty, invoking the precautionary principle--in the absence of clear data, if a policy has significant risk of significant harm, the burden of proof that it is not harmful falls on those recommending the policy--as the guiding moral standard for hospitals and professional organizations considering whether to adopt a procedural approach to medical futility. On the basis of this principle, we argue that any new futility guideline must include a significant commitment to collecting prospective data on its application.

Who should Decide for the Unrepresented

Unrepresented patients lack the capacity to make medical decisions for themselves, have no clear documentation of preferences for medical treatment, and have no surrogate decision maker or obvious candidate for that role. There is no consensus about who should serve as the decision maker for these patients, particularly regarding whether to continue or to limit life-sustaining treatment. Several authors have argued that ethics committees should play this role rather than the patients treating physician, a common current default. We argue that concerns about the adequacy of physicians as surrogates are either empirically unfounded or apply equally to ethics committees. We suggest that physicians should be the primary decision maker for the unrepresented because of their fiduciary duties toward their patients. As part of the process of fulfilling these duties, they should seek the advice of third parties such as ethic committees; but final end-of-life decision-making for the unrepresented should rest with the treating physician.

Health Disparities and Autonomy

Disparities in socioeconomic status correlate closely with health, so that the lower a persons social position, the worse his health, an effect that the epidemiologist Michael Marmot has labeled the status syndrome. Marmot has argued that differences in autonomy, understood in terms of control, underlie the status syndrome. He has, therefore, recommended that the American medical profession champion policies that improve patient autonomy. In this paper, I clarify the kind of control Marmot sees as connecting differences in socioeconomic status to health disparities. I then discuss his use of Amartya Sens capabilities approach to justice, arguing that he is unsuccessful in relating autonomy as a descriptive property with a normative framework that can adequately explain why and to what extent we should reduce health disparities.

Shackled: The Challenge of Caring for an Incarcerated Patient:

Hospice care for inmates is widely recognized as an important way of providing efficient, cost-effective palliative care to a growing number of dying inmates. The case presented here is of a 34-year-old inmate who was admitted to a tertiary-care hospital for diagnostic tests and treatment of non-small cell lung cancer. While he was in the hospital, his clinical status rapidly deteriorated and it was clear that palliative care was most appropriate. Prison restrictions prevented the health care team from sharing the patients clinical status with his family. He was forbidden many interventions that would have improved his comfort, such as watching television. The problems illustrated by this case occur many times in United States tertiary-care hospitals, and it is hoped that by describing it, more compassionate care for inmate patients, regardless of location, can be provided.