Donald R. Miller

A Novel Nanoparticle Drug Delivery System: The Anti-inflammatory Activity of Curcumin Is Enhanced When Encapsulated in Exosomes

Monocyte-derived myeloid cells play vital roles in inflammation-related autoimmune/inflammatory diseases and cancers. Here, we report that exosomes can deliver anti-inflammatory agents, such as curcumin, to activated myeloid cells in vivo. This technology provides a means for anti-inflammatory drugs, such as curcumin, to target the inflammatory cells as well as to overcome unwanted off-target effects that limit their utility. Using exosomes as a delivery vehicle, we provide evidence that curcumin delivered by exosomes is more stable and more highly concentrated in the blood. We show that the target specificity is determined by exosomes, and the improvement of curcumin activity is achieved by directing curcumin to inflammatory cells associated with therapeutic, but not toxic, effects. Furthermore, we validate the therapeutic relevance of this technique in a lipopolysaccharide (LPS)-induced septic shock mouse model. We further show that exosomes, but not lipid alone, are required for the enhanced anti-inflammatory activity of curcumin. The specificity of using exosomes as a drug carrier creates opportunities for treatments of many inflammation-related diseases without significant side effects due to innocent bystander or off-target effects.

Treatment of Brain Inflammatory Diseases by Delivering Exosome Encapsulated Anti-inflammatory Drugs From the Nasal Region to the Brain

In this study, exosomes used to encapsulate curcumin (Exo-cur) or a signal transducer and activator of transcription 3 (Stat3) inhibitor, i.e., JSI124 (Exo-JSI124) were delivered noninvasively to microglia cells via an intranasal route. The results generated from three inflammation-mediated disease models, i.e., a lipopolysaccharide (LPS)-induced brain inflammation model, experimental autoimmune encephalitis and a GL26 brain tumor model, showed that mice treated intranasally with Exo-cur or Exo-JSI124 are protected from LPS-induced brain inflammation, the progression of myelin oligodendrocyte glycoprotein (MOG) peptide induced experimental autoimmune encephalomyelitis (EAE), and had significantly delayed brain tumor growth in the GL26 tumor model. Intranasal administration of Exo-cur or Exo-JSI124 led to rapid delivery of exosome encapsulated drug to the brain that was selectively taken up by microglial cells, and subsequently induced apoptosis of microglial cells. Our results demonstrate that this strategy may provide a noninvasive and novel therapeutic approach for treating brain inflammatory-related diseases.

Acute Kidney Injury Associates with Increased Long-Term Mortality

Acute kidney injury (AKI) associates with higher in-hospital mortality, but whether it also associates with increased long-term mortality is unknown, particularly after accounting for residual kidney function after hospital discharge. We retrospectively analyzed data from US veteran patients who survived at least 90 d after discharge from a hospitalization. We identified AKI events not requiring dialysis from laboratory data and classified them according to the ratio of the highest creatinine during the hospitalization to the lowest creatinine measured between 90 d before hospitalization and the date of discharge. We estimated mortality risks using multivariable Cox regression models adjusting for demographics, comorbidities, medication use, primary diagnosis of admission, length of stay, mechanical ventilation, and postdischarge estimated GFR (residual kidney function). Among the 864,933 hospitalized patients in the study cohort, we identified 82,711 hospitalizations of patients with AKI. In the study population of patients who survived at least 90 d after discharge, 17.4% died during follow-up (AKI 29.8%, without AKI 16.1%). The adjusted mortality risk associated with AKI was 1.41 (95% confidence interval [CI] 1.39 to 1.43) and increased with increasing AKI stage: 1.36 (95% CI 1.34 to 1.38), 1.46 (95% CI 1.42 to 1.50), and 1.59 (95% CI 1.54 to 1.65; P < 0.001 for trend). In conclusion, AKI that does not require dialysis associates with increased long-term mortality risk, independent of residual kidney function, for patients who survive 90 d after discharge. Long-term mortality risk is highest among the most severe cases of AKI.

Protective effects of NSAIDs on the development of Alzheimer disease

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimer disease (AD), but observational studies and trials have offered contradictory results. Prior studies have also been relatively short and small. We examined the effects on AD risk of NSAID use for >5 years and of NSAIDs that suppress formation of Aβ1-42 amyloid in a large health care database. Methods: Cases were veterans aged 55 years and older with incident AD using the US Veterans Affairs Health Care system. Matched controls were drawn from the same population. NSAID exposure was categorized into seven time periods: no use, ≤1 year, >1 but ≤2 years, and so on. Using conditional logistic regression, adjusted for race and comorbidities, we tested the association between AD development and the use of 1) any NSAID, 2) any NSAID excluding nonacetylated salicylates, 3) each NSAID class, 4) each individual NSAID, and 5) Aβ1-42-suppressing NSAIDs. Results: We identified 49,349 cases and 196,850 controls. Compared with no NSAID use, the adjusted odds ratios for AD among NSAID users decreased from 0.98 for ≤1 year of use (95% CI 0.95–1.00) to 0.76 for >5 years of use (0.68–0.85). For users of ibuprofen, it decreased from 1.03 (1.00–1.06) to 0.56 (0.42–0.75). Effects of other NSAID classes and individual NSAIDs were inconsistent. There was no difference between a group of Aβ1-42-suppressing NSAIDs and others. Discussion: Long-term nonsteroidal anti-inflammatory drug (NSAID) use was protective against Alzheimer disease. Findings were clearest for ibuprofen. Aβ1-42-suppressing NSAIDs did not differ from others.

