The institutional and community norms that lead to the stigmatization of tuberculosis (TB) are thought to hinder TB control. We performed a systematic review of the literature on TB stigma to identify the causes and evaluate the impact of stigma on TB diagnosis and treatment. Several themes emerged: fear of infection is the most common cause of TB stigma; TB stigma has serious socioeconomic consequences, particularly for women; qualitative approaches to measuring TB stigma are more commonly utilized than quantitative surveys; TB stigma is perceived to increase TB diagnostic delay and treatment noncompliance, although attempts to quantify its impact have produced mixed results; and interventions exist that may reduce TB stigma. Future research should continue to characterize TB stigma in different populations; use validated survey instruments to quantify the impact of TB stigma on TB diagnostic delay, treatment compliance, and morbidity and mortality; and develop additional TB stigma-reduction strategies.

Bacteriophage therapy (BT) employs bacteriophages to treat pathogenic bacteria and is an emerging strategy against multidrug-resistant (MDR) infections. Experience in solid organ transplant is limited. We describe BT in three lung transplant recipients (LTR) with life-threatening MDR infections caused by Pseudomonas aeruginosa (n=2) and Burkholderia dolosa (n=1). For each patient, lytic bacteriophages were selected against their bacterial isolates. BT was administered for variable durations under emergency Investigational New Drug applications and with patient informed consent. Safety was assessed using clinical/laboratory parameters and observed clinical improvements described as appropriate. All patients received concurrent antibiotics. Two ventilator-dependent LTR with large airway complications and refractory MDR P. aeruginosa pneumonia received BT. Both responded clinically and were discharged from the hospital off ventilator support. A third patient had recurrent B. dolosa infection following transplant. Following BT initiation, consolidative opacities improved and ventilator weaning was begun. However, infection relapsed on BT and the patient expired. No BT-related adverse events were identified in the three cases. BT was well tolerated and associated with clinical improvement in LTRs with MDR bacterial infection not responsive to antibiotics alone. BT may be a viable adjunct to antibiotics for patients with MDR infections.

Pulmonary hypertension is defined as a mean pulmonary artery pressure ≥25 mm Hg and is a recently recognized complication of chronic kidney disease and end-stage renal disease. There is significant epidemiological overlap with kidney disease and the underlying causes of World Health Organization group 1-4 pulmonary hypertension (pulmonary arteriopathy, left heart disease, chronic pulmonary disease, and chronic thromboembolic disease, respectively). In addition, an entity of 'unexplained pulmonary hypertension,' group 5, in patients with chronic kidney disease and end-stage renal disease has emerged, with prevalence estimates of 30-50%. The pathogenesis of pulmonary hypertension in this population is due to alterations in endothelial function, increased cardiac output, and myocardial dysfunction leading to elevated left heart filling pressure, with recent data suggesting that left heart dysfunction may account for the vast majority of pulmonary hypertension in patients with kidney disease. Pulmonary hypertension is an independent predictor of increased mortality in patients on dialysis and those undergoing kidney transplantation. This review summarizes what is known about the epidemiology, pathogenesis, transplantation outcomes, mortality, and treatment of pulmonary hypertension in patients with chronic kidney disease and end-stage renal disease.

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/Ca 2+ 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. [Cancer Res 2009;69(11):4621-8]

Improved communication among surgeons, patients, and surrogates is necessary to ensure that patients receive the care that they want and to avoid nonbeneficial treatment. Further research is needed to learn how to best structure these conversations in the emergency surgical setting.

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 Crohn's 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 marijuana's potential as an IBD therapy and to guide prescribing decisions.

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.

Telomeres are repetitive nucleotide sequences that cap linear chromosomes, thereby limiting progressive chromosomal shortening during cell replication. In conjunction with environmental factors, common single-nucleotide polymorphisms and rare and ultra-rare telomere-related mutations are associated with accelerated telomere shortening resulting in organ dysfunction, including interstitial lung disease (ILD). The most common telomere-related mutation-associated ILD is idiopathic pulmonary fibrosis (IPF). Up to one-third of individuals with familial IPF have shortened telomeres and/or carry a telomererelated mutation, and 1 in 10 individuals with sporadic IPF have telomere-related mutations. Regardless of ILD phenotype, individuals with short telomeres and/or known telomere-related mutations have more rapid disease progression and shorter lung transplant-free survival. Management should include initiation of antifibrotic agents for those with an IPF phenotype and early referral to a transplant center. Patients with ILD being considered for transplant should be screened for short telomeres if there is a significant family history of pulmonary fibrosis or evidence of extrapulmonary organ dysfunction associated with a short telomere syndrome. Post-transplant management of recipients with telomere-related mutations should include careful adjustment of immunosuppression regimens on the basis of bone marrow reserve. Data on the impact of shortened telomeres on post-transplant outcomes, however, remain mixed.