Susceptibility of cyclooxygenase-2-deficient mice to pulmonary fibrogenesis

The cyclooxygenase (COX)-2 enzyme has been implicated as an important mediator of pulmonary fibrosis. In this study, the lung fibrotic responses were investigated in COX-1 or COX-2-deficient (-/-) mice following vanadium pentoxide (V(2)O(5)) exposure. Lung histology was normal in saline-instilled wild-type and COX-deficient mice. COX-2(-/-), but not COX-1(-/-) or wild-type mice, exhibited severe inflammatory responses by 3 days following V(2)O(5) exposure and developed pulmonary fibrosis 2 weeks post-V(2)O(5) exposure. Western blot analysis and immunohistochemistry showed that COX-1 protein was present in type 2 epithelial cells, bronchial epithelial cells, and airway smooth muscle cells of saline or V(2)O(5)-exposed wild-type and COX-2(-/-) mice. COX-2 protein was present in Clara cells of wild-type and COX-1(-/-) terminal bronchioles and was strongly induced 24 hours after V(2)O(5) exposure. Prostaglandin (PG) E(2) levels in the bronchoalveolar lavage (BAL) fluid from wild-type and COX-1(-/-) mice were significantly up-regulated by V(2)O(5) exposure within 24 hours, whereas PGE(2) was not up-regulated in COX-2(-/-) BAL fluid. Tumor necrosis factor-alpha was elevated in the BAL fluid from all genotypes after V(2)O(5) exposure, but was significantly and chronically elevated in the BAL fluid from COX-2(-/-) mice above wild-type or COX-1(-/-) mice. These findings indicate that the COX-2 enzyme is protective against pulmonary fibrogenesis, and we suggest that COX-2 generation of PGE(2) is an important factor in resolving inflammation.     

Differential effects of growth factors on tissue-engineered cartilage

The effects of four regulatory factors on tissue-engineered cartilage were examined with specific focus on the ability to increase construct growth rate and concentrations of glycosaminoglycans (GAG) and collagen, the major extracellular matrix (ECM) components. Bovine calf articular chondrocytes were seeded onto biodegradable polyglycolic acid (PGA) scaffolds and cultured in medium with or without supplemental insulin-like growth factor (IGF-I), interleukin-4 (IL-4), transforming growth factor-beta1 (TGF-beta1) or platelet-derived growth factor (PDGF). IGF-I, IL-4, and TGF-beta1 increased construct wet weights by 1.5-2.9-fold over 4 weeks of culture and increased amounts of cartilaginous ECM components. IGF-I (10-300 ng/mL) maintained wet weight fractions of GAG in constructs seeded at high cell density and increased by up to fivefold GAG fractions in constructs seeded at lower cell density. TGF-beta1 (30 ng/mL) increased wet weight fractions of total collagen by up to 1.4-fold while maintaining a high fraction of type II collagen (79 plus minus 11% of the total collagen). IL-4 (1-100 ng/mL) minimized the thickness of the GAG-depleted region at the construct surfaces. PDGF (1-100 ng/mL) decreased construct growth rate and ECM fractions. Different regulatory factors thus elicit significantly different chondrogenic responses and can be used to selectively control the growth rate and improve the composition of engineered cartilage.     

Offering patients the opportunity to choose their hospital for total knee replacement: impact on satisfaction with the surgery

OBJECTIVE: To describe the extent to which patients were offered a choice between 2 or more hospitals for total knee replacement (TKR); to examine the association between having a choice of hospital for TKR and satisfaction with the surgery; and to identify population groups less likely to be offered a choice. METHODS: We studied a population-based sample of 932 Medicare beneficiaries who underwent elective TKR in 2000. We surveyed patients about their participation in choosing a hospital and their satisfaction with surgery. We examined whether lack of hospital choice influenced satisfaction with surgery after adjusting for age, sex, preoperative function, and socioeconomic status. RESULTS: Among 932 TKR recipients (mean age 74 years, 67% women), more than half (53%) reported having a lack of hospital choice. After adjusting for socioeconomic status, patients reporting lack of choice were approximately twice as likely to be dissatisfied with the results of surgery as patients who reported choosing among 2 or more hospitals for TKR (odds ratio [OR] 2.09, 95% confidence interval [95% CI] 1.13-3.87). Results of logistic regression revealed that patients reporting lack of choice were more likely to be women (OR 1.52, 95% CI 1.14-2.04), >80 years of age (as compared with 65-70 years; OR 1.63, 95% CI 1.03-2.57), living in suburban areas (OR 1.68, 95% CI 1.23-2.30), nonwhite (OR 1.57, 95% CI 0.86-2.87), and were less likely to have TKR performed by a high-volume surgeon (OR 0.71, 95% CI 0.53-0.96). CONCLUSION: More than half of the patients did not have a choice in selecting the hospital where they had TKR. Patients reporting lack of choice were more likely to be dissatisfied with surgery. Interventions to address preferences for hospital may improve satisfaction with care for patients with advanced knee arthritis.     