Cigarette smoking and the risk of endometrial cancer

Because of evidence of reduced estrogen excretion in the urine of women who smoke cigarettes and evidence linking estrogen levels to the risk of cancer of the female reproductive system, we evaluated the risk of endometrial cancer in relation to cigarette use in a hospital-based case-control study of 510 women with endometrial cancer (cases) and 727 women with other cancers (controls). The rate-ratio estimate (relative risk) for current smokers as compared with women who had never smoked was 0.7 (95 per cent confidence interval, 0.5 to 1.0), and for former smokers the estimate was 0.9 (0.6 to 1.2). For women currently smoking 25 or more cigarettes per day, the rate-ratio estimate was 0.5 (0.3 to 0.8). The effect of current smoking of at least 25 cigarettes per day appeared to be confined to postmenopausal women, among whom the estimate was 0.5 (0.2 to 0.9). Among premenopausal women the estimate was 0.9 (0.4 to 2.2), but the difference between these two estimates could have been due to chance. The data suggest that women who smoke heavily may have a lower risk of endometrial cancer than nonsmokers. The present findings do not have direct public health importance since cigarettes, overall, have serious deleterious effects. However, if these results are confirmed, elucidation of the underlying mechanisms whereby smoking reduces the risk would be of interest and might be useful in the development of strategies for preventing endometrial cancer.

Differences in Health-Related Quality of Life in Rural and Urban Veterans

OBJECTIVES We sought to determine whether disparities in health-related quality of life exist between veterans who live in rural settings and their suburban or urban counterparts. METHODS We determined health-related quality-of-life scores (physical and mental health component summaries) for 767109 veterans who had used Veterans Health Administration services within the past 3 years. We used rural/urban commuting area codes to categorize veterans into rural, suburban, or urban residence. RESULTS Health-related quality-of-life scores were significantly lower for veterans who lived in rural settings than for those who lived in suburban or urban settings. Rural veterans had significantly more physical health comorbidities, but fewer mental health comorbidities, than their suburban and urban counterparts. Rural-urban disparities persisted in all survey subscales, across regional delivery networks, and after we controlled for sociodemographic factors. CONCLUSIONS When compared with their urban and suburban counterparts, veterans who live in a rural setting have worse health-related quality-of-life scores. Policymakers, within and outside the Veterans Health Administration, should anticipate greater health care demands from rural populations.

Angioedema Incidence in US Veterans Initiating Angiotensin-Converting Enzyme Inhibitors

Angioedema is a rare but potentially serious complication of angiotensin-converting enzyme inhibitor (ACE) use. We conducted a study to estimate incidence of ACE-related angioedema and explore its determinants in a large racially diverse patient population. We used linked medical and pharmacy records to identify all patients in the US Veterans Affairs Health Care System from April 1999 through December 2000 who received first prescriptions for antihypertensive medications. We studied 195 192 ACE initiators and 399 889 patients initiating other antihypertensive medications (OAH). New angioedema was identified by diagnosis codes using methods validated in a national sample of 869 angioedema cases with confirmation for over 95% of cases. Overall, 0.20% of ACE initiators developed angioedema while on the medication and the incidence rate was 1.97 (1.77 to 2.18) cases per 1000 person years. This compares with a rate of 0.51 (0.43 to 0.59) in OAH initiators and the adjusted relative risk estimate was 3.56 (2.82 to 4.44). Fifty five percent of cases occurred within 90 days of first ACE use but risk remained elevated with prolonged use, even beyond 1 year. We estimate that 58.3% of angioedema in patients starting antihypertensives was related to ACE. We also found that angioedema rates were nearly 4-fold higher in blacks, 50% higher in women, and 12% lower in those with diabetes. This study provides a reliable estimate of angioedema incidence associated with ACE use in a diverse nontrial patient population, confirming that the incidence is low, but finding substantial variation by race, sex, and diabetes status.

Screening for malignant melanoma: A cost-effectiveness analysis

BACKGROUND Skin cancer is the most common cancer in the United States. Increasing evidence suggests that screening for malignant melanoma is effective, but its cost-effectiveness has not been determined. OBJECTIVE We attempted to determine the effectiveness and costs of a visual screen to diagnose malignant melanoma in high-risk persons. METHODS We developed a decision analysis comparing no skin cancer screen with a single screen by a dermatologist. Clinical outcomes included malignant melanoma, nonmelanoma skin cancer, or no skin cancer. Life expectancy and costs of care were projected on the basis of clinical findings. RESULTS Skin cancer screening increased average discounted life expectancy from 15.0963 years to 15.0975 years. Based on the prevalence of malignant melanoma, however, this translates into an increased discounted life expectancy of 0.9231 years for each person with diagnosed melanoma. Using a cost of

Melanoma awareness and self-examination practices: Results of a United States survey

30 per screen, total skin cancer-related costs for a cohort of 1 million people increased from

Prevalence of depressive and alcohol abuse symptoms among women VA outpatients who report experiencing sexual assault while in the military

826 million with no screen to