Anti-inflammatory Effects of Flavonoids on TNBS-induced Colitis of Rats

It has been shown that the extracts including eupatilin and quercetin-3-β-D-glucuronopyranoside had mucoprotective effects on the esophagus and stomach through their antioxidant activities. This study was designed to investigate the anti-inflammatory effect of these flavonoid compounds in an animal model of inflammatory bowel disease induced by 2,4,6-trinitrobenzene sulfonic acid. Experimental colitis was induced by intracolonic administration of 2,4,6-trinitrobenzene sulfonic acid. Extracts including eupatilin or quercetin-3-β-D-glucuronopyranoside were orally administered to animals 48, 24, and 1 h prior to the induction of colitis and then again 24 h later. The animals were sacrificed 48 h after by 2,4,6-trinitrobenzene sulfonic acid treatment and the macroscopic appearance of the colonic lesions was scored in a blinded manner on a scale of 1 to 10. The inflammatory response to colitis induction was assessed by measuring myeloperoxidase activity, nitric oxide production, tumor necrosis factor-α expression, total glutathione levels, and malondialdehyde concentrations in the colon. The results indicated that extracts including eupatilin and extracts including quercetin-3-β-D-glucuronopyranoside dose-dependently improved the morphology of the lesions induced by 2,4,6-trinitrobenzene sulfonic acid and reduced the ulcer index accordingly. In addition, rats receiving extracts including eupatilin and extracts including quercetin-3-β-D-glucuronopyranoside showed significantly decreased levels of mucosal myeloperoxidase activity, nitric oxide production, tumor necrosis factor-α expression, and malondialdehyde levels, and increased total glutathione levels. Extracts including eupatilin and extracts including quercetin-3-β-D-glucuronopyranoside ameliorated the inflammatory response and colonic injury in acute colitis by decreasing oxidative stress and neutrophil activation. Extracts including eupatilin and extracts including quercetin-3-β-D-glucuronopyranoside may inhibit acute colitis.     

Food Insecurity and Cost-Related Medication Underuse Among Nonelderly Adults in a Nationally Representative Sample

Objectives. We investigated whether nonelderly US adults (aged 18–64 years) in food-insecure households are more likely to report cost-related medication underuse than the food-secure, and whether the relationship between food insecurity and cost-related medication underuse differs by gender, chronic disease, and health insurance status.Methods. We analyzed data from the 2011 and 2012 National Health Interview Survey (n = 67 539). We examined the relationship between food insecurity and cost-related medication underuse with the χ² test and multivariate logistic regression with interaction terms.Results. Bivariate and multivariate analyses showed a dose–response relationship between food insecurity and cost-related medication underuse, with an increasing likelihood of cost-related medication underuse with increasing severity of food insecurity (P < .001). This association was conditional on health insurance status, but not substantially different by gender or chronic disease status. Being female, low-income, having no or partial health insurance, chronic conditions, functional limitations, or severe mental illness were positively associated with cost-related medication underuse.Conclusions. Using food insecurity as a risk factor to assess cost-related medication underuse could help increase identification of individuals who may need assistance purchasing medications and improve health for those in food-insecure households.Food insecurity refers to “limited or uncertain availability of nutritionally adequate and safe foods or limited or uncertain ability to acquire acceptable foods in socially acceptable ways.”1^(p6) Food insecurity is associated with poor health status and risk factors such as obesity, metabolic conditions, and chronic diseases, potentially attributable to intake of poor-quality diets, which increase the risk for obesity and cardiometabolic diseases.2–5 Studies of diabetic patients living in food-insecure households have shown poor outcomes such as poor glycemic control and increased physician use.6,7 Moreover, there is evidence that people living in food-insecure households are more likely to have poor mental health outcomes,8,9 use alcohol,10 and smoke cigarettes11—factors also associated with poor health status.Recent research suggests that people living in food-insecure households may adjust their behaviors in ways that are potentially detrimental to their health. Ivers and Cullen suggest that the vulnerability of food insecurity puts individuals at risk for engaging in coping strategies (e.g., withdrawal of children from school, theft, and risky sexual behaviors), particularly among women who tend to be children’s primary caregivers.12 One set of behaviors that has received relatively little attention as a potential coping mechanism for food insecurity until recently is reducing, skipping, delaying, or using lower-cost medications to compensate for lack of household resources to purchase food. These behaviors have been described as cost-related medication underuse.13,14Studies have demonstrated the relationship between cost-related medication underuse and poor health outcomes,15–19 but, to our knowledge, only 1 study has examined the relationship between food insecurity and cost-related medication underuse in the United States in a nationally representative sample.13 This study, which was restricted to individuals with chronic diseases, found that those living in food-insecure households were more likely to report cost-related medication underuse. Similar findings have been demonstrated from smaller studies in different parts of the country among people with diabetes, people with HIV/AIDS, and patients presenting at emergency departments.20–24We extend the literature on behaviors individuals living in food-insecure households may adopt to save money for food by examining the relationships between food insecurity and cost-related medication underuse in a nationally representative sample of nonelderly adults living in the United States. The objective of this analysis was to determine whether nonelderly adults (aged 18–64 years) living in food-insecure households in the United States are more likely to report cost-related medication underuse. We also examined whether the relationship between food insecurity and cost-related medication underuse differs by gender, chronic disease status, and health insurance status.     

Retrograde Mitochondrial Transport Is Essential for Organelle Distribution and Health in Zebrafish Neurons

In neurons, mitochondria are transported by molecular motors throughout the cell to form and maintain functional neural connections. These organelles have many critical functions in neurons and are of high interest as their dysfunction is associated with disease. While the mechanics and impact of anterograde mitochondrial movement toward axon terminals are beginning to be understood, the frequency and function of retrograde (cell body directed) mitochondrial transport in neurons are still largely unexplored. While existing evidence indicates that some mitochondria are retrogradely transported for degradation in the cell body, the precise impact of disrupting retrograde transport on the organelles and the axon was unknown. Using long-term, in vivo imaging, we examined mitochondrial motility in zebrafish sensory and motor axons. We show that retrograde transport of mitochondria from axon terminals allows replacement of the axon terminal population within a day. By tracking these organelles, we show that not all mitochondria that leave the axon terminal are degraded; rather, they persist over several days. Disrupting retrograde mitochondrial flux in neurons leads to accumulation of aged organelles in axon terminals and loss of cell body mitochondria. Assays of neural circuit activity demonstrated that disrupting mitochondrial transport and function has no effect on sensory axon terminal activity but does negatively impact motor neuron axons. Taken together, our work supports a previously unappreciated role for retrograde mitochondrial transport in the maintenance of a homeostatic distribution of mitochondria in neurons and illustrates the downstream effects of disrupting this process on sensory and motor circuits.SIGNIFICANCE STATEMENT Disrupted mitochondrial transport has been linked to neurodegenerative disease. Retrograde transport of this organelle has been implicated in turnover of aged organelles through lysosomal degradation in the cell body. Consistent with this, we provide evidence that retrograde mitochondrial transport is important for removing aged organelles from axons; however, we show that these organelles are not solely degraded, rather they persist in neurons for days. Disrupting retrograde mitochondrial transport impacts the homeostatic distribution of mitochondria throughout the neuron and the function of motor, but not sensory, axon synapses. Together, our work shows the conserved reliance on retrograde mitochondrial transport for maintaining a healthy mitochondrial pool in neurons and illustrates the disparate effects of disrupting this process on sensory versus motor circuits